Ulcerative colitis (UC) is a chronic inflammatory disease with increasing incidence and prevalence worldwide. Currently used treatments of UC are unsatisfactory, while natural bioactive compounds are ...considered to be emerging therapeutic agents. Luteolin (Lut) is a natural compound with beneficial effects in a variety of diseases, however, its effect in UC has been poorly studied. In this study we investigated the effect of Lut in posttreatment and cotreatment of dextran sulfate sodium (DSS)-induced experimental colitis in mice. In addition, the role of extracellular signal-regulated kinases 1/2 (ERK1/2) in the mechanism of action of Lut in experimental colitis was investigated using the ERK inhibitor PD0325901. Lut attenuated symptoms of DSS-induced colitis in mice, ameliorated colon tissue damage and reduced inflammation, apoptosis and autophagy. The effect was more pronounced if Lut was administered simultaneously with DSS. The administration of ERK inhibitor exacerbated DSS-induced colitis symptoms and prevented the protective effects of Lut. The results provide new mechanistic details underlying the anti-inflammatory, anti-apoptotic and anti-autophagic effects of Lut through the activation of the ERK signaling pathway. This suggested that Lut can be used as a novel therapeutic candidate in the treatment of UC or could be used as a supplement to existing therapy.
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•Luteolin ameliorated symptoms of experimental colitis in mice.•The protective activity of luteolin was achieved through its anti-inflammatory, anti-apoptotic and anti-autophagic effects.•The mechanism of action of luteolin is mediated by the induction of the ERK1/2 signaling pathway.
Chlorogenic acid (ChA) exhibits a multitude of positive health effects, however, the signaling mechanisms by which ChA could influence the inflammatory response in experimental colitis are unknown. ...To answer this question, we induced colitis in mice by administration of 2.5% dextran sulfate sodium (DSS) in drinking water for seven days. Oral administration of ChA significantly ameliorated clinical symptoms, improved disease activity index and colon shortening induced by DSS. Furthermore, ChA administration resulted in a suppression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases 1 and 2 (JNK1/2), Akt and signal transducer and activator of transcription 3 (STAT3) with concomitant upregulation of phosphatase and tensin homolog (PTEN) expression. Immunohistochemical analysis showed a dose-dependent decrease in expression and nuclear translocation of nuclear factor-kappa B (NF-κB) p65 subunit, which was accompanied by suppression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) expression. Induction of apoptosis and oxidative stress was attenuated in a dose-dependent manner by suppressing Bax, caspase-8, caspase-9 and heme oxygenase-1 (HO-1) protein expression in mice administrated with ChA. The results of the current study suggest that ChA could be useful for the treatment of inflammation and attenuating colitis severity by suppressing activation of pro-inflammatory and apoptotic signaling pathways.
•Chlorogenic acid ameliorated experimental colitis in mice.•Chlorogenic acid suppressed inflammatory response, apoptosis and oxidative stress in the colon.•The mechanism of action involved suppression of NF-κB, p-STAT3, p-Akt, p-JNK and p-ERK expression in the colon.
Ulcerative colitis (UC) is a multifactorial condition characterized by a destructive immune response that failed to be attenuated by common regulatory mechanisms which reduce inflammation and promote ...mucosa healing. The inhibition of CD26, a multifunctional glycoprotein that controls the immune response via its dipeptidyl peptidase (DP) 4 enzyme activity, was proven to have beneficial effects in various autoimmune inflammatory diseases. The polarization of macrophages into either pro-inflammatory M1 or anti-inflammatory M2 subclass is a key intersection that mediates the immune-inflammatory process in UC. Hence, we hypothesized that the deficiency of CD26 affects that process in the dextran sulfate sodium (DSS)-induced model of UC. We found that mRNA expression of M2 markers arginase 1 and Fizz were increased, while the expression of M1 marker inducible NO synthase was downregulated in CD26
mice. Decreased STAT1 mRNA, as well as upregulated pSTAT6 and pSTAT3, additionally support the demonstrated activation of M2 macrophages under CD26 deficiency. Finally, we investigated DP8 and DP9, proteins with DP4-like activity, and found that CD26 deficiency is not a key factor for the noted upregulation of their expression in UC. In conclusion, we demonstrate that CD26 deficiency regulates macrophage polarization toward the anti-inflammatory M2 phenotype, which is driven by STAT6/STAT3 signaling pathways. This process is additionally enhanced by the reduction of M1 differentiation via the suppression of proinflammatory STAT1. Therefore, further studies should investigate the clinical potential of CD26 inhibitors in the treatment of UC.
Individuals with inflammatory bowel disease (IBD) have an increased risk of bone impairment, which is a process controlled by the RANKL/RANK/OPG system, mostly due to chronic inflammation and ...corticosteroid treatment. Bone morphogenic protein 7 (BMP7) has a complex role in maintaining inflammation and bone remodeling but little is known about its anti-inflammatory potential in chronic colitis. We investigated the effect of systemically administered BMP7 and corticosteroids on the severity of inflammation, macrophage differentiation, and bone regeneration in a chronic IBD model. Methods: Chronic colitis was induced in male Sprague Dawley rats via weekly administration of 2,4,6-trinitrobenzenesulfonic acid over 21 days following BMP7 or corticosteroid treatment for five days. The levels of serum and colon tissue inflammatory cytokines, RANKL/OPG system, as well as markers of macrophage polarization, were detected using RT-PCR, ELISA, or immunohistochemistry. Long bone and spine analyses were performed using microcomputed tomography (micro-CT). Results: The administration of BMP7 reduced the adverse effects of colitis and led to elevated OPG and RANK in the colon with a simultaneous decrease in TNF-α and an increase in IL-10 and TGF-β. Decreased expression of the M2 macrophage marker CD163 was found in the BMP7-treated rats compared with the colitis group, whereas the number of M1 marker iNOS-positive cells did not differ between the groups. As a result of the BMP7 treatment, morphometric parameters of trabecular bone increased, and increased trabecular separation noted in the colitis group did not appear. Conclusions: We showed that BMP7 suppressed the inflammatory response in chronic colitis, mainly by shifting the cytokine balance and by triggering alterations in the RANKL/OPG system rather than through a macrophage polarization imbalance. In addition, considering the demonstrated effect of BMP7 on bone morphology and structure, it can be suggested that BMP7 plays a role in the managing of osteoporosis in chronic colitis, and thus, its therapeutic potential in the treatment of IBD should be further evaluated.
Drug-specific therapeutic approaches for colorectal cancer (CRC) have contributed to significant improvements in patient health. Nevertheless, there is still a great need to improve the ...personalization of treatments based on genetic and epigenetic tumor profiles to maximize the quality and efficacy while limiting cytotoxicity. Currently, CEA and CA 19-9 are the only validated blood biomarkers in clinical practice. For this reason, laboratories are trying to identify new specific prognostics and, more importantly, predictive biomarkers for CRC patient profiling. Thus, the unique landscape of personalized biomarker data should have a clinical impact on CRC treatment strategies and molecular genetic screening tests should become the standard method for diagnosing CRC. This review concentrates on recent molecular testing in CRC and discusses the potential modifications in CRC assay methodology with the upcoming clinical application of novel genomic approaches. While mechanisms for analyzing circulating tumor DNA have been proven too inaccurate, detecting and analyzing circulating tumor cells and protein analysis of exosomes represent more promising options. Blood liquid biopsy offers good prospects for the future if the results align with pathologists' tissue analyses. Overall, early detection, accurate diagnosis and treatment monitoring for CRC with specific markers and targeted molecular testing may benefit many patients.
The objective of this study was to determine and describe the age-related changes in intestinal brush border membrane enzyme activities that occur in C57Bl/6 mice. Specifically, jejunal, duodenal, ...and ileal dipeptidyl peptidase IV/CD26, disaccharidase (lactase, sucrase, and maltase), and alkaline phosphatase activities were determined. A significant correlation between analyzed intestinal brush border membrane enzyme activities and animal age was found. Our study revealed that intestinal dipeptidyl peptidase IV/CD26, lactase, sucrase, maltase, and alkaline phosphatase activities decline significantly with age (
p
< .05). Nevertheless, the horizontal (duodenum to ileum) enzyme activity patterns are not affected by age.
The goal of each professional athlete is to reach maximal performance. In order to achieve that, physical as well as mental training needs to be part of a regular training routine. Anxiety ...significantly affects athletic performance while extreme anxiety levels are associated with reduced athletic achievements. Therefore, controlling sport-related anxiety seems to be one of the most significant aspects for elite athletes. In order to understand the biology behind sport-related anxiety, this review is focused on the biochemical responses to such a stressor. Knowing the biochemistry of stress and its limiting factors on athletic performance enables us a greater understanding of the influence of anxiety on professional athletes. It might help to better understand the importance of sport psychology and how our mindset influences our performance. Furthermore, the correlation between the placebo effect and the manner in which the mind controls the body are considered as it might prove an important tool for future athletic training and sport psychology.
Cilj svakog profesionalnog sportaša jest postizanje najviše razine sportskih performansi. U tu svrhu fizička i mentalna priprema trebaju biti dio redovitih treninga. Anksioznost značajno utječe na sportsku izvedbu a izrazita tjeskoba povezana je sa smanjenim atletskim dostignućima. Stoga je za sportaše jedna od vrlo važnih značajki sposobnost kontroliranja anksioznosti. Kako bismo razumjeli biološke odgovore povezane s anksioznošću, ovaj je pregledni rad usmjeren na razjašnjavanje biokemijskih odgovora navedenog stresora. Poznavanje biokemijskog odgovora organizma uzrokovanog stresom te njegovih ograničavajućih učinaka na sportsku izvedbu omogućuje nam veće razumijevanje utjecaja tjeskobe na profesionalne sportaše. Navedeno nam daje uvid u bolje razumijevanje važnosti sportske psihologije te pojašnjava na koji način mentalno stanje utječe na fizičku izvedbu. U radu se opisuje i korelacija između placebo učinka i načina na koji um kontrolira fizičku snagu, s obzirom na to da ova saznanja mogu predstavljati važnu komponentu sportske psihologije, te daje mogućnost poboljšanja načina pripreme sportaša.
Cilj svakog profesionalnog sportaša jest postizanje najviše razine sportskih performansi. U tu svrhu fizička i mentalna priprema trebaju biti dio redovitih treninga. Anksioznost značajno utječe na ...sportsku izvedbu a izrazita tjeskoba povezana je sa smanjenim atletskim dostignućima. Stoga je za sportaše jedna od vrlo važnih značajki sposobnost kontroliranja anksioznosti. Kako bismo razumjeli biološke odgovore povezane s anksioznošću, ovaj je pregledni rad usmjeren na razjašnjavanje biokemijskih odgovora navedenog stresora. Poznavanje biokemijskog odgovora organizma uzrokovanog stresom te njegovih ograničavajućih učinaka na sportsku izvedbu omogućuje nam veće razumijevanje utjecaja tjeskobe na profesionalne sportaše. Navedeno nam daje uvid u bolje razumijevanje važnosti sportske psihologije te pojašnjava na koji način mentalno stanje utječe na fizičku izvedbu. U radu se opisuje i korelacija između placebo učinka i načina na koji um kontrolira fizičku snagu, s obzirom na to da ova saznanja mogu predstavljati važnu komponentu sportske psihologije, te daje mogućnost poboljšanja načina pripreme sportaša.
The involvement of dipeptidyl peptidase (DP) IV/CD26 (DPP IV/CD26) family members in the pathogenesis of Crohn's disease (CD), an autoimmune inflammatory condition of the gut, is effected mainly ...through proteolytic cleavage of immunomodulatory substrates and DPP IV/CD26's costimulatory function. DP8 and DP9 are proteases with diverse functions including cell interactions, apoptosis, and immune response but their localization remains to be clarified. We assessed the impact of DPP IV/CD26 deficiency (CD26−/−) on the expression profiles of DP8 and DP9 by qPCR and immunodetection as well as quantified DP8/9 enzyme activity in distinctive phases of a chemically‐induced CD model in mice. CD26−/− did not affect colon DP8 mRNA expression, while the physiological concentration of DP8 protein is decreased in CD26−/− mice but rises in inflammation (P < 0.05). On the other hand, DP9 mRNA level is significantly increased in CD26−/− mice in inflammation as well as healing with the DP9 concentration being almost twofold increased (P < 0.05) in all experimental points in CD26−/− mice compared to wild‐type indicating the expected up‐regulation in CD26−/− conditions. Surprisingly, dominantly intracellular DP8 and DP9 were found in abundance in serum. DP8/9 activity is decreased in the inflamed colon, whereas its contribution to the overall serum DPP IV/CD26‐like activity is negligible, suggesting the importance of their extra‐enzymatic functions. To summarize, CD induction generated gene, protein and enzymatic changes of DP8 and DP9 so their involvement in inflammation development and/or healing process is implicated, especially in CD26−/−, and the question of their subcellular localization should be revised.
CD26 deficiency caused a decrease of DP8 colon protein concentration in physiological conditions, while in inflammation the opposite occurs and its concentration rises. On the other hand, DP9's concentration is almost twofold increased in physiological conditions but not subjected to changes caused by inflammation onset and resolution. In serum, CD26 deficiency caused a systematically lower concentration of DP8 but not of DP9 physiologically and during colitis development, while inflammation onset caused a twofold increase of DP9 protein in CD26 deficient mice.
Dipeptidyl peptidase IV (DPP IV/CD26) is a widely distributed multifunctional protein that plays a significant role in different physiological as well as pathological processes having a broad ...spectrum of bioactive substrates and immunomodulative properties. It has potential influence on different processes crucial for wound healing, including cell adhesion, migration, apoptosis, and extracellular matrix degradation. However, despite its known enzymatic and immunomodulative functions, limited data characterize the role of DPP IV/CD26 in cutaneous wound healing mechanisms. The aim of this study was to investigate the process of wound healing in conditions of CD26 deficiency in order to obtain better insights on the role of DPP IV/CD26 in cutaneous regeneration. Experimental wounds were made on the dorsal part of CD26 deficient (CD26−/−) and wild‐type mice (C57BL/6). The process of cutaneous wound healing was monitored on defined time schedule postwounding by macroscopic, microscopic, and biochemical analyses. Obtained results revealed a better rate of wound closure, revascularization and cell proliferation in CD26−/− mice, with enhanced local expression of hypoxia‐inducible factor 1α and vascular endothelial growth factor. CD26 deficiency induced prompt macrophage recruitment at the site of skin damage but did not influence mobilization of T‐cells in comparison with wild‐type mice. CD26−/− mice have significantly higher values of IP‐10 in serum and control skins compared with wild‐type mice but values in wounds did not differ significantly on days 2, 4, and 7 of wound healing. DPP IV/CD26 activity was found to be decreased 4 days postwounding in serum and 2, 4, and 7 days postwounding in wounds of wild‐type animals compared with control skins. These findings contribute to better understanding of wound healing mechanisms and could give a support in finding new therapeutic approaches for wound healing and tissue regeneration.
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