Activation of Free Fatty Acid Receptor 4 Affects Intestinal Inflammation and Improves Colon Permeability in Mice.

Diet is considered an important trigger in inflammatory bowel diseases (IBD), as feeding habits can affect intestinal permeability and clearance of bacterial antigens, consequently influencing the immune system. Free fatty acid receptors (FFARs), expressed on the intestinal epithelial cells, belong to the family of luminal-facing receptors that are responsive to nutrients. The objective of this study was to characterize the anti-inflammatory activity and the effect on intestinal barrier function of synthetic FFAR agonists in mouse models of colitis. Therapeutic activity of GW9508 (FFAR1 agonist), 4-CMTB (FFAR2 agonist), AR420626 (FFAR3 agonist), and GSK137647 (FFAR4 agonist) was investigated in two models of semi-chronic colitis: induced by trinitrobenzenesulfonic acid (TNBS), mimicking Crohn's disease, as well as induced by dextran sulfate sodium (DSS), which recapitulates ulcerative colitis in humans. Moreover, we assessed the influence of FFARs agonists on epithelial ion transport and measured the ion flow stimulated by forskolin and veratridine. Administration of FFAR4 agonist GSK137647 attenuated both TNBS-induced and DSS-induced colitis in mice, as indicated by macroscopic parameters and myeloperoxidase activity. The action of FFAR4 agonist GSK137647 was significantly blocked by pretreatment with selective FFAR4 antagonist AH7614. Moreover, FFAR1 and FFAR4 agonists reversed the increase in the colon permeability caused by inflammation. FFAR4 restored the tight junction genes expression in mouse colon. This is the first evaluation of the anti-inflammatory activity of selective FFAR agonists, showing that pharmacological intervention targeting FFAR4, which is a sensor of medium and long chain fatty acids, attenuates intestinal inflammation.

Free Fatty Acid Receptors as New Potential Targets in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide. In developed countries, its mortality remains high, yet the prevalence has established owing to effective screening programs; however due to the westernization of lifestyle, the incidences in many other countries have increased. Although the treatment of CRC has improved in the last few years, the side effects of these approaches cannot be neglected. Recently, members of the family of free fatty acid receptors (FFARs) have become attractive pharmacological targets in many diseases, including asthma; studies also point to their role in carcinogenesis. Here, we discuss current knowledge and future directions in FFAR research related to CRC. Contradictory results of FFARs modulation may derive from the pleiotropic effects of FFAR ligands, receptor distribution and different signal transduction. Hence, we indicate directions of further studies to fully use the potential of FFARs in CRC.

Alterations of colonic sensitivity and gastric dysmotility after acute cisplatin and granisetron.

BACKGROUND: Cisplatin is a highly emetogenic antineoplastic drug and induces peripheral neuropathy when given in cycles. Granisetron, a 5-HT3 antagonist, is clinically used to prevent chemotherapy-induced nausea/emesis and abdominal pain in irritable bowel syndrome. The effects of cisplatin on visceral sensitivity and those of granisetron in the context of cancer chemotherapy are not well known. METHODS: Adult male Wistar rats received two intraperitoneal injections 30 minutes apart: granisetron (1 mg kg-1 )/vehicle and cisplatin (6 mg kg-1 )/vehicle. Thereafter, nausea-like behavior was measured as bedding intake for 4 hours, and gastric dysmotility was measured radiographically for 8 hours. Gastric weight and size were determined ex vivo and samples of the forestomach, corpus, ileum, and colon were obtained for histological analysis at 4 and 30 hours after cisplatin/vehicle. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation 2 hours after cisplatin/vehicle. KEY RESULTS: Cisplatin-induced bedding intake and gastric dysmotility, and granisetron blocked these effects, which occurred in the absence of frank mucositis. Visceral sensitivity was reduced to a similar extent by both drugs alone or in combination. CONCLUSIONS AND INFERENCES: Cisplatin-induced bedding intake and gastric dysmotility were blocked by granisetron, confirming the involvement of serotonin acting on 5-HT3 receptors. Unexpectedly, visceral sensitivity to colonic distension was reduced, to the same extent, by cisplatin, granisetron, and their combination, suggesting important mechanistic differences with nausea and gastric dysmotility that warrant further investigation.

One step ahead: miRNA-34 in colon cancer-future diagnostic and therapeutic tool?

The discovery that microRNAs (miRNAs) - short, non-coding RNA molecules which regulate gene expression - are implicated in many types of cancer has revolutionised cancer research, giving hope for a new perspective in diagnostics and treatment. Dysregulation of miRNAs occurs in various malignancies, including colorectal cancer (CRC). CRC is one of the leading causes of cancer-related death and in most countries its incidence is still rising. Among several miRNAs which have been linked to CRC, miR-34 has attracted particular attention. This miRNA is involved in the regulation of cell cycle and apoptosis through multiple signaling pathways such as p53, Ra and Wnt signaling. Understanding its role in CRC may facilitate its future use as a diagnostic tool and therapeutic target.

Diagnostic value of chemerin in lower gastrointestinal diseases-a review.

Chemerin is a protein secreted among others by adipose tissue and liver, with a dual pro- and anti-inflammatory role in the body. These molecules exert systemic effects by modulating tissue-specific immune response and metabolism. Chemerin isoforms correlate with the turnover of fatty acids and lipoproteins that could affect intestinal inflammation. Although chemerin may interact with three types of receptors, CMKLR1 is the best studied. In this paper we reviewed current knowledge about the relationship between chemerin and lower gastrointestinal (GI) diseases, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and colorectal cancer (CRC). A more detailed understanding of the role of the adipose tissue in the GI tract will not only unravel the pathophysiology of chronic intestinal diseases, but may also indicate a new therapeutic tool for their management.

Triphala: current applications and new perspectives on the treatment of functional gastrointestinal disorders.

BACKGROUND: Ayurvedic medicine is based on natural healing methods that use herbal medicine to cleanse the body of toxins and to attain physical and mental regeneration. Triphala (TLP) is one of the most important ayurvedic supplements and is believed to have a beneficial effect on the entire gastrointestinal (GI) tract. PURPOSE: We aim to summarize available literature focused on the components of TLP (Terminalia chebula, Terminalia bellerica and Phyllanthus emblica) and discusse their effectiveness and therapeutic value for improving lower GI symptoms in functional GI disorders, particularly irritable bowel syndrome (IBS). METHODS: This study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect databases. RESULTS: The components of TLP are believed to cause restoration of the epithelium lining of the digestive tract, and by exhibiting mild laxative properties facilitate passage of stool in the colon. TLP is rich in polyphenols, vitamin C and flavonoids, which provide antioxidant and anti-inflammatory effects. It also contains various types of acids, such as gallic, chebulagic and chebulinic, which additionally possess cytoprotective and antifungal properties. CONCLUSION: Triphala holds potential in improving lower GI symptoms and may be a valuable and effective addition to standard treatment of IBS. Supplementation of TLP herbal formulations alone or along with other probiotics can be recommended in ongoing clinical studies.

The mechanisms linking obesity to colon cancer: An overview.

Obesity, characterised as a chronic low-grade inflammation is a crucial risk factor for colon cancer. The expansion of the adipose tissue is related to elevated triglyceride and low-density lipoprotein (LDL) levels and hyperinsulinemia, which all are presumed mediators of the tumour development. Obesity is also believed to support carcinogenesis by activating the insulin/IGF-1 pathway. Moreover, obesity increases the level of proinflammatory cytokines (e.g. TNF-α, IL-1, and IL-6) and has a significant impact on selected adipokines. This paper briefly outlines the latest evidence of the linkage between the obesity and colon cancer and discusses its possible implication for the improvement of anticancer prevention and treatment strategies connected with nutrition.

Dual Functional Capability of Dendritic Cells - Cytokine-Induced Killer Cells in Improving Side Effects of Colorectal Cancer Therapy.

The aim of cancer therapy is to eradicate cancer without affecting healthy tissues. Current options available for treating colorectal cancer (CRC), including surgery, chemotherapy or radiotherapy, usually elicit multiple adverse effects and frequently fail to completely remove the tumor cells. Thus, there is a constant need for seeking cancer cell-specific therapeutics to improve the course of cancer therapy and reduce the risk of relapse. In this review we elaborate on the mechanisms underlying the immunotherapy with dendritic cells (DCs) and cytokine-induced killer (CIK) cells, and summarize their effectiveness and tolerability available clinical studies. Finally, we discuss the up-to-date combinatorial adoptive anti-cancer immunotherapy with CIK cells co-cultured with DCs that recently showed encouraging efficacy and usefulness in treating malignant disease, including CRC.

Polyunsaturated Fatty Acids and Their Derivatives: Therapeutic Value for Inflammatory, Functional Gastrointestinal Disorders, and Colorectal Cancer.

Polyunsaturated fatty acids (PUFAs) are bioactive lipids which modulate inflammation and immunity. They gained recognition in nutritional therapy and are recommended dietary supplements. There is a growing body of evidence suggesting the usefulness of PUFAs in active therapy of various gastrointestinal (GI) diseases. In this review we briefly cover the systematics of PUFAs and their metabolites, and elaborate on their possible use in inflammatory bowel disease (IBD), functional gastrointestinal disorders (FGIDs) with focus on irritable bowel syndrome (IBS), and colorectal cancer (CRC). Each section describes the latest findings from in vitro and in vivo studies, with reports of clinical interventions when available.