Archives

  • 2018-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • d-amphetamine synthesis It is important to note that the GC

    2022-06-27

    It is important to note that the GC-C expression is retained in colon tumours, and therefore GC-C expression can be used as a marker to diagnose metastatic colon cancer [42]. However, expression of uroguanylin and guanylin is often lost in colorectal cancer progression [43]. Therefore, the anti-proliferative activity of GC-C could perhaps be restored by administration of ST peptide analogs such as linaclotide, or by the elevation of intracellular cGMP following inhibition of cyclic nucleotide phosphodiesterases such as PDE5 [44]. A characteristic feature of most colorectal cancers is the high activity of c-src tyrosine kinase seen in colon carcinoma d-amphetamine synthesis [45]. We have demonstrated that GC-C is regulated by c-src mediated inhibitory phosphorylation of a specific tyrosine residue in GC-C. Consequently, the addition of ligands of GC-C to colonic cancer cells that contain elevated levels of active c-src does not result in an increase in intracellular cGMP [46], and therefore would prevent anti-proliferative signaling mediated by GC-C. Thus, a combinatorial therapy of c-src inhibitors, such as dasatinib [47], which is in phase-2 clinical trials for the treatment of colorectal cancer, along with activators of GC-C, such as linaclotide, may be an effective regime in the treatment of colon cancers.
    Roles of GC-C and cGMP in intestinal inflammation Inflammatory bowel disease (IBD) is a chronic inflammatory disorder and two main clinical presentations are Crohn’s disease and ulcerative colitis [48]. Genetic factors, the host immune system and the gut microbiome contribute to IBD, and disturbances in the interaction between the intestinal epithelial cells and the immune cells in the intestine appear to be responsible for these syndromes. Therefore, any malfunctioning of the epithelial cells could alter the responses of the immune cells in the gut, resulting in inflammation. Heightened inflammation, as a result of intestinal electrolyte imbalance, is seen in infectious diarrheal disease and in patients suffering from congenital chloride diarrhea [49]. Since GC-C regulates ion secretion, it may be a mitigating factor in causing the inflammation. Intestinal biopsies from patients suffering from inflammatory bowel disease (IBD) showed down regulation of the sodium-hydrogen ion exchanger 3 (NHE3) [50], and NHE3 knock-out mice overproduce inflammatory cytokines, and are more susceptible to dextran sodium sulfate (DSS)-induced epithelial injury [51]. Thus, the inhibition of NHE3 activity that is seen following GC-C activation may contribute to the inflammation seen in diarrheal disease. Suggestive of this is the observation that GC-C knock-out mice, and to a lesser extent, guanylin knock-outs, show reduced TNFβ production and diminished apoptosis in the distal colon following acute administration of DSS [52]. This may be correlated with the lower levels of cGMP in the intestinal epithelia of GC-C and guanylin knock-out mice, which may have resulted in hyper activation of NHE3, and therefore reduced inflammation. Paradoxically, a disruption of the integrity of the intestinal barrier is also seen in GC-C knock-out mice [53]. It is known that a disruption of epithelial barrier function can result in pathological inflammatory responses as is seen in IBD. Moreover, down regulation of guanylin and uroguanylin mRNA is seen in Crohn’s disease and ulcerative colitis [54] implying that reduced cGMP levels may actually aggravate inflammation. It is therefore apparent that the molecular bases, if any, of GC-C and cGMP-mediated regulation of inflammation in the intestine, either via tight junction breakdown or altered pro-inflammatory cytokine expression in the gut, are far from clear. An interaction between intestinal microflora and host factors is necessary for the development of intestinal inflammation, since in the background of a genetic mutation in the host, specific viruses or bacteria need to be present, along with environmental factors, in the intestine in order to manifest disease [55]. We speculate that perhaps fluid and ion secretion regulated by GC-C could affect the composition of the microbiome. Therefore, in GC-C knock-out mice, the microbiota may differ from wild-type mice, and this could contribute to the reduced inflammation that is seen, in spite of tight junction disassembly.