Inhibitory effects of mixed flavonoid supplements on unraveled DSS-induced ulcerative colitis and arthritis
Siva Prasad PandaMahamat Sami Adam MahamatMalikyahia Abdul RasoolDSNBK PrasanthIdris Adam IsmailMoyed Abasher Ahmed AbasherBikash Ranjan Jena
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Introduction: The mixed flavonoid supplement (MFS) [Trimethoxy Flavones (TMF) + epigallocatechin-3-gallate (EGCG)] can be used to suppress inflammatory ulcers as an ethical medicine in Ayurveda. The inflammation of the rectum and anal regions is mostly attributed to nuclear factor kappa beta (NF-κB) signaling. NF-κB stimulates the expression of matrix metalloproteinase (MMP9), inflammatory cytokines tumor necrosis factor (TNF-α), and interleukin-1β (IL-1β). Although much research targeted the NF-κB and MMP9 signaling pathways, a subsequent investigation of target mediators in the inflammatory ulcer healing and NF-κB pathway has not been done. Methods: The docking studies of compounds TMF and EGCG were performed by applying PyRx and available software to understand ligand binding properties with the target proteins. The synergistic ulcer healing and anti-arthritic effects of MFS were elucidated using dextran sulfate sodium (DSS)-induced colon ulcer in Swiss albino rats. The colon mucosal injury was analyzed by colon ulcer index (CUI) and anorectic tissue microscopy. The IL-1β, tumor necrosis factor (TNF-α), and the pERK, MMP9, and NF-κB expressions in the colon tissue were determined by ELISA and Western blotting. RT-PCR determined the mRNA expression for inflammatory marker enzymes. Results: The docking studies revealed that EGCG and TMF had a good binding affinity with MMP9 (i.e., -6.8 and -6.0 Kcal/mol) and NF-kB (-9.4 and 8.3 kcal/mol). The high dose MFS better suppressed ulcerative colitis (UC) and associated arthritis with marked low-density pERK, MMP9, and NF-κB proteins. The CUI score and inflammatory mediator levels were suppressed with endogenous antioxidant levels in MFS treated rats. Conclusion: The MFS effectively unraveled anorectic tissue inflammation and associated arthritis by suppressing NF-κB-mediated MMP9 and cytokines.Keywords:
MMP9
Matrix metalloproteinases (MMPs) have many functions in the cellular microenvironment through cleavage of proteins leading to their activation, inactivation or removal. As a result broad‐spectrum inhibitors of these enzymes were unsuccessful in clinical trials in cancer patients. We have examined the nature of protumorigenic and antitumorigenic targets and functions of MMPs. Our data indicate that MMP9, MMP13 and MMP14 dependent remodeling of the collagen scaffold regulates angiogenesis, tumor cell invasion and migration and inflammatory cell infiltration. The outcomes vary with oncogenes, tumor type and location. MMPs increase VEGF bioavailability and also increase production of antiangiogenic extracellular matrix fragments.
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Molecular mechanisms involved in mediating alteration in cell matrix interaction have been examined by studying the changes in the activity of matrix metalloproteinases (MMPs) in CCl4-induced regenerating liver, using zymography and ELISA. Activity of MMPs (72 kD, 92 kD and 130 kD gelatinases) in the rat liver increased progressively during acute injury till the 4th day and then decreased to near normal level after CCl4 administration (0.5 ml/100 g body wt.) on the 6th day. Hepatocyte lysate of injured liver on the 4th day showed significantly higher levels of MMP2 and MMP9 compared to the control. In the culture medium of hepatocytes, the levels of MMP2 and MMP9 increased progressively with the duration of culture, indicating that hepatocytes are the major source of these MMPs in regenerating liver. These results suggest an involvement of MMPs in matrix degradation and remodeling during regeneration after acute liver injury induced by CCl4.
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Zymography
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Gelatinases
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Objective To observe the levels of plasma P-selection(P-sel) and in patients with ulcerative colitis and to study the clinical significance of them. Methods the concentrations of P-sel in 18 patients with active ulcerative colitis and 13 relief ulcerative colitis were determined with ELISA method. Results The results shown that the levels of P-sel in active ulcerative colitis patients were markedly elevated and were correlated with the severity of the disease. But the levels of P-sel in relief ulcerative colitis patients have no difference with normal controls. Conclusion It is suggested that the occurrence and development of ulcerative colitis may be related to the increase of plasma P-sel. Measurement of levels of plasma P-sel and might therefore provide a tool for monitoring the clinical course and for gaiding the treatment of ulcerative colitis.
Clinical Significance
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Animal models of experimentally induced inflammatory bowel disease (IBD) are useful for understanding more about the mechanistic basis of disease, identifying new targets for therapeutic intervention, and testing novel therapeutic agents. This unit provides detailed protocols for four of the most commonly used mouse models of experimentally induced intestinal inflammation: chemical induction of colitis by dextran sodium sulfate (DSS), hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS), Helicobacter-induced colitis in mdr1a(-/-) mice, and the CD4(+) CD45RB(hi) SCID transfer colitis model.
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Objective:To investigate the action of TNF-a,IL-6 and sIL-2R in the mechanism of ulcerative colitis.Methods:Bi-antibody radioimmune methods and ELISA methods were used to analysis the samples in TNF-a,IL-6 and sIL-2R of 25 cases with active ulcerative colitis.30 normal persons were assigned as the contrast group.The data of cytokines(TNF-a,IL-6,sIL-2R)among contrast group,the active and catabolic phases of ulcerative colitis were compared.That in catabolic phases of ulcerative colitis was also compared with that in contrast group,the difference were compared among slight,moderate and severe groups,The relativity among the serum level in TNF-a,IL-6 of active ulcerative colitis had been observed.Results:The level of serum TNF-a,IL-6 and sIL-2R in active ulcerative colitis was much more higher than catabolic ulcerative colitis and contrast group(P0.05).The level had no significant difference between catabolic ulcerative colitis and contrast group(P0.005).The level in severe group is higher than that in moderate and slight group(P0.05).Serum cytokines,TNF-a and IL-6 are positively related to active ulcerative colitis.(r=0.8476,P0.05).Conclusion:There is a severe disorders of cellular immunity in the patients with active ulcerative colitis.TNF-a,IL-6,sIL-2R etc play the very important roles in the genesis and development of ulcerative colitis.The serum level of the above cytokines not only reflected the development of ulcerative colitis but also could be used as biological index of the effect and estimate the prognosis.
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Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestinal tract and is primarily comprised of Crohn's disease (CD) and ulcerative colitis (UC). Several murine models that include both chemical induced and genetic models have been developed that mimic some aspects of either CD or UC. These models have been instrumental in our understanding of IBD. Of the chemical induced colitis models, dextran sodium sulfate (DSS) induced colitis model is a relatively simple and very widely used model of experimental colitis.
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Objective To observe the severity correlation of TNF-α、IL-6 and IL-8 levels in plasma in patients with ulcerative colitis and investigate mechanism of ulcerative colitis.Methods TNF-α,IL-6 and IL-8 levels in plasma were measured with ELISA methods in 56 patients with ulcerative colitis and 20 normal persons as a control group.The active and catabolic phases of ulcerative colitis were compared and the difference were compared among slight,moderate and sever groups.Results The level of serum TNF-α,IL-6 and IL-8 in active ulcerative colitis was much more higher than catabolic ulcerative colitis and contrast group(P0.05).The level had no significant differences between catabolic ulcerative colitis and contrast group(P0.05).The level in severe group was higher than that in moderate and slight group(P0.05).Conclusions There is a sever disorders of cellular immunity in the patients with active ulcerative colitis.TNF-α,IL-6 and IL-8 play the very important roles in the genesis and development of ulcerative colitis.The measurement of TNF-α,IL-6 and IL-8 levels in plasma may contribute to predict the severity of ulcerative colitis.
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Animal models of experimentally induced inflammatory bowel disease (IBD) are useful for understanding more about the mechanistic basis of the disease, identifying new targets for therapeutic intervention, and testing novel therapeutics. This unit provides detailed protocols for five widely used mouse models of experimentally induced intestinal inflammation: chemical induction of colitis by dextran sodium sulfate (DSS), hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS), Helicobacter-induced colitis in mdr1a(-/-) mice, the CD4(+) CD45RB(hi) SCID transfer colitis model, and the IL-10(-/-) colitis model. © 2016 by John Wiley & Sons, Inc.
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