Revisiting fibrosis in inflammatory bowel disease: the gut thickens

D’Alessio, Silvia; Ungaro, Federica; Noviello, Daniele; Lovisa, Sara; Peyrin–Biroulet, Laurent; Danese, Silvio

doi:10.1038/s41575-021-00543-0

Cited by 116 publications

(85 citation statements)

References 210 publications

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“…In summary, zedoary turmeric and trisomes influence each other and act together to treat IBD intestinal fibrosis through multiple pathways with their multiple components and targets, and this finding fully reflects the holistic and comprehensive characteristics of TCMs in the treatment of diseases[ 45 ]. The results of the analysis of their mechanism of action in the treatment of IBD intestinal fibrosis via a technical approach consisting of network pharmacology and molecular interconnections lay the foundation for further research and provide a new perspective for multidimensional and multilevel research on treatments with TCM compounds.…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology and molecular docking reveal zedoary turmeric-trisomes in Inflammatory bowel disease with intestinal fibrosis

Ji¹,

Dai²,

Wen³

et al. 2022

WJCC

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BACKGROUND Inflammatory bowel disease (IBD) is a complex chronic IBD that is closely associated with risk factors such as environment, diet, medications and lifestyle that may influence the host microbiome or immune response to antigens. At present, with the increasing incidence of IBD worldwide, it is of great significance to further study the pathogenesis of IBD and seek new therapeutic targets. Traditional Chinese medicine (TCM) treatment of diseases is characterized by multiple approaches and multiple targets and has a long history of clinical application in China. The mechanism underlying the effect of zedoary turmeric-trisomes on inducing mucosal healing in IBD is not clear. AIM To explore the effective components and potential mechanism of zedoary turmeric-trisomes in the treatment of IBD with intestinal fibrosis using network pharmacology and molecular docking techniques. METHODS The chemical constituents and targets of Rhizoma zedoary and Rhizoma sanarum were screened using the TCMSP database. The GeneCards database was searched to identify targets associated with intestinal fibrosis in IBD. The intersection of chemical component targets and disease targets was obtained using the Venny 2.1 online analysis platform, and the common targets were imported into the STRING 11.0 database to construct a protein interaction regulatory network. A “zedoary turmeric-trisomes-chemical composition-target-disease” network diagram was subsequently constructed using Cytoscape 3.7.2 software, and the topological properties of the network were analyzed using the “Network Analysis” plug-in. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the common targets were performed using the DAVID 6.8 database to elucidate the mechanism of zedoary turmeric-trisomes in the treatment of IBD. Subsequently, molecular docking of the compounds and targets with the highest intermediate values in the “zedoary turmeric-trisomes-chemical composition-target-disease” network was performed using Sybyl-x 2.1.1 software. RESULTS A total of 5 chemical components with 60 targets were identified, as well as 3153 targets related to IBD and 44 common targets. The protein-protein interaction network showed that the core therapeutic targets included JUN, MAPK14, CASP3, AR, and PTGS2. The GO enrichment analysis identified 759 items, and the KEGG enrichment analysis yielded 52 items, including the cancer pathway, neuroactive ligand-receptor interaction, hepatitis B, and the calcium signaling pathway, reflecting the complex biological processes of the multicomponent, multitarget and multipathway treatment of diseases with zedoary turmeric-trisomes. Molecular docking showed that the compound bonded with the target through hydrogen bond interactions and exhibited good docking activity. CONCLUSION This study identified the potential m...

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Section: Discussionmentioning

confidence: 99%

Network pharmacology and molecular docking reveal zedoary turmeric-trisomes in Inflammatory bowel disease with intestinal fibrosis

Ji¹,

Dai²,

Wen³

et al. 2022

WJCC

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“…Intestinal fibrosis is a common complication of IBD and represents a great challenge for clinicians and scientists [ 8 ]. It is still unknown which factors trigger intestinal fibrosis; therefore, investigating novel molecules underlying fibrogenesis is a necessary step towards gaining effective control of fibrotic onset, progression, and cure.…”

Section: Discussionmentioning

confidence: 99%

“…However, most evidence indicates that gastrointestinal tract fibrosis occurs only in previously or actively inflamed regions, implying that persisting inflammation is a necessary condition for developing fibrosis. In physiological conditions, acute inflammation is normally followed by healing with tissue restoration and functional recovery; in pathological conditions, the fibrotic process is established by the persistence of the inflammatory stimulus [ 4 , 5 , 6 , 7 , 8 , 9 ]. Many studies have demonstrated that TGF-β stimulates the activation and proliferation of fibroblasts, resulting in extracellular matrix deposition and fibrosis in several organs, including lungs, kidneys, liver, skin, and gut [ 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis

Laudadio

Bastianelli

Fulci

et al. 2022

IJMS

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Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis.

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“…Histologically, it has been well documented that CD strictures are characterized by the hypertrophy and hyperplasia of intestinal smooth muscle. 46 , 47 However, a recent study has identified a novel histopathological phenotype in a subset of CD patients with ileal strictures, in which part of strictures were due to mural constriction rather than due to fibromuscular hypertrophy. 48 CD patients who presented with constrictive ileal strictures are featured by earlier onset, frequent multiplicity, and little fibromuscular mural expansion, which are pathologically and clinically distinct from those with hypertrophic strictures.…”

Section: Search Strategymentioning

confidence: 99%

Intestinal strictures in Crohn’s disease: a 2021 update

Lin

Wang

Liu

et al. 2022

Therap Adv Gastroenterol

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Intestinal strictures remain one of the most intractable and common complications of Crohn’s disease (CD). Approximately 70% of CD patients will develop fibrotic strictures after 10 years of CD diagnosis. Since specific antifibrotic therapies are unavailable, endoscopic balloon dilation and surgery remain the mainstay treatments despite a high recurrence rate. Besides, there are no reliable methods for accurately evaluating intestinal fibrosis. This is largely due to the fact that the mechanisms of initiation and propagation of intestinal fibrosis are poorly understood. There is growing evidence implying that the pathogenesis of stricturing CD involves the intricate interplay of factors including aberrant immune and nonimmune responses, host-microbiome dysbiosis, and genetic susceptibility. Currently, the progress on intestinal strictures has been fueled by the advent of novel techniques, such as single-cell sequencing, multi-omics, and artificial intelligence. Here, we perform a timely and comprehensive review of the substantial advances in intestinal strictures in 2021, aiming to provide prompt information regarding fibrosis and set the stage for the improvement of diagnosis, treatment, and prognosis of intestinal strictures.

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Revisiting fibrosis in inflammatory bowel disease: the gut thickens

Cited by 116 publications

References 210 publications

Network pharmacology and molecular docking reveal zedoary turmeric-trisomes in Inflammatory bowel disease with intestinal fibrosis

Network pharmacology and molecular docking reveal zedoary turmeric-trisomes in Inflammatory bowel disease with intestinal fibrosis

ZNF281 Promotes Colon Fibroblast Activation in TGFβ1-Induced Gut Fibrosis

Intestinal strictures in Crohn’s disease: a 2021 update

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