benzofurans and Colitis

Ulcerative colitis (UC) is the major type of inflammatory ailment with elevated prevalence worldwide. Dieckol (DEK) is a phlorotannin that is extensively found in marine algae and has been found to have different pharmacological properties. Nevertheless, the impact of DEK in UC has not been investigated earlier. Therefore, we appraised DEK's function in dextran sulfate sodium (DSS)-induced UC in the mouse. An overall of 30 mice was randomized into 5 equal groups. Control mice treated with a standard diet (group I), colitis mice challenged with 3% of DSS through drinking water for 7 consecutive days (group II), DEK was supplemented via oral gavage from day 1 to 10 at the dosages of 5, 10, and 15 mg/kg b.wt, respectively. All animals were sacrificed on the 11th day. The body weight (bwt), colon length, disease activity index, malondialdehyde (MDA), myeloperoxidase (MPO), and histological features were observed using suitable techniques, and COX-2 expression was investigated by immunohistochemistry. Moreover, TNF-α, IL-1β, p65, IκBα, HO-1, and Nrf2 expressions were measured using ELISA and RT-PCR techniques, respectively. DEK treatment to the colitis mice considerably lessened, DSS-challenged alterations in body weight, DAI, colonic length shortening and histological changes. DEK exhibited potent antioxidant effects due to the reduced MDA and MPO, and Nrf2 expression markers while the HO-1 marker was augmented. Additionally, DEK also suppressed the expression s of TNF-α, IL-1β, and the p-p65, p-IκBα, and p65 and augmented the expression of IκBα, which eventually proved the anti-inflammatory potential of DEK against the DSS-challenge. Based on these results, DEK has been found effective in mitigating colitis, conceivably alleviating colon inflammation through the NF-κB inhibition and triggering of Nrf2/HO-1 signaling cascade.

Topics: Animals; Benzofurans; Colitis; Dextran Sulfate; Disease Models, Animal; Mice; NF-E2-Related Factor 2; NF-kappa B; Signal Transduction

Degree of mucosal recovery is an important indicator for evaluating the therapeutic effects of drugs in treatment of inflammatory bowel disease (IBD). Increasing evidences has proved that tight junction (TJ) barrier dysfunction is one of the pathological mechanisms of IBD. The aim of this study was to observe whether enhancement of TJ can decrease colitis recurrence.. Eighty C57BL/6 mice were randomly divided into four groups including normal group, colitis group, sulfasalazine (SASP) treated group, and traditional Chinese drug salvianolic acid B (Sal B) treated group. Colitis was established in mice by free drinking water containing dextran sulfate sodium, after treatments by SASP and Sal B, recombinant human interleukin-1β (IL-1β) was injected intraperitoneally to induce colitis recurrence.. Compared with sham control, cell apoptosis in colitis group was increased from 100.85 ± 3.46% to 162.89 ± 11.45% (P = 0.0038), and TJ dysfunction marker myosin light chain kinase (MLCK) was also significantly increased from 99.70 ± 9.29% to 296.23 ± 30.78% (P = 0.0025). The increased cell apoptosis was reversed by both SASP (125.99 ± 8.45% vs. 162.89 ± 11.45%, P = 0.0059) and Sal B (104.27 ± 6.09% vs. 162.89 ± 11.45%, P = 0.0044). High MLCK expression in colitis group was reversed by Sal B (182.44 ± 89.42% vs. 296.23 ± 30.78%, P = 0.0028) but not influenced by SASP (285.23 ± 41.04% vs. 296.23 ± 30.78%, P > 0.05). The recurrence rate induced by recombinant human IL-1β in Sal B-treated group was significantly lower than that in SASP-treated group.. These results suggested a link between intestinal mucosal barrier dysfunction, especially TJ barrier dysfunction, and colitis recurrence. The TJ barrier dysfunction in remission stage of colitis increased the colitis recurrence. This study might provide potential treatment strategies for IBD recurrence.

Topics: Animals; Benzofurans; Colitis; Dextran Sulfate; Disease Models, Animal; Interleukin-1beta; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Myosin-Light-Chain Kinase

Abnormal glycerophospholipid (GPL) metabolism represented by phosphatidylcholine (PC) and phosphatidylethanolamine (PE) has been as a universal metabolic hallmark of cancer, which is involved in tumor progression. Our previous finding showed that peroxidase from foxtail millet bran (FMBP) exhibited significant anticolorectal cancer (CRC) activity in vitro and in nude mice. Presently, the potential of FMBP in clinical application was further evaluated by an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated carcinogenesis (CAC) mice model, revealed the pivotal role of GPL metabolism in anti-CRC effects of FMBP. Excitedly, FMBP significantly reduced the number and volume of CAC polyps of mice and effectively improved physiological indexes of CAC mice. Meanwhile, the elevated expressions of CRC early markers (cyclooxygenase 2, tumor-proliferating nuclear antigen Ki-67, and EGF module-containing mucin-like receptor 1) in CAC mice were efficiently prevented by FMBP treatment. Metabolomics analysis showed that the elevated abundances of PC and PE involved in GPL metabolism in CAC mice were markedly decreased in FMBP-treated groups, which was also verified in human CRC cells. Further, FMBP reduced the expression levels of PE and PC key metabolic enzymes, resulting in the blockage of GPL metabolism and insufficient adenosine triphosphate to maintain CRC growth. Collectively, FMBP has the potential as a preventive and therapeutic candidate for CRC through the blockage of GPL metabolism.

Topics: Animals; Benzofurans; Carcinogenesis; Cell Line, Tumor; Colitis; Colorectal Neoplasms; Dextran Sulfate; Disease Models, Animal; Glycerophospholipids; Humans; Male; Mice; Mice, Nude; Peroxidase; Plant Proteins; Quinolines; Setaria Plant

To develop effective therapeutics for inflammatory bowel disease (IBD), 2-benzylidene-2,3-dihydro-1H-inden-1-one and benzofuran-3(2H)-one derivatives, were designed and synthesized and their structure-activity relationships (SAR) were investigated. Compounds 7, 25, 26, 32, 39, 41, 52, 54, and 55 showed potent inhibitory effect (>70%) on the TNF-α-induced adhesion of monocytes to colon epithelial cells, which is one of the hallmark events leading to IBD. Such inhibitory activity of the compounds correlated with their suppressive activities against the TNF-α-induced production of ROS; ICAM-1 and MCP-1 expression, critical molecules involved in monocyte-epithelial adhesion; and NF-κB transcriptional activity. In addition, compounds 41 and 55 significantly suppressed the lipopolysaccharide (LPS)-induced expression of the TNF-α gene, with compound 55 showing better efficacy. This inhibition of TNF-α expression by compounds 41 and 55 corresponded to their additional inhibitory activity against AP-1 transcriptional activity, which is another transcription factor required for high level TNF-α expression. The strong inhibitory activity of compound 55 against an in vivo colitis model was confirmed by its dose-dependent inhibitory activity in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, demonstrating compound 55 as a new potential candidate for the development of therapeutics against IBD.

Topics: Animals; Benzofurans; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Female; HT29 Cells; Humans; Indenes; Inflammatory Bowel Diseases; Molecular Structure; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Transcription Factor AP-1; Trinitrobenzenesulfonic Acid; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; U937 Cells

Flavaglines are a family of natural compounds shown to have anti-inflammatory and cytoprotective effects in neurons and cardiomyocytes. Flavaglines target prohibitins as ligands, which are scaffold proteins that regulate mitochondrial function, cell survival, and transcription. This study tested the therapeutic potential of flavaglines to promote intestinal epithelial cell homeostasis and to protect against a model of experimental colitis in which inflammation is driven by epithelial ulceration.. Survival and homeostasis of Caco2-BBE and IEC-6 intestinal epithelial cell lines were measured during treatment with the flavaglines FL3 or FL37 alone and in combination with the proinflammatory cytokines tumor necrosis factor (TNF) α and interferon γ. Wild-type mice were intraperitoneally injected with 0.1 mg/kg FL3 or vehicle once daily for 4 days during dextran sodium sulfate-induced colitis to test the in vivo anti-inflammatory effect of FL3.. FL3 and FL37 increased basal Caco2-BBE and IEC-6 cell viability, decreased apoptosis, and decreased epithelial monolayer permeability. FL3 and FL37 inhibited TNFα- and interferon γ-induced nuclear factor kappa B and Cox2 expression, apoptosis, and increased permeability in Caco2-BBE cells. FL3 and FL37 protected against TNFα-induced mitochondrial superoxide generation by preserving respiratory chain complex I activity and prohibitin expression. p38-MAPK activation was essential for the protective effect of FL3 and FL37 on barrier permeability and mitochondrial-derived reactive oxygen species production during TNFα treatment. Mice administered FL3 during dextran sodium sulfate colitis exhibited increased colonic prohibitin expression and p38-MAPK activation, preserved barrier function, and less inflammation.. These results suggest that flavaglines exhibit therapeutic potential against colitis and preserve intestinal epithelial cell survival, mitochondrial function, and barrier integrity.

Topics: Animals; Apoptosis; Benzofurans; Biological Products; Caco-2 Cells; Colitis; Cytokines; Dextran Sulfate; Epithelial Cells; Female; Humans; Inflammation Mediators; Intestinal Mucosa; Intestines; Male; Mice; Mice, Inbred C57BL; Mitochondria; Reactive Oxygen Species

Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b(+) macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation.

Topics: Animals; Benzofurans; Cell Line; Colitis; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammasomes; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

Muscarinic acetylcholine receptors (mAChRs) are major regulators of gut epithelial functions. However, the precise subtype composition has not been clarified.. We characterized the pharmacological profile of mAChRs on mouse colonic crypts, employing [(3)H]-N-methyl scopolamine chloride as a radioligand and several subtype-selective chemicals, and the functional aspect by measuring short-circuit current (I sc) in Ussing chambers and by evaluating MAP kinase phosphorylation in mouse colonic mucosal sheets.. The mAChRs were detected on the crypts (K d = 163.2 ± 32.3 pM, B max = 47.3 ± 2.6 fmol/mg of total cell protein). Muscarinic toxin 7 (MT-7, M1 subtype selective) gave a displacement curve with high affinity, but there was a part insensitive to MT-7 (18.8 ± 0.4 % of the total specific binding). The MT-7-insensitive component was displaced completely by darifenacin (M3 selective) with high affinity. ACh induced an increase in I sc, which was significantly enhanced by MT-7 but was completely inhibited by darifenacin or atropine. Colitis induction resulted in a significant decrease in the density of mAChRs, which occurred mainly in the MT-7-sensitive component (M1 subtype). Immunological experiments exhibited a reduction of M1 but not of M3 signal after colitis induction. Muscarinic stimulation induced an increase in MAP kinase phosphorylation, which was completely suppressed by MT-7 and was attenuated by inflammation, in mouse colonic epithelium.. These results suggest that mAChRs in mouse colonic epithelial cells consist of two subtypes, M1 (80 %) and M3 (20 %). The major M1 subtype was likely to regulate epithelial chloride secretion negatively and was susceptible to inflammation and may be relevant to inflammatory gut dysfunction.

Topics: Animals; Atropine; Benzofurans; Colitis; Colon; Elapid Venoms; Epithelial Cells; Inflammation; Intestinal Mucosa; Male; Mice; Mice, Inbred BALB C; N-Methylscopolamine; Parasympatholytics; Pyrrolidines; Radioligand Assay; Receptor, Muscarinic M1; Receptor, Muscarinic M3

Despite being a mainstay of inflammatory bowel disease (IBD) therapy, glucocorticoids (GCs) still carry significant risks with respect to unwanted side effects. Alternative drugs with a more favorable risk/benefit ratio than common GCs are thus highly desirable for the management of IBD. New and supposedly selective glucocorticoid receptor (GR) agonists (SEGRAs), with dissociated properties, have been described as promising candidates for circumventing therapeutic problems while still displaying full beneficial anti-inflammatory potency. Here, we report on compound A [CpdA; (2-((4-acetophenyl)-2-chloro-N-methyl)ethylammonium-chloride)] and N-(4-methyl-1-oxo-1H-2,3-benzoxazine-6-yl)-4-(2,3-dihydrobenzofuran-7-yl)-2-hydroxy-2-(trifluoromethyl)-4-methylpentanamide (ZK216348), two GR agonists for the treatment of experimental colitis. Their therapeutic and anti-inflammatory effects were tested in the acute trinitrobenzene sulfonic acid-mediated colitis model in mice against dexamethasone (Dex). In addition to their influence on immunological pathways, a set of possible side effects, including impact on glucose homeostasis, steroid resistance, and induction of apoptosis, was surveyed. Our results showed that, comparable with Dex, treatment with CpdA and ZK216348 reduced the severity of wasting disease, macroscopic and microscopic damage, and colonic inflammation. However, both SEGRAs exhibited no GC-associated diabetogenic effects, hypothalamic pituitary adrenal axis suppression, or development of glucocorticoid resistance. In addition, CpdA and ZK216348 showed fewer transactivating properties and successfully dampened T helper 1 immune response. Unlike ZK216348, the therapeutic benefit of CpdA was lost at higher doses because of toxic apoptotic effects. In conclusion, both SEGRAs acted as potent anti-inflammatory agents with a significantly improved profile compared with classic GCs. Although CpdA revealed a narrow therapeutic window, both GR agonists might be seen as a starting point for a future IBD treatment option.

Topics: Acute Disease; Animals; Benzofurans; Benzoxazines; Caco-2 Cells; Cells, Cultured; Colitis; HEK293 Cells; Humans; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred BALB C; Receptors, Glucocorticoid; Treatment Outcome; Trinitrobenzenesulfonic Acid

A new rat model was established up to evaluate the antinociceptive effect of compounds in visceral pain. The test consisted in measuring the performance of rats in an aversive light stimulus avoidance experimental device. Rats with TNBS-induced colitis had a lower number of total active lever pressings and did not discriminate the active lever from the inactive one. Morphine (1 mg/kg, s.c.) and CI-977 (0.001 mg/kg, s.c.) treatment restored the level of pressing activity of animals and their ability to discriminate the active lever from the inactive one. Naloxone treatment antagonized the improvement of performance produced by morphine. The results obtained indicate that this behavioral paradigm may be used to evaluate the antinociceptive potential of compounds.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Benzofurans; Cognition; Colitis; Colon; Discrimination, Psychological; Male; Morphine; Pain; Pyrrolidines; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid; Viscera

Neutrophils have been implicated as major contributors to tissue injury in inflammatory bowel disease. In this study, we have assessed the effects of an inhibitor of neutrophil activation and adherence, NPC-18915 (4-¿2-[2-(2-benzofuranyl)phenyl]-(E)-ethenyl¿benzoic acid sodium salt), in models of both acute and reactivated colitis. Acute colitis was induced by intracolonic administration of a hapten. In other rats, colitis was reactivated 6 wk after a bout of acute colitis by subcutaneous administration of the hapten. NPC-18915 given during the first 4 days after induction of acute colitis significantly reduced tissue injury and the incidence of diarrhea and adhesions. When treatment of NPC-18915 was initiated after colitis was firmly established (48 h posthapten), it did not produce a significant effect. NPC-18915 was effective at significantly reducing colonic injury and granulocyte infiltration in the reactivated colitis model, and a similar effect could be observed in rats treated with antineutrophil serum. These results demonstrate that an inhibitor of neutrophil activation is effective in both acute and reactivated colitis, although in the former case, effectiveness is only seen when the drug is given before full establishment of colitis. These results also suggest that neutrophils, are a critical effector cell of hapten-induced colitis in the rat, particularly in the case of reactivated colitis.

Topics: Acute Disease; Animals; Benzoates; Benzofurans; Colitis; Colon; Ferric Compounds; Immunization, Passive; Leukocyte Count; Leukotriene B4; Male; Neutrophils; Rats; Rats, Wistar; Recurrence; Regional Blood Flow