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• Free fatty acid receptors are involved in colorectal cancer pathophysiology. • Free fatty acid receptor ligands are considered promising antitumor agents. • Polyunsaturated fatty acids have proven anticancer properties. • Butyrate can support conventional therapy against colorectal cancer. Colorectal cancer (CRC) is one of the leading causes of cancer-related death. Currently, dietary factors are being emphasized in the pathogenesis of CRC. There is strong evidence that fatty acids (FAs) and free FA receptors (FFARs) are involved in CRC. This comprehensive review discusses the role of FAs and their receptors in CRC pathophysiology, development, and treatment. In particular, butyrate and n-3 polyunsaturated fatty acids have been found to exert anticancer properties by, among others, inhibiting proliferation and metastasis and inducing apoptosis in tumor cells. Consequently, they are used in conjunction with conventional therapies. Furthermore, FFAR gene expression is down-regulated in CRC, suggesting their suppressive character. Recent studies showed that the FFAR4 agonist, GW9508, can inhibit tumor growth. In conclusion, natural as well as synthetic FFAR ligands are considered promising candidates for CRC therapy. Schematic representation of the role of fatty acids on CRC development. Dietary fat components, mainly SCFAs (such as butyrate) and PUFAs, influence the risk of CRC through several mechanisms, such as inhibition of cell proliferation, maintenance of intestinal barrier, immune system modulation, epigenetic modification, and induction of apoptosis and autophagy. It is proven that free fatty acid receptors are involved in these mechanisms. Abbreviations: CRC, colorectal cancer; FFAR, free fatty acid receptor; HDACs, histone deacetylases; LCFAs, long chain fatty acids; PUFAs, polyunsaturated fatty acids; SCFAs, short chain fatty acids. [Display omitted] [ABSTRACT FROM AUTHOR]

Functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome (IBS) and chronic constipation (CC), are commonly diagnosed conditions in clinical practice which create a substantial global burden. Since the farnesoid X receptor (FXR) and bile acids (BAs) are responsible for maintaining homeostasis in the GI tract, any disturbances in the expression of FXR or the composition of BAs may contribute to the development of the GI symptoms. Alterations in the mechanism of action of FXR directly affect the BAs pool and account for increased intestinal permeability and changes in abundance and diversity of gut microbiota leading to intestinal dysmotility. Current review focuses on the correlation between the FXR, BAs and the composition of gut microbiota and its influence on the occurrence of GI symptoms in FGIDs. [ABSTRACT FROM AUTHOR]

Summary 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. [ABSTRACT FROM AUTHOR]

The present study examines the chemical composition of an evening primrose flavanol preparation (EPFP) and its chemopreventive activity in colon cancer SW-480 cells. EPFP was found to inhibit SW-480 cell viability by 67% vs. controls at 150 µM catechin equivalents (CE) following 72 h incubation (IC 50 = 65 µM CE). EPFP decreased both NF-κB protein expression (33% vs. control at 100 µM CE) and phosphorylation at serine 529 of the p65 subunit (49% vs. control at 100 µM CE) in SW-480 cells. Moreover, 100 µM CE EPFP suppressed COX-2 mRNA expression to 23% of control values and protein expression to 78%. In addition, EPFP reduced MMP-9 protein expression to 24% vs. controls at 100 µM CE. These results provide the first evidence that EPFP reduces NF-κB, COX-2, and MMP-9 expression, which may suggest it has cytotoxic, anti-inflammatory, and anti-metastatic activities towards colon cancer cells. [ABSTRACT FROM AUTHOR]

As evidenced by a growing number of respective clinical trials, a promising and increasingly valued approach to cancer prevention is chemoprevention which is based on using synthetic, semisynthetic, or natural compounds with the aim of preventing, delaying, arresting, or reversing carcinogenesis. Research carried out in the last two decades indicates that natural polyphenols isolated from plants (as well as their derivatives and synthetic analogs) exhibit pleiotropic actions toward cancer cells and therefore they could be used in both cancer prevention and therapy. This review discusses selected covalent modifications of polyphenols as a means for increasing their anticancer potential in relation to the parent compounds. The modifications include hydroxylation, methylation, acylation, and galloylation, among others. They were demonstrated to enhance cytotoxic, pro-oxidant, antiproliferative, proapoptotic, proautophagic, and antimigratory activities of phenolics toward various cancer cell lines in vitro . Importantly, some derivatives proved to suppress tumor growth and metastasis in animal models more strongly than the parent compounds. Some of the above-mentioned covalent modifications were also shown to increase absorption and tissue distribution of tested phenolic compounds in vivo . Anticancer clinical trials with polyphenol derivatives therefore seem warranted. [ABSTRACT FROM AUTHOR]

Mitochondria are the respiratory and energetic centers of the cell where multiple intra- and extracellular signal transduction pathways converge leading to dysfunction of those organelles and, consequently, apoptotic or/and necrotic cell death. Mitochondria-targeted anticancer drugs are referred to as mitocans; they have recently been classified by Neuzil et al. (2013) according to their molecular mode of action into: hexokinase inhibitors; mimickers of the Bcl-2 homology-3 (BH3) domains; thiol redox inhibitors; deregulators of voltage-dependent anionic channel (VDAC)/adenine nucleotide translocase (ANT) complex; electron redox chain-targeting agents; lipophilic cations targeting the mitochondrial inner membrane; tricarboxylic acid cycle-targeting agents; and mitochondrial DNA-targeting agents. Polyphenols of plant origin and their synthetic or semisynthetic derivatives exhibit pleiotropic biological activities, including the above-mentioned modes of action characteristic of mitocans. Some of them have already been tested in clinical trials. Gossypol has served as a lead compound for developing more efficient BH3 mimetics such as ABT-737 and its orally available structural analog ABT-263 (Navitoclax). Furthermore, mitochondriotropic derivatives of phenolic compounds such as quercetin and resveratrol have been synthesized and reported to efficiently induce cancer cell death in vitro . [ABSTRACT FROM AUTHOR]

Red cabbage is an important source of vitamins, micro- and macroelements and polyphenols. The aim of our study was to evaluate the anti-inflammatory effect of red cabbage extract (RCE) in mouse models of inflammatory bowel disease (IBD). The effect of RCE on experimental colitis was determined using clinical, macro- and microscopic parameters of inflammation. To study the mechanism of RCE action, the expression of pro-inflammatory cytokines and parameters of oxidative stress were assessed. RCE produced a potent anti-inflammatory action in the mouse model of Crohn's disease, as shown by decreased macroscopic damage score in acute (2.70 ± 0.24 vs. 5.78 ± 0.58 for control group) and chronic (1.81 ± 0.38 vs. 2.94 ± 0.29) colitis model. In the animal model of ulcerative colitis, total macroscopic score was decreased after prophylactic and therapeutic administration (11.9 ± 0.5 and 11.2 ± 0.9 vs. 14.2 ± 0.4 in control group, respectively). Red cabbage extract may be applied as a potential dietary supplement in IBD therapy. [ABSTRACT FROM AUTHOR]

Abstract: We report the synthesis and pharmacological characterization of a novel glycosylated analog of a potent and selective endogenous μ-opioid receptor (MOP) agonist, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2), obtained by the introduction in position 3 of the tyrosine residue possessing the glucose moiety attached to the phenolic function via a β-glycosidic bond. The improved blood–brain barrier permeability and enhanced antinociceptive effect of the novel glycosylated analog suggest that it may be a promising template for design of potent analgesics. Furthermore, the described methodology may be useful for increasing the bioavailability and delivery of opioid peptides to the CNS. [Copyright &y& Elsevier]

Abstract: Objective: The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid (CB) receptor, whose role in the gastrointestinal (GI) tract remains unknown. Here we studied the significance of GPR55 in the regulation of GI motility. Design: GPR55 mRNA and protein expression were measured by RT-PCR and immunohistochemistry. The effects of the GPR55 agonist O-1602 and a selective antagonist cannabidiol (CBD) were studied in vitro and in vivo and compared to a non-selective cannabinoid receptor agonist WIN55,212-2. CB1/2 −/− and GPR55−/− mice were employed to identify the receptors involved. Results: GPR55 was localized on myenteric neurons in mouse and human colon. O-1602 concentration-dependently reduced evoked contractions in muscle strips from the colon (∼60%) and weakly (∼25%) from the ileum. These effects were reversed by CBD, but not by CB1 or CB2 receptor antagonists. I.p. and i.c.v. injections of O-1602 slowed whole gut transit and colonic bead expulsion; these effects were absent in GPR55−/− mice. WIN55,212-2 slowed whole gut transit effects, which were counteracted in the presence of a CB1 antagonist AM251. WIN55,212-2, but not O-1602 delayed gastric emptying and small intestinal transit. Locomotion, as a marker for central sedation, was reduced following WIN55,212-2, but not O-1602 treatment. Conclusion: GPR55 is strongly expressed on myenteric neurons of the colon and it is selectively involved in the regulation of colonic motility. Since activation of GPR55 receptors is not associated with central sedation, the GPR55 receptor may serve as a future target for the treatment of colonic motility disorders. [Copyright &y& Elsevier]

Abstract: The activation of the mu-opioid receptors (MOR) in the central nervous system has a proconvulsant effect and seizures are a common side effect of high doses of short acting opioids, like morphine or fentanyl. However, the correct assessment of the role of MOR blockade in the initiation and propagation of epilepsy was hampered by the lack of potent and selective MOR antagonists. In this study we aimed at characterizing the effect of MOR blockade on the seizure threshold in mice using recently developed selective antagonists antanal-1 and antanal-2 and a classical MOR antagonist, β-funaltrexamine (β-FNA). The effect of the centrally administered MOR antagonists was characterized in the maximal electroshock seizure threshold (MEST), the 6Hz psychomotor seizure threshold and the intravenous pentylenetetrazole (PTZ) seizure threshold test in mice. The acute effect of the studied compounds on skeletal muscular strength in mice was quantified in the grip-strength test. Antanal-1 and antanal-2 (30 and 50nmol/mouse, i.c.v.), but not β-FNA significantly increased the seizure threshold in the MEST test in mice. In the 6-Hz test, all tested MOR antagonists significantly increased the psychomotor seizure threshold and the most potent anticonvulsant effect was observed for antanal-2 (2, 10 and 30nmol/mouse, i.c.v.). The i.c.v. administration of β-FNA (10 and 30nmol/mouse, i.c.v.), antanal-1 and antanal-2 (both 30, 50 and 100nmol/mouse, i.c.v.) did not produce any significant effect on PTZ seizure threshold, the generalized clonus or the forelimbs tonus. All tested compounds did not affect muscle strength, as determined in the grip strength test. Our study demonstrated that the novel MOR-selective antagonists antanal-1 and antanal-2 displayed a potent and dose-dependent anticonvulsant action involving non-GABA-ergic, but some other pathways and mechanisms in animal models of epileptic seizures. We suggest that antanals are promising drug templates for future therapeutics, which may be used in the treatment of epilepsy in humans. [Copyright &y& Elsevier]

Abstract: The biological effects of endomorphins (EMs) are short-lasting due to their rapid degradation by endogenous enzymes. Competing enzymatic degradation is an approach to prolong EM bioavailability. In the present study, a series of tetra- and tripeptides of similar to EMs structure was synthesized and tested in vitro and in vivo for their ability to inhibit degradation of EMs. The obtained results indicated that, among the series of analogs, the tetrapeptide Tyr–Pro–d–ClPhe–Phe–NH2 and the tripeptide Tyr–Pro–Ala–NH2, which did not bind to the μ-opioid receptors, were potent inhibitors of EM catabolism in rat brain homogenate. In vivo, these two peptides significantly prolonged the analgesic and antidepressant-like effects, induced by exogenous EMs, by blocking EM degrading enzymes. These new potent inhibitors may therefore increase the level and the half life of endogenous EMs and could be used in a new therapeutic strategy against pain and mood disorders, based on increasing of EM bioavailability. [Copyright &y& Elsevier]

Abstract: This study reports the synthesis and biological evaluation of a series of new side-chain-to-side-chain cyclized endomorphin-2 (EM-2) and morphiceptin analogs of a general structure Tyr-c(Xaa-Phe-Phe-Yaa)NH2 or Tyr-c(Xaa-Phe-d-Pro-Yaa)NH2, respectively, where Xaa and Yaa were l/d Asp or l/d Lys. Further modification of these analogs was achieved by introduction of 2′,6′-dimethyl-l-tyrosine (Dmt) instead of Tyr in position 1. Peptides were synthesized by solid phase method and cleaved from the resin by a microwave-assisted procedure. Dmt1-substituted analogs displayed high affinity at the μ-opioid receptors, remained intact after incubation with the rat brain homogenate and showed remarkable, long-lasting μ-opioid receptor-mediated antinociceptive activity after central, but not peripheral administration. Our results demonstrate that cyclization is a promising strategy in the development of new opioid analgesics, but further modifications are necessary to enhance the blood–brain barrier permeability. [Copyright &y& Elsevier]

Abstract: The synthesis and in vitro evaluation of a new series of salvinorin A analogues substituted at the C(2) position with natural amino acids is reported. Compound 12, containing Val, displayed high affinity and full agonist activity at the kappa-opioid receptor. Analogues with bulky and/or aromatic residues were inactive, showing the importance of size and electronegativity of C(2)-substituents for binding affinity of salvinorin A derivatives. [Copyright &y& Elsevier]

Abstract: The morphiceptin-derived peptide [Dmt1, d-1-Nal3]morphiceptin, labeled μ-opioid receptor (MOP) with very high affinity and selectivity in the receptor binding assays. In the mouse hot plate test, [Dmt1, d-1-Nal3]morphiceptin given intracerebroventricularly (i.c.v.) produced profound supraspinal analgesia, being approximately 100-fold more potent than the endogenous MOP receptor ligand, endomorphin-2. The antinociceptive effect of this new analog lasted up to 120min. Thus, [Dmt1, d-1-Nal3]morphiceptin is an interesting and extraordinarily potent analgesic, raising the possibility of novel approaches in the design of clinically useful drugs for pain treatment. [Copyright &y& Elsevier]

Abstract: The μ-opioid agonists endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) exhibit an extremely high selectivity for the μ-opioid receptor and thus represent a potential framework for modification into μ-antagonists. Here we report on the synthesis and biological evaluation of novel [d-2-Nal4]endomorphin-2 analogs, [Sar2,d-2-Nal4]endomorphin-2 and [Dmt1,Sar2,d-2-Nal4]endomorphin-2 (Dmt=2′6′-dimethyltyrosine; Sar= N-methylglycine, sarcosine; d-2-Nal=3-(2-naphthyl)-d-alanine). [Dmt1,Sar2,d-2-Nal4]endomorphin-2 possessed very high affinity for the μ-opioid receptor (IC50 =0.01±0.001nM) and turned out to be a potent and extremely selective μ-opioid receptor antagonist, as judged by the in vitro aequorin luminescence-based calcium assay (pA2 =9.19). However, in the in vivo hot plate test in mice this analog was less potent than our earlier μ-opioid receptor antagonist, [Dmt1,d-2-Nal4]endomorphin-2 (antanal-2). The exceptional μ-opioid receptor in vitro activity and selectivity of [Dmt1, Sar2,d-2-Nal4]endomorphin-2 makes this analog a valuable pharmacological tool, but further modifications are needed to improve its in vivo profile. [Copyright &y& Elsevier]

Abstract: A functional assay, based on aequorin-derived luminescence triggered by receptor-mediated changes in Ca2+ levels, was used to examine relative potency and efficacy of the μ-opioid receptor antagonists. A series of position 3- and 4-substituted endomorphin-2 (Tyr–Pro–Phe–Phe–NH2) analogues containing d-3-(1-naphthyl)-alanine (d-1-Nal) or d-3-(2-naphthyl)-alanine (d-2-Nal), which were previously shown to reverse antinociception induced by endomorphin-2 in the in vivo hot-plate test in mice, was tested in the aequorin luminescence-based calcium assay to examine their μ-opioid antagonist potency in vitro. A recombinant mammalian cell line expressing the μ-opioid receptor together with a luminescent reporter protein, apoaequorin, was used in the study. The results obtained in this functional assay indicated that analogues with d-1-Nal or d-2-Nal substitutions in position 4 of endomorphin-2 are strong μ-opioid receptor antagonists, while those substituted in position 3 are partial agonists. Exceptional antagonist potency in the calcium assay was observed for [d-1-Nal4]endomorphin-2. The pA2 value for this analogue was 7.95, compared to the value of 8.68 obtained for the universal, non-selective opioid antagonist of the alkaloid structure, naloxone. The obtained results were compared with the data from the hot-plate test in mice. In that in vivo assay [d-1-Nal4]endomorphin-2 was also the most potent analogue of the series. [Copyright &y& Elsevier]

Abstract: Cyclic analogs of the opioid peptides endomorphin-2 and morphiceptin of the type Tyr-X-Phe-Phe-Y-NH2 and Tyr-X-Phe-d-Pro-Y-NH2 (X=Lys or Asp and Y=Lys or Asp), respectively, were synthesized in order to test their structure–activity relationships. Antinociceptive activity of the new analogs was assessed in the hot-plate test after intracerebroventricular administration in mice. The strong analgesic effect was observed for the analogs with Asp in position 2, while the analogs with Lys in the second position were inactive. Antinociception caused by Asp2 analogs was dose-dependent and reversed by the concomitant administration of the universal opioid antagonist naloxone and by the selective κ antagonist, nor-BNI. However, receptor binding studies revealed poor affinity of all cyclic analogs at the μ-opioid receptor and no affinity at δ- and κ-opioid receptors. It is most likely that the new cyclic analogs produced their antinociception by the release of dynorphin A, which subsequently acted on the κ-opioid receptor. [Copyright &y& Elsevier]

Abstract: In this paper, we describe the synthesis of a series of endomorphin-2 analogs containing N-methylated amino acids, consecutively in each position. The μ-opioid receptor binding affinities of the new analogs were determined in the displacement experiments. Their in vivo antinociceptive activity was assessed in the hot-plate test in mice after central (icv) and peripheral (ip) administration. [Sar2]endomorphin-2, which had the highest μ-receptor affinity, also showed the strongest analgesic effect when administered centrally and was the only analog that retained activity after peripheral injection. [Copyright &y& Elsevier]

Abstract: In the present study, the expression of the μ-opioid receptor on protein level has been demonstrated in MCF7 breast cancer cells. Binding of the [125I]-labeled μ-opioid receptor selective ligand endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) was examined in vitro using a cross-linking assay followed by a Western blot technique. The radioactive complex had a molecular weight of about 65kDa and was detectable by anti-μ-opioid receptor antibody, indicating the presence of μ-opioid receptors in MCF7 cell membranes. Characterization of endomorphin-2 binding to the membranes obtained from MCF7 cells was performed. Cold saturation experiments with [125I]endomorphin-2 showed biphasic binding curves in Scatchard coordinates. One component represents a high affinity and low capacity, and the other low affinity and higher capacity binding sites. The obtained Bmax values for [125I]endomorphin-2 binding to MCF7 membranes were much higher than those obtained for mouse brain. Pharmacological characterization of the [125I]endomorphin-2 binding sites was made using endomorphin-2 and two other μ selective ligands, morphiceptin, and [d-1-Nal3]morphiceptin on MCF7 cell membrane preparations and whole MCF7 cells. In both cases, the rank order of potency was [d-1-Nal3]morphiceptin>endomorphin-2>morphiceptin, but in case of whole MCF7 cells the IC50 values were about 40 times higher. [Copyright &y& Elsevier]