Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer

Troncone, Edoardo; Marafini, Irene; Stolfi, Carmine; Monteleone, Giovanni

doi:10.3390/ijms22083922

Cited by 14 publications

(10 citation statements)

References 106 publications

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“…To conclude, the present study evaluated the effects of anti-TNF-α and 5-ASA on the TGF-β/Smad7 signaling pathway in a mouse experimental model of colitis. Similar studies were performed in the colon ( 40 , 52 – 57 ), peripheral blood ( 58 ) or in chronic pathologies ( 53 , 56 ), whereas the present experiment studied the small intestine and acute response to injury. It was found that anti-TNF-α and 5-ASA both improved the permeability of the intestinal epithelium on this model of UC.…”

Section: Discussionmentioning

confidence: 82%

Molecular mechanism of the TGF‑β/Smad7 signaling pathway in ulcerative colitis

Bai

Han

et al. 2022

Mol Med Rep

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aberrant TGF-β/Smad7 signaling has been reported to be an important mechanism underlying the pathogenesis of ulcerative colitis. Therefore, the present study aimed to investigate the effects of a number of potential anti-colitis agents on intestinal epithelial permeability and the TGF-β/Smad7 signaling pathway in an experimental model of colitis. a mouse model of colitis was first established before anti-TNF-α and 5-aminosalicyclic acid (5-aSa) were administered intraperitoneally and orally, respectively. Myeloperoxidase (MPo) activity, histological index (Hi) of the colon and the disease activity index (dai) scores were then detected in each mouse. Transmission electron microscopy (TeM), immunohistochemical and functional tests, including evans blue (eB) and FiTc-dextran (Fd-4) staining, were used to evaluate intestinal mucosal permeability. The expression of epithelial phenotype markers e-cadherin, occludin, zona occludens (Zo-1), TGF-β and Smad7 were measured. in addition, epithelial myosin light chain kinase (MlcK) expression and activity were measured. anti-TnF-α and 5-aSa treatments was both found to effectively reduce the dai score and Hi, whilst decreasing colonic MPo activity, plasma levels of Fd-4 and eB permeation of the intestine. Furthermore, anti-TnF-α and 5-aSa treatments decreased MlcK expression and activity, reduced the expression of Smad7 in the small intestine epithelium, but increased the expression of TGF-β. in mice with colitis, TeM revealed partial epithelial injury in the ileum, where the number of intercellular tight junctions and the expression levels of e-cadherin, Zo-1 and occludin were decreased, all of which were alleviated by anti-TnF-α and 5-aSa treatment. in conclusion, anti-TnF-α and 5-aSa both exerted protective effects on intestinal epithelial permeability in an experimental mouse model of colitis. The underlying mechanism may be mediated at least in part by the increase in TGF-β expression and/or the reduction in Smad7 expression, which can inhibit epithelial MlcK activity and in turn reduce mucosal permeability during the pathogenesis of ulcerative colitis.

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Section: Discussionmentioning

confidence: 82%

Molecular mechanism of the TGF‑β/Smad7 signaling pathway in ulcerative colitis

Bai

Han

et al. 2022

Mol Med Rep

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“…Of note, EAE induction was dependent on the presence of a full gut microbiota (132). At the human level, the analysis of intestinal tissue biopsies from 27 MS patients and 27 control individuals revealed an altered TGFb-dependent Th-cell differentiation pattern in the lamina propria with increased frequencies of inflammatory T cells and reduced FoxP3 expression (132), a process akin to the defective TGF-b1/ Smad signaling in IBD (134). Interestingly, it has been suggested that the levels of circulating mucosal-associated invariant T cells, which are abundant in gut lamina propria, may reflect disease activity in MS, with reduced numbers observed during exacerbation correlating with increased MRI activity in some patients, while at remission increased numbers coincided with decreased MRI activity (135).…”

Section: The Gut Environment Drives Ms Pathogenesismentioning

confidence: 99%

Section: What Comes First In Ms Gut or Cns Inflammation?mentioning

confidence: 99%

The Gut-Brain Axis in Multiple Sclerosis. Is Its Dysfunction a Pathological Trigger or a Consequence of the Disease?

Parodi

Rosbo

2021

Front. Immunol.

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A large and expending body of evidence indicates that the gut-brain axis likely plays a crucial role in neurological diseases, including multiple sclerosis (MS). As a whole, the gut-brain axis can be considered as a bi-directional multi-crosstalk pathway that governs the interaction between the gut microbiota and the organism. Perturbation in the commensal microbial population, referred to as dysbiosis, is frequently associated with an increased intestinal permeability, or “leaky gut”, which allows the entrance of exogeneous molecules, in particular bacterial products and metabolites, that can disrupt tissue homeostasis and induce inflammation, promoting both local and systemic immune responses. An altered gut microbiota could therefore have significant repercussions not only on immune responses in the gut but also in distal effector immune sites such as the CNS. Indeed, the dysregulation of this bi-directional communication as a consequence of dysbiosis has been implicated as playing a possible role in the pathogenesis of neurological diseases. In multiple sclerosis (MS), the gut-brain axis is increasingly being considered as playing a crucial role in its pathogenesis, with a major focus on specific gut microbiota alterations associated with the disease. In both MS and its purported murine model, experimental autoimmune encephalomyelitis (EAE), gastrointestinal symptoms and/or an altered gut microbiota have been reported together with increased intestinal permeability. In both EAE and MS, specific components of the microbiota have been shown to modulate both effector and regulatory T-cell responses and therefore disease progression, and EAE experiments with germ-free and specific pathogen-free mice transferred with microbiota associated or not with disease have clearly demonstrated the possible role of the microbiota in disease pathogenesis and/or progression. Here, we review the evidence that can point to two possible consequences of the gut-brain axis dysfunction in MS and EAE: 1. A pro-inflammatory intestinal environment and “leaky” gut induced by dysbiosis could lead to an altered communication with the CNS through the cholinergic afferent fibers, thereby contributing to CNS inflammation and disease pathogenesis; and 2. Neuroinflammation affecting efferent cholinergic transmission could result in intestinal inflammation as disease progresses.

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“…Colon cancer is a common malignant tumor of the digestive system ( 1 , 2 ). Colon cancer has high morbidity and mortality rates in developed western countries and is the third commonest tumor in the world ( 3 – 5 ).…”

Section: Introductionmentioning

confidence: 99%

NR3C2 suppresses the proliferation, migration, invasion and angiogenesis of colon cancer cells by inhibiting the AKT/ERK signaling pathway

Zhao

2022

Mol Med Rep

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nuclear receptor subfamily 3, group c, member 2 (nr3c2) serves an antitumorigenic role in several types of cancer; however, its role and mechanisms of action in colon cancer remains to be elucidated. The aim of the present study was to explore the effects of nr3c2 on the proliferation, migration, invasion and angiogenesis of colon cancer cells. The expression levels of nr3c2 in human colon epithelial ncM460 cells (spontaneously immortalized cell line) and colon cancer cell lines was detected using reverse transcription-quantitative Pcr and western blotting. cell counting Kit-8 (ccK-8) and colony formation assays were used to assess cell viability and wound healing and Transwell assays were used to detect cell invasion and migration. eliSa was used to detect the expression levels of VeGF and tube formation assays were used to assess angiogenesis. The expression levels of angiogenesis-related proteins and aKT/erK signaling pathway-related proteins were detected by western blotting. nr3c2 expression was downregulated in colon cancer cells and overexpression of nr3c2 inhibited proliferation, colony formation, migration and invasion of colon cancer cells. overexpression of nr3c2 inhibited angiogenesis and activity of the aKT/erK signaling pathway in colon cancer cells. Thus, it was demonstrated that nr3c2 inhibited the proliferation, colony formation, migration, invasion and angiogenesis of colon cancer cells through the aKT/erK signaling pathway. These results may highlight novel targets for the treatment of colon cancer.

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Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer

Cited by 14 publications

References 106 publications

Molecular mechanism of the TGF‑β/Smad7 signaling pathway in ulcerative colitis

Molecular mechanism of the TGF‑β/Smad7 signaling pathway in ulcerative colitis

The Gut-Brain Axis in Multiple Sclerosis. Is Its Dysfunction a Pathological Trigger or a Consequence of the Disease?

NR3C2 suppresses the proliferation, migration, invasion and angiogenesis of colon cancer cells by inhibiting the AKT/ERK signaling pathway

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