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Simple Summary: Hydrogen sulfide (H2S) has been produced by certain gut bacteria and associated with the development of inflammatory bowel disease (IBD) and colon cancer. H2S is produced by these bacteria regulate the gut inflammation and cell proliferation. The resulted H2S produced by an enzyme Isethionate sulfite-lyase (Isla) in the colonial Bilophila wadsworthia bacteria. Literature has suggested a potential association between Isla and cancer and the production of hydrogen sulfide (H2S). Studies suggest that reducing the H2S concentration by targeting Isla is a novel and potential therapeutic target for IBD and colon cancer. We apply structure-based drug-designing approaches for Isla and isolate six compounds from natural products and their synthetic derivatives having improved drug-like properties. The molecular dynamics approach was used to confirm the stability and affinity of the selected compounds. Our finding suggests that these compounds can be possible potential inhibitors for the Isla protein. A glycal radical enzyme called isethionate sulfite-lyase (Isla) breaks the C–S bond in isethionate to produce acetaldehyde and sulfite. This enzyme was found in the Gram-negative, colonial Bilophila wadsworthia bacteria. Sulfur dioxide, acetate, and ammonia are produced by the anaerobic respiration route from (sulfonate isethionate). Strong genotoxic H2S damages the colon's mucous lining, which aids in the development of colorectal cancer. H2S production also contributes to inflammatory bowel diseases such as colitis. Here, we describe the structure-based drug designing for the Isla using an in-house database of naturally isolated compounds and synthetic derivatives. In structure-based drug discovery, a combination of methods was used, including molecular docking, pharmacokinetics properties evaluation, binding free energy calculations by the molecular mechanics/generalized born surface area (MM/GBSA) method, and protein structure dynamics exploration via molecular dynamic simulations, to retrieve novel and putative inhibitors for the Isla protein. Based on the docking score, six compounds show significant binding interaction with the Isla active site crucial residues and exhibit drug-like features, good absorption, distribution, metabolism, and excretion profile with no toxicity. The binding free energy reveals that these compounds have a strong affinity with the Isla. In addition, the molecular dynamics simulations reveal that these compounds substantially affect the protein structure dynamics. As per our knowledge, this study is the first attempt to discover Isla potential inhibitors. The compounds proposed in the study using a multi-fold computational technique may be verified in vitro as possible inhibitors of Isla and possess the potential for the future development of new medications that target Isla. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the fourth most common neoplasia in Europe, where it accounts for 28.2 new cases per 100,000 inhabitants. In an effort to decrease the incidence of this disease, various prevention measures are being studied, one of which are anthocyanin-rich foods. Anthocyanins are potent antioxidant flavonoids mainly found in flowers and colorful fruits and vegetables. These nutraceuticals have diverse biological functions once ingested, including immunomodulatory, anti-inflammatory and antitumor functions. In order to test the preventive effect of these flavonoids against colorectal cancer, an animal model (Rattus norvegicus F344) was developed. In this model two doses of azoxymethane (10 mg/kg) and two treatments with dextran sodium sulfate (DSS) were administered to the animals. For 20 weeks they were fed either control rat feed, control sausages, or functional sausages containing 0.1% (w/w) of anthocyanins from a mixture of dehydrated blackberries and strawberries. At the end of that period, the animals were sacrificed and their antioxidant plasma levels and digestive tract tissues were analyzed. The results revealed a statistically significant reduction in the number of colon tumors in the functional sausages cohort with respect to the control animals and an increase in the FRAP (ferric reducing ability of plasma) total antioxidant activity in that same cohort. Colon microbiota differences were also examined via metagenomics 16S ribosomal RNA (rRNA) sequencing, revealing a significant reduction in populations of the pro-inflammatory Bilophila wadsworthia. Therefore, the design of functional processed meat products, such as ones enriched with anthocyanins, may be an effective strategy for preventing inflammatory digestive diseases and colorectal cancer in human populations. [ABSTRACT FROM AUTHOR]