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Inflammatory bowel diseases (IBD) are characterized by chronic and relapsing inflammation affecting the gastrointestinal (GI) tract. The incidence and prevalence of IBD are relatively high and still increasing. Additionally, current therapeutic strategies for IBD are not optimal. These facts urge todays' medicine to find a novel way to treat IBD. Here, we focused on the group of anti-diabetic drugs called gliflozins, which inhibit sodium glucose co-transporter type 2 (SGLT-2). Numerous studies demonstrated that gliflozins exhibit pleiotropic effect, including anti-inflammatory properties. In this study, we tested the effect of three gliflozins; empagliflozin (EMPA), dapagliflozin (DAPA), and canagliflozin (CANA) in in vitro and in vivo models of intestinal inflammation. Our in vitro experiments revealed that EMPA and DAPA suppress the production of nitric oxide in LPS-treated murine RAW264.7 macrophages. In in vivo part of our study, we showed that EMPA alleviates acute DSS-induced colitis in mice. Treatment with EMPA reduced macro- and microscopic colonic damage, as well as partially prevented from decrease in tight junction gene expression. Moreover, EMPA attenuated biochemical inflammatory parameters including reduced activity of myeloperoxidase. We showed that SGLT-2 inhibitors act as anti-inflammatory agents independently from their hypoglycemic effects. Our observations suggest that gliflozins alleviate inflammation through their potent effects on innate immune cells. [ABSTRACT FROM AUTHOR]

Opinion statement: Pancreatic cancer (PC) remains the deadliest cancer worldwide. Most patients are diagnosed at the advanced or metastatic stage, leading to a poor prognosis. Awareness of the limitations of current therapy and accompanying pain, depression, malnutrition, and side effects of chemoradiotherapy may lead patients and physicians towards complementary and alternative medicine (CAM). CAM refers to a diverse set of medical and healthcare practices, products, and systems that are not part of conventional Western medicine. Despite the low-quality evidence supporting the efficacy of these methods, they remain appealing due to patients' beliefs, fear of death, and the slow development of conventional therapy. Hence, the possibility of using natural products for pancreatic cancer is increasing. CAM options such as: medical cannabis, plants, fungi, herbal formulas, and injections, which originate primarily from traditional Chinese or Japanese medicine i.e. Curcuma longa, Panax ginseng, Poria cocos, Hochuekkito, Juzentaihoto, and Rikkunshito, Shi-quan-da-bu-tang/TJ-48, Huang-qin-tang, Shuangbai San, Wen Jing Zhi Tong Fang, Xiang-Sha-Liu-jun-zi-tang, Aidi injection, Brucea javanica oil emulsion/Yadanziyouru injection, Compound Kushen injection, Huachansu injection, Kangai injection and Kanglaite injections are becoming promising candidates for the management of pancreatic cancer. The abovementioned substances/medications are the most popular or potentially effective in PC treatment and consequently CAM-based adjuvant therapy through improving patients' quality of life, might be a useful addition in the treatment of pancreatic cancer patients. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) and chronic pancreatitis (CP) are debilitating diseases of gastrointestinal tract and constitute great threat for human health in high-income countries. Recent studies emphasize the impact of oxidative stress on development of these pathologies, and numerous authors evaluate the effect of the antioxidant therapy on the course of AP and CP. Though several antioxidative agents were discovered in the past decades, vitamins remain canonical antioxidants. Despite the fact that vitamin A is known for its antioxidative effect, there is little data about the impact of vitamin A on oxidative stress in the pathogenesis of AP and CP. The scope of the review is to evaluate molecular targets for vitamin A, which may be involved in oxidative stress occurring in the course of AP and CP. Our research of available literature revealed that several mechanisms are responsible for attenuation of oxidative stress in AP and CP, including Nrf2, MAPK, AMPK, TLR3, and TLR4. Furthermore, these factors are at least partially expressed in vitamin A-dependent manner, though further investigations are required for elucidating in detail the role of vitamin A in defense against reactive oxygen species. Our review revealed that vitamin A might influence the expression of several molecular pathways involved in antioxidative defense and cytoprotection; thus, its administration during AP and CP may change the course of the disease. [ABSTRACT FROM AUTHOR]

Purpose: We hypothesize that different types of dietary fatty acids (FAs) affect gastrointestinal (GI) motility and visceromotor function and that this effect can be regulated by the fatty acid binding protein 4 (FABP4). Methods: Mice were fed for 60 days with standard diet (STD), STD with 7% (by weight) coconut oil, rich in medium-chain FAs (MCFAs) (COCO), or with 7% evening primrose oil, rich in long-chain FAs (LCFAs) (EPO). In each group, half of the mice received FABP4 inhibitor, BMS309403 (1 mg/kg; i.p.) twice a week. Body weight (BW) and food intake were measured; well-established tests were performed to characterize the changes in GI motility and visceral pain. White adipose tissue and colonic samples were collected for cell culturing and molecular studies. Results: COCO significantly increased GI transit, but not colonic motility. COCO and EPO delayed the onset of diarrhea, but none affected the effect of loperamide. EPO reduced BW and increased the visceromotor response (VMR) to colorectal distension (CRD). COCO and EPO reduced differentiation of preadipocytes. Treatment with BMS309403: (1) reversed the effects induced by COCO in physiological conditions and in mouse models of diarrhea; (2) prevented the effects of EPO on BW, VMR to CRD and castor oil-induced diarrhea; (3) affected proliferation of preadipocytes; (4) changed the expression of Fabp4 in colonic and adipocyte samples from COCO and EPO. Conclusion: Modifying dietary intake of MCFAs and LCFAs may be used to control GI motility or visceral pain and thus modulate the symptoms of functional GI disorders. The effect is dependent on the expression of FABP4. [ABSTRACT FROM AUTHOR]

TRPV1 are involved in the control of the gastrointestinal (GI) functions and pain sensation. Their activation induces pain but it is followed by desensitization, which in turn causes analgesia. The studies from the last two decades indicate that TRPV1 are involved in visceral hypersensitivity in the GI tract and pathogenesis of irritable bowel syndrome (IBS). Therefore, the aim of this study is to assess the action of fast desensitizing agonist of TRPV1, palvanil (N-palmitoyl-vanillamine), in the murine GI tract and on nociception to evaluate its potential application in the therapy of IBS. The effect of palvanil on smooth muscle contractility was evaluated using organ baths. The impact of palvanil on intestinal secretion was assessed in Ussing chambers. In vivo, the action of palvanil (0.1–1 mg/kg) was assessed in whole GI transit, fecal pellet output, and colonic bead expulsion tests. The antinociceptive potency of palvanil was tested in the mustard oil-induced pain test. Palvanil inhibited colonic contractions (evoked by electrical field stimulation, EFS) and decreased the ion transport in the colon stimulated with forskolin. It did not affect secretion in experiments with veratridine. In vivo, palvanil prolonged whole GI transit at all doses tested. At the lower dose tested, it accelerated colonic motility during first 60 min following injection. By contrast, at the dose of 1 mg/kg, colonic motility was inhibited. Palvanil induced antinociceptive action at all tested doses in mustard oil-induced pain test. TRPV1 fast-desensitizing compounds, i.e., palvanil, may be promising agents in the therapy of IBS since it modulates intestinal motility and reduces visceral pain. [ABSTRACT FROM AUTHOR]

Opinion Statement: So far, opioids have been successfully used to reduce cancer pain in patients in order to improve their quality of life. However, the use of opioids leads to numerous side effects such as constipation, drowsiness, nausea, itching, increased sweating and hormonal changes. In this review, we described the action of opioids in several molecular pathways significant for maintenance of the intestinal homeostasis including the impact on the intestinal epithelium integrity, changes in microbiome composition, modulation of the immune system or induction of apoptosis and inhibition of angiogenesis. We summed up the role of individual opioids in the processes involved in the growth and development of cancer and elucidated if targeting opioid receptors may constitute novel therapeutic option in colon cancer. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, intestinal inflammatory disorders with complex and yet unrevealed pathogenesis in which genetic, immunological, and environmental factors play a role. Nowadays, a higher proportion of elderly IBD patients with coexisting conditions, such as cardiovascular disease and/or diabetes is recorded, who require more complex treatment and became a great challenge for gastroenterologists. Furthermore, some patients do not respond to anti-IBD therapy. These facts, together with increasing comorbidities in patients with IBD, imply that urgent, more complex, novel therapeutic strategies in the treatment are needed. Glucagon-like peptides (GLPs) possess numerous functions in the human body such as lowering blood glucose level, controlling body weight, inhibiting gastric emptying, reducing food ingestion, increasing crypt cell proliferation, and improving intestinal growth and nutrient absorption. Thus, GLPs and dipeptidyl peptidase IV (DPP-IV) inhibitors have recently gained attention in IBD research. Several animal models showed that treatment with GLPs may lead to improvement of colitis. This review presents data on the multitude effects of GLPs in the inflammatory intestinal diseases and summarizes the current knowledge on GLPs, which have the potential to become a novel therapeutic option in IBD therapy. [ABSTRACT FROM AUTHOR]

Rat sialorphin (Gln-His-Asn-Pro-Arg) is a natural blocker of neprilysin (NEP) that belongs to the family of endogenous opioid peptide-degrading enzymes. Studies have confirmed the efficiency of sialorphin in blocking the activity of NEP, both in vitro and in vivo. It has been demonstrated that this inhibitor has a strong analgesic, anti-inflammatory, immunological and metabolic effect either directly or indirectly by affecting the level of Met/Leu-enkephalins. In this work, sialorphin and their 12 analogues were synthesised using the solid-phase method. The effect of the peptides on the degradation of Met-enkephalin by NEP and metabolic degradation in human plasma was investigated in vitro. We show that the change in the N-terminal amino acid configuration from l to d in almost all peptides, except d-Arg-His-Asn-Pro-Arg (peptide XI), led to the abolition of their inhibitory activity. With molecular modelling technique we explained the structural properties of the l and d-arginine located on the N-terminal part of the peptide. The detailed analysis of the protein binding pocket allowed us to explain why d-arginine is so unique among all d residues. Peptide XI showed the highest stability among the tested peptides in human plasma. For instance sialorphin after a 2-hour incubation in human plasma was almost completely decomposed, while the level of peptide XI dropped to 45% after 48 h under these conditions. [ABSTRACT FROM AUTHOR]

Introduction: Visceral pain is a symptom reported by over 70% of inflammatory bowel disease (IBD) sufferers. So far, a single, specific cause of this debilitating state has not been established. Chronic pain is one of the most important factors decreasing the quality of life in IBD course. Concurrently, management of pain is the most challenging issue encountered by clinicians in IBD treatment.Areas covered: This review focuses on pathophysiology of inflammatory bowel disease-caused visceral pain and explores currently available approaches to its management. We also covered recent pharmacological developments in the field.Conclusions: Pain-related disability has major effects on quality of life and on functional and social outcomes in IBD patients. Currently, there is no one standardized method of managing chronic visceral pain in IBD. Therefore, future development, focusing primarily on alleviating the pain, but also on reducing inflammation, is essential. [ABSTRACT FROM AUTHOR]

Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibril dissolution and abnormal accumulation of degradation products. The diagnosis of muscular disorders based on clinical presentation is difficult due to phenotypic heterogeneity and overlapping symptoms. In addition, precise diagnosis does not always explain the disease etiopathology or the highly variable clinical course even among patients diagnosed with the same type of myopathy. The advent of high-throughput next-generation sequencing (NGS) has provided a successful and cost-effective strategy for identification of novel causative genes in myopathies, including MFM. So far, pathogenic mutations associated with MFM phenotype, including atypical MFM-like cases, have been identified in 17 genes: DES, CRYAB, MYOT, ZASP, FLNC, BAG3, FHL1, TTN, DNAJB6, PLEC, LMNA, ACTA1, HSPB8, KY, PYROXD1, and SQSTM + TIA1 (digenic). Most of these genes are also associated with other forms of muscle diseases. In addition, in many MFM patients, numerous genomic variants in muscle-related genes have been identified. The various myopathies and muscular dystrophies seem to form a single disease continuum; therefore, gene identification in one disease impacts the genetic etiology of the others. In this review, we describe the heterogeneity of the MFM genetic background focusing on the role of rare variants, the importance of whole genome sequencing in the identification of novel disease-associated mutations, and the emerging concept of variant load as the basis of the phenotypic heterogeneity. [ABSTRACT FROM AUTHOR]

Enkephalins are involved in a number of physiological processes. However, these peptides are quickly degraded by peptidases, e.g. the neutral endopeptidase (NEP). Inhibition of the enzymatic degradation of enkephalins is one of the possible approaches to prolong their activity. Selective inhibitor of NEP, sialorphin, is the attractive lead compound for enkephalins degradation studies. In this work, an alanine scan of sialorphin and a series of its hybrids with opiorphin, synthesised by the solid phase method, were performed. The effect of the peptides on degradation of Met-enkephalin by NEP in vitro was investigated. Molecular modelling technique was used to identify residues responsible for protein-ligand interactions. We showed that substitution of amino acids Gln1, Pro4 and Arg5 of sialorphin for Ala significantly reduced the half-life of Met-enkephalin in the presence of NEP. [Ala3]sialorphin displayed a higher inhibitory potency against NEP than sialorphin. Substitution of His2 for Ala led to a compound which was as active as lead compound. Sialorphin has a structure which hardly tolerates substitution in its sequence at positions 1, 4 and 5. The conversion of His2 for alanine in sialorphin is tolerated very well. The higher inhibitory potency of [Ala3]sialorphin than sialorphin against NEP is caused by removal of the hydrophilic residue (Asn) and a better fit of the peptide to the enzyme-binding pocket. The role of side chains of sialorphin in degradation of enkephalin by NEP has been explored. This study also provides an important SAR information essential for further drug design. [ABSTRACT FROM AUTHOR]

Background: Cyclophilin A (CyPA) is an immunomodulatory protein, high expression of which correlates with poor outcome of patients with inflammatory diseases. However, its role in inflammatory bowel disease (IBD) has not been studied.Aim: This study analyzes the correlation between cyclophilin A, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP (TIMP)/MMP-9 complexes in the inflamed and non-inflamed colon mucosa of UC and CD patients.Methods: Serum and biopsy specimens from inflamed and non-inflamed colonic mucosa of 38 patients with IBD (19 with UC and 19 with CD) and 16 controls were included in our study. We measured serum and tissue level of CyPA, and tissue level of TNF-α, MMP-9, TIMP-1/MMP-9, and TIMP-2/MMP-9 using ELISA method.Results: Our results indicated that serum, but not tissue CyPA is increased in UC, rather than in CD patients, compared to the control. The increase correlated with higher tissue concentration of MMP-9 and TNF-α, especially in the UC group. Moreover, we observed significantly higher level of TIMP-1/MMP-9 in UC and CD group, which overlapped with the change in MMP-9. There was no change in TIMP-2/MMP-9 in the analyzed groups.Conclusion: The current study suggests that serum CyPA may be an independent additional marker of IBD, especially of UC. Higher CyPA level may be followed by increased MMP-9 in those patients. However, further studies are necessary to verify the role of CyPA in IBD development. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is strongly associated with inflammation and intestinal barrier disorder. The nonselective cannabinoid receptor agonist HU210 has been shown to ameliorate inflamed colon in colitis, but its effects on intestinal barrier function and extraintestinal inflammation are unclear.Aims: To investigate the effects and the underlying mechanism of HU210 action on the UC in relation to a role of TLR4 and MAP kinase signaling.Methods: Wild-type (WT) and TLR4 knockout (Tlr4 -/-) mice were exposed to 4% dextran sulfate sodium (DSS) for 7 days. The effects of HU210 on inflammation and intestinal barrier were explored.Results: Upon DSS challenge, mice suffered from bloody stool, colon shortening, intestinal mucosa edema, pro-inflammatory cytokine increase and intestinal barrier destruction with goblet cell depletion, increased intestinal microflora accompanied with elevated plasma lipopolysaccharide, reduced mRNA expression of the intestinal tight junction proteins, and abnormal ratio of CD4+/CD8+ T cells in the intestinal Peyer's patches. Pro-inflammatory cytokines in the plasma and the lung, as well as pulmonary myeloperoxidase activity, indicators of extraintestinal inflammation were increased. Protein expression of p38α and pp38 was up-regulated in the colon of WT mice. Tlr4 -/- mice showed milder colitis. HU210 reversed the intestinal barrier changes in both strains of mice, but alleviated inflammation only in WT mice.Conclusions: Our study indicates that in experimental colitis, HU210 displays a protective effect on the intestinal barrier function independently of the TLR4 signaling pathway; however, in the extraintestinal tissues, the anti-inflammatory action seems through affecting TLR4-mediated p38 mitogen-activated protein kinase pathway. [ABSTRACT FROM AUTHOR]

This study evaluates the neuropharmacological effects of the aqueous extract of the Mexican plant Calea zacatechichi Schltdl., which is commonly used in folk medicine to treat cough, asthma, and gastrointestinal disorders. Moreover, it has been used for centuries in traditional rituals based on divination and is thought to possess hallucinogenic activity. To test the neuropharmacological effects of the aqueous extract of C. zacatechichi we used mouse models of convulsions, an elevated plus-maze test and measured locomotor activity. We also evaluated the effect of the extract on antidepressant-like behavior in forced swim test, as well as on muscular strength in a grip test. Moreover the antinociceptive action of the extract was evaluated in the hot-plate and writhing tests. The chemical composition of the extract was evaluated using LC-MS techniques. The aqueous extract of C. zacatechichi did not affect any of the parameters measured in seizure models. It had also no influence on anxiety, exploratory behavior and muscular strength in the applied doses. On the other hand, the extract exhibited antinociceptive effect in the mouse model of abdominal pain. Chemical characterization of the extract showed the presence of chlorogenic acid, acacetin, and germacranolides. Based on this report we suggest that aqueous extract of C. zacatechichi has insignificant neuropharmacological effects in vivo and reduces abdominal pain perception. Our results, together with previous studies showing beneficial effects of the extracts obtained from C. zacatechichi suggest that these preparations may be used to treat medical conditions. [ABSTRACT FROM AUTHOR]

Melatonin is known as a strong antioxidant and possesses anti-inflammatory properties. Recently, melatonin was shown to improve colitis in animal models of inflammatory bowel diseases. The aim of the present study was to characterize the role of melatonin receptors (MT) in the anti-inflammatory effect of melatonin and to assess the anti-inflammatory potential of two novel MT receptor agonists, Neu-P11 and Neu-P67, in the mouse model of trinitrobenzenesulfonic acid (TNBS)-induced colitis. Colitis was induced on day 1 by intracolonic (i.c.) administration of TNBS in 30 % ethanol in saline. Melatonin (4 mg/kg, per os (p.o.)), Neu-P11 (20 mg/kg, p.o.; 50 mg/kg, intraperitoneally (i.p.), 50 mg/kg, i.c.), and Neu-P67 (20 mg/kg, p.o.) were given twice daily for 3 days. Luzindole (5 mg/kg, i.p.) was injected 15 min prior to melatonin administration. On day 4, macroscopic and microscopic damage scores were assessed and myeloperoxidase (MPO) activity quantified using O-dianisidine-based assay. Melatonin significantly attenuated colitis in mice, as indicated by the macroscopic score (1.90 ± 0.34 vs. 3.82 ± 0.62 for melatonin- and TNBS-treated mice, respectively), ulcer score (0.87 ± 0.18 vs. 1.31 ± 0.19, respectively), and MPO activity (4.68 ± 0.70 vs.6.26 ± 0.94, respectively). Luzindole, a MT receptor antagonist, did not inhibit the anti-inflammatory effect of melatonin (macroscopic score 1.12 ± 0.22, ulcer score 0.50 ± 0.16); however, luzindole increased MPO activity (7.57 ± 1.05). MT receptor agonists Neu-P11 and Neu-P67 did not improve inflammation induced by TNBS. Melatonin, but not MT receptor agonists, exerts potent anti-inflammatory action in acute TNBS-induced colitis. Our data suggests that melatonin attenuates colitis by additional, MT receptor-independent pathways. [ABSTRACT FROM AUTHOR]

Background: The loss of response to infliximab in Crohn's disease (CD) patients is currently a major clinical problem. Recently, mean platelet volume (MPV) has been proposed as a new biomarker of CD activity. Here, we hypothesized that MPV may be used as cheap and efficient biomarker of subclinical inflammation during 52-week therapy in CD patients responding to infliximab induction treatment.Aims: The aim of study was to establish whether MPV at baseline and pre-infusion at week 14 are good predictors of sustained response after week 14 in CD patients undergoing 52-week infliximab therapy.Methods: A retrospective study of 30 adult CD patients who underwent a 52-week course of treatment with infliximab and achieved response at week 14 to induction treatment was performed. The association between MPV, baseline disease parameters and maintained clinical response or remission during infliximab therapy was assessed.Results: Higher MPV at week 14 was observed in CD patients with sustained response to infliximab after week 14 than in patients with loss of response (p = 0.0019). In patients with loss of response to maintenance infliximab treatment, lower ΔMPV between baseline and week 14 was calculated (p = 0.0003). MPV > 10.3 fl at week 14 predicts sustained response with 67 % sensitivity and 80 % specificity. ΔMPV between baseline and week 14 >0.4 fl predicts sustained response with 87 % sensitivity and 93 % specificity.Conclusion: MPV at week 14 and ΔMPV between baseline and week 14 are good predictors of sustained response to infliximab maintenance treatment in CD patients. [ABSTRACT FROM AUTHOR]

Epidemiological data suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease, and inflammation. Chlorogenic acid (CGA), an ester of caffeic and quinic acids, is one of the most abundant polyphenol compounds in human diet with proven biological effectiveness both in vitro and in vivo. The aim of the study is to investigate the possible anti-inflammatory effect of CGA in the gastrointestinal (GI) tract and its mechanism of action. We used a well-established model of colitis, induced by intracolonic (i.c.) administration of trinitrobenzenesulfonic acid (TNBS) in mice. The anti-inflammatory effect of CGA in the colon was evaluated based on the clinical and macroscopic and microscopic parameters. To investigate the mechanism of protective action of CGA, myeloperoxidase (MPO), HO, and NF-κB levels were assessed in the colon tissue. CGA administered i.c. at the dose of 20 mg/kg (two times daily) protected against TNBS-induced colitis more effectively than the same dose administered orally (p.o.), as evidenced by significantly lower macroscopic and ulcer scores. Furthermore, CGA (20 mg/kg, i.c.) reduced neutrophil infiltration, as demonstrated by decreased MPO activity. Moreover, CGA suppressed activation of NF-κB, as evidenced by lower levels of phospho-NF-κB/NF-κB ratio in the tissue. CGA did not affect the oxidative stress pathways. CGA exhibits anti-inflammatory properties through reduction of neutrophil infiltration and inhibition of NF-κB-dependent pathways. Our results suggest that CGA may have the potential to become a valuable supplement in the treatment of GI diseases. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory gastrointestinal (GI) disorders, mainly represented by Crohn's disease and ulcerative colitis. Although the etiology of IBD is not fully understood, there is substantial evidence that immunologic, genetic, and environmental factors are the main contributors in IBD pathogenesis. Conventional therapies for IBD include anti-inflammatory and immunosuppressive drugs, such as 5-aminosalicylic acid, corticosteroids, antibiotics, and biologicals, such as anti-TNFα antibodies. However, because of low efficacy and high risk of side effects, there is a clear need for the development of novel and efficient pharmacologic strategies in IBD treatment. Among various complementary and alternative medicine (CAM) approaches, which are used for the treatment of gastrointestinal (GI) disorders, traditional Chinese medicine (TCM) is one of the most developed and diversified. TCM encompasses methods and therapies that emerged over centuries and is based mostly on ethnic wisdom and observations transmitted from generation to generation. In the recent years, the efficacy of TCM as treatment of IBD has been extensively characterized in preclinical and clinical studies, which resulted in a significant number of research reports. Moreover, the popularity of TCM among patients with IBD has rapidly increased not only in Asia, but also in the Western hemisphere. [ABSTRACT FROM AUTHOR]

In this review, we focus on the role of oxidative stress in the aetiology of inflammatory bowel diseases (IBD) and colitis-associated colorectal cancer and discuss free radicals and free radical-stimulated pathways as pharmacological targets for anti-IBD drugs. We also suggest novel anti-oxidative agents, which may become effective and less-toxic alternatives in IBD and colitis-associated colorectal cancer treatment. A Medline search was performed to identify relevant bibliography using search terms including: 'free radicals,' 'antioxidants,' 'oxidative stress,' 'colon cancer,' 'ulcerative colitis,' 'Crohn's disease,' 'inflammatory bowel disease.' Several therapeutics commonly used in IBD treatment, among which are immunosuppressants, corticosteroids and anti-TNF-α antibodies, could also affect the IBD progression by interfering with cellular oxidative stress and cytokine production. Experimental data shows that these drugs may effectively scavenge free radicals, increase anti-oxidative capacity of cells, influence multiple signalling pathways, e.g. MAPK and NF-kB, and inhibit pro-oxidative enzyme and cytokine concentration. However, their anti-oxidative and anti-inflammatory effectiveness still needs further investigation. A highly specific antioxidative activity may be important for the clinical treatment and relapse of IBD. In the future, a combination of currently used pharmaceutics, together with natural and synthetic anti-oxidative compounds, like lipoic acid or curcumine, could be taken into account in the design of novel anti-IBD therapies. [ABSTRACT FROM AUTHOR]

Opioid receptors are widely distributed in the human body and are crucially involved in numerous physiological processes. These include pain signaling in the central and the peripheral nervous system, reproduction, growth, respiration, and immunological response. Opioid receptors additionally play a major role in the gastrointestinal (GI) tract in physiological and pathophysiological conditions. This review discusses the physiology and pharmacology of the opioid system in the GI tract. We additionally focus on GI disorders and malfunctions, where pathophysiology involves the endogenous opioid system, such as opioid-induced bowel dysfunction, opioid-induced constipation or abdominal pain. Based on recent reports in the field of pharmacology and medicinal chemistry, we will also discuss the opportunities of targeting the opioid system, suggesting future treatment options for functional disorders and inflammatory states of the GI tract. [ABSTRACT FROM AUTHOR]

The role of metabolic acidosis in the progression of chronic kidney disease (CKD) remains unclear. The aim of the present study was to investigate the direct effects of acid loading on the proliferation of rat glomerular mesangial cells (GMCs) in vitro and the possible role of sodium-hydrogen ion exchanger isoform 1 (NHE1). Rat GMCs were treated with acidic medium as acid loading. Growth and proliferation of GMCs was studied by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, thymidine (H-TdR) incorporation, and flow cytometry. NHE1 protein expression and activity were quantified by Western blot and dual wavelength epifluorescent illumination with 2′,7′-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein, respectively. 5-( N,N-dimethyl) amiloride hydrochloride (DMA), a specific inhibitor of NHE1, was used to investigate the possible involvement of NHE1 in the proliferation of GMCs. The MTT assay, H-TdR incorporation, and cell cycle distribution analysis indicated that acid loading stimulated the proliferation of GMCs. Acid loading increased NHE1 activity, but had no effects on NHE1 expression at the protein level. The effects of acid loading on the proliferation of GMCs were inhibited by DMA. Acid loading induced GMC proliferation through NHE1-dependent pathways. Our findings may contribute to the understanding of metabolic acidosis in the progression of CKD. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica (NMO) is an inflammatory disease that selectively affects the optic nerves and spinal cord. The discovery of NMO-IgG targeting aquaporin-4 (AQP4) in NMO patients suggested that NMO is a distinct entity, with a fundamentally different etiology from that of multiple sclerosis (MS). Although NMO usually leads to grave disability because of the more severe tissue destruction compared with classical MS, there have been several reports describing a benign form of NMO over a long disease term. NMO-IgG/AQP4 antibodies show high specificity but medium sensitivity for NMO, while the clinical relevance of AQP4 antibody titers remains to be determined. We aimed to clarify the clinical relevance of AQP4 antibody levels determined by a bridging enzyme-linked immunosorbent assay in 38 patients with NMO or NMO spectrum disorder. The AQP4 antibody levels were higher in patients with optic neuritis (ON) than in those without ON ( p = 0.0164). Among the 12 patients examined in a longitudinal study, four showed an increase in the ELISA values during some relapses, and eight showed no clear correlation between the ELISA values and relapse. Of the four patients who demonstrated a steady rise in the antibody levels over time, two patients had no concomitant relapses, despite elevation of the AQP4 antibody levels. We conclude that high AQP4 antibody levels are associated with the occurrence of ON, but that the antibody levels themselves are not closely correlated with the onset of relapse. [ABSTRACT FROM AUTHOR]

Endomorphins (EMs), two endogenous μ-opioid receptor selective ligands, are attractive lead compounds for opioid-based pain management studies. However, these peptides are quickly degraded by peptidases, in particular by dipeptidylpeptidase IV (DPP IV) and aminopeptidase M (APM). Targeting enzymatic degradation is one approach to prolong endomorphin activity. In this study we characterized the action of two new inhibitors of similar to endomorphins structure, Tyr-Pro-Ala-NH (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3), which were designed earlier in our laboratory. The presented data give evidence that EMDB-2 and EMDB-3 are potent inhibitors of enzymes responsible for endomorphin cleavage. These compounds are stable and easily synthesized. EMDB-2 and EMDB-3 are competitive inhibitors of both, DPP IV and APM, with K values in micromolar range. They are less potent than diprotin A in protecting EMs against DPP IV but more potent than actinonin in protecting these peptides against APM. [ABSTRACT FROM AUTHOR]

Morphine is considered the 'gold standard' for relieving pain and is currently one of the most effective drugs available clinically for the management of severe pain associated with cancer. In addition to its use in the treatment of pain, morphine appears to be important in the regulation of neoplastic tissue. Although morphine acts directly on the central nervous system to relieve pain, its activities on peripheral tissues are responsible for many of the secondary complications. Therefore, understanding the impact, other than pain control, of morphine on cancer treatment is extremely important. The effect of morphine on tumor growth is still contradictory, as both growth-promoting and growth-inhibiting effects have been observed. Accumulating evidence suggests that morphine can affect proliferation and migration of tumor cells as well as angiogenesis. Various signaling pathways have been suggested to be involved in these extra-analgesic effects of morphine. Suppression of immune system by morphine is an additional complication. This review provides an update on the influence of morphine on the growth and migration potential of tumor cells. [ABSTRACT FROM AUTHOR]

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) are two recently isolated μ-opioid selective peptides with a potent antinociceptive activity, involved in a number of physiological processes, including food intake, vasomotricity, sexual behavior, as well as neuroendocrine and cardiorespiratory functions. The neuroanatomical distribution of endomorphins prompted us to study their antidepressant activity in two animal behavioral models of depression: forced-swimming and tail-suspension tests. In both tests, the intracerebroventricular (i.c.v.) injection of either endomorphin-1 or endomorphin-2 significantly decreased the duration of immobility, interpreted as an expression of ‘behavioral despair’, which could be related to the depression syndrome. These effects of endomorphins did not result from the stimulation of the animal motor activity. We have also demonstrated that the antidepressant-like effect of endomorphins was antagonized by the universal opioid antagonist, naloxone and the μ-opioid receptor selective antagonist, β-funaltrexamine. In contrast, this effect was not antagonized by δ- and κ-opioid receptor selective antagonists, naltrindole and nor-binaltorphimine, respectively. The results of the present study demonstrate that endomorphin-1 and endomorphin-2 produce potent antidepressant-like effects after i.c.v. injection in mice. We may suggest that endomorphins and the μ-opioid receptors might be involved in the physiopathology of depressive disorders, and that the endomorphinergic system could serve as a novel target for the development of antidepressant drugs.Neuropsychopharmacology (2007) 32, 813–821. doi:10.1038/sj.npp.1301149; published online 5 July 2006 [ABSTRACT FROM AUTHOR]

LGMD2L is a subtype of limb-girdle muscular dystrophy (LGMD), caused by recessive mutations in ANO5, encoding anoctamin-5 (ANO5). We present the analysis of five patients with skeletal muscle weakness for whom heterozygous mutations within ANO5 were identified by whole exome sequencing (WES). Patients varied in the age of the disease onset (from 22 to 38 years) and severity of the morphological and clinical phenotypes. Out of the nine detected mutations one was novel (missense p.Lys132Met, accompanied by p.His841Asp) and one was not yet characterized in the literature (nonsense, p.Trp401Ter, accompanied by p.Asp81Gly). The p.Asp81Gly mutation was also identified in another patient carrying a p.Arg758Cys mutation as well. Also, a c.191dupA frameshift (p.Asn64LysfsTer15), the first described and common mutation was identified. Mutations were predicted by in silico tools to have damaging effects and are likely pathogenic according to criteria of the American College of Medical Genetics and Genomics (ACMG). Indeed, molecular modeling of mutations revealed substantial changes in ANO5 conformation that could affect the protein structure and function. In addition, variants in other genes associated with muscle pathology were identified, possibly affecting the disease progress. The presented data indicate that the identified ANO5 mutations contribute to the observed muscle pathology and broaden the genetic spectrum of LGMD myopathies. [ABSTRACT FROM AUTHOR]

Estrogens exert immunomodulatory action in many autoimmune diseases. Accumulating evidence highlights the meaningful impact of estrogen receptors in physiology and pathophysiology of the colon. However, the significance of G protein-coupled estrogen receptor (GPER) on Crohn's disease (CD), one of the inflammatory bowel disease (IBD) types, is still elusive. Our study revealed GPER overexpression at the mRNA and protein levels in patients with CD. To evaluate the effects of GPER activation/inhibition on colitis development, a murine 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced model of CD was used. We showed that activation of GPER reduces mortality, improves macroscopic and microscopic scores and lowers C-reactive protein (CRP) level. The impact of estrogen signaling on the suppression of the intestinal inflammation was proved by immunohistochemistry. It was demonstrated that GPER activation is accompanied by modulation of extracellular-signal regulated kinase (ERK) signaling pathway and expression level of genes involved in signal transmission and immune response as well as the expression of some microRNAs (miR-145, miR-148-5p and miR-592). Our study revealed that the membrane-bound estrogen receptor GPER mediates anti-inflammatory action and seems to be a potent therapeutic target in maintaining remission in CD. [ABSTRACT FROM AUTHOR]

Calprotectin is a positive acute-phase protein participating in innate immune responses and inflammatory processes. This protein is produced mainly in neutrophils, which infiltrate inflamed tissues and then increase the level of calprotectin in plasma, urine, or body secretions. Its measurement is used in the diagnosis of many inflammatory diseases of the gastrointestinal tract. Here, we reviewed the studies evaluating the utility of calprotectin when the patient is suspected of acute appendicitis, one of the most common causes of abdominal pain. Fecal and serum calprotectin provide clinicians additional information as compared to routinely performed laboratory analyses. Moreover, among all forms of the protein, the fecal calprotectin seems to be a particularly promising biomarker due to its high resistance to degradation in the stool. In the future, innovative methods in the form of neural networks may play a valuable role in developing such panels. These findings are important because current literature showed that sensitive and specific markers of acute appendicitis are still urgently needed. [ABSTRACT FROM AUTHOR]