Tackling Inflammatory Bowel Diseases: Targeting Proinflammatory Cytokines and Lymphocyte Homing

Song, Yijie; Yuan, Man; Xu, Yu; Xu, Hong‐Xi

doi:10.3390/ph15091080

Cited by 19 publications

(22 citation statements)

References 162 publications

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“…IFN-α, IFN-γ signaling, and TNF signaling via NF-κB were negatively enriched pathways in the T cells of sham and PL8177 50 µg groups. IFN-α, IFN-γ, and TNF are characteristic of IBD ( 39 , 50 , 51 ), so negative enrichment of these pathways suggests a role in reducing inflammation. Increased K18 positive enterocytes in PL8177-treated DSS colon tissue validates results from snRNA-seq and suggests maintenance of key cell structures to protect the colon barrier.…”

Section: Discussionmentioning

confidence: 99%

A novel oral formulation of the melanocortin-1 receptor agonist PL8177 resolves inflammation in preclinical studies of inflammatory bowel disease and is gut restricted in rats, dogs, and humans

et al. 2023

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IntroductionPL8177 is a potent and selective agonist of the melanocortin 1 receptor (MC1R). PL8177 has shown efficacy in reversing intestinal inflammation in a cannulated rat ulcerative colitis model. To facilitate oral delivery, a novel, polymer-encapsulated formulation of PL8177 was developed. This formulation was tested in 2 rat ulcerative colitis models and evaluated for distribution, in vivo, in rats, dogs, and humans. MethodsThe rat models of colitis were induced by treatment with 2,4-dinitrobenzenesulfonic acid or dextran sulfate sodium. Single nuclei RNA sequencing of colon tissues was performed to characterize the mechanism of action. The distribution and concentration of PL8177 and the main metabolite within the GI tract after a single oral dose of PL8177 was investigated in rats and dogs. A phase 0 clinical study using a single microdose (70 µg) of [14C]-labeled PL8177 investigated the release of PL8177 in the colon of healthy men after oral administration.ResultsRats treated with 50 µg oral PL8177 demonstrated significantly lower macroscopic colon damage scores and improvement in colon weight, stool consistency, and fecal occult blood vs the vehicle without active drug. Histopathology analysis resulted in the maintenance of intact colon structure and barrier, reduced immune cell infiltration, and increased enterocytes with PL8177 treatment. Transcriptome data show that oral PL8177 50 µg treatment causes relative cell populations and key gene expressions levels to move closer to healthy controls. Compared with vehicle, treated colon samples show negative enrichment of immune marker genes and diverse immune-related pathways. In rats and dogs, orally administered PL8177 was detected at higher amounts in the colon vs upper GI tract. [14C]-PL8177 and the main metabolite were detected in the feces but not in the plasma and urine in humans. This suggests that the parent drug [14C]-PL8177 was released from the polymer formulation and metabolized within the GI tract, where it would be expected to exert its effect. ConclusionCollectively, these findings support further research into the oral formulation of PL8177 as a possible therapeutic for GI inflammatory diseases in humans.

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Section: Discussionmentioning

confidence: 99%

A novel oral formulation of the melanocortin-1 receptor agonist PL8177 resolves inflammation in preclinical studies of inflammatory bowel disease and is gut restricted in rats, dogs, and humans

et al. 2023

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“…Specifically, the increase in lymphocyte populations was positively associated with MA-4: SPP1+ FABP5+ intermediate class, whose inflammatory cytokines/chemokines production may be responsible for lymphocyte homing 96 , and negatively associated with MA-2: LYVE1+ TIMD4+ TRM, whose gene markers were found more often on synovial TRMs from healthy and remission RA than active RA patients 14 (Fig. 8b).…”

Section: Cell Neighborhood Associations With Histological Metrics And...mentioning

confidence: 96%

The Chromatin Landscape of Pathogenic Transcriptional Cell States in Rheumatoid Arthritis

Weinand

Sakaue

Nathan

et al. 2023

Preprint

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Synovial tissue inflammation is the hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. We measured genome-wide open chromatin at single cell resolution from 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identified 24 chromatin classes and predicted their associated transcription factors, including a CD8+ GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating an RA tissue transcriptional atlas, we found that the chromatin classes represented 'superstates' corresponding to multiple transcriptional cell states. Finally, we demonstrated the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.

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“…Current research suggests a combination of genetic predisposition, enhanced autophagic response, epigenetic modulation, and microbiome disruptions may be involved [ 4 ]. Current IBD medications include aminosalicylic acids, disease-modifying antirheumatic drugs (DMARDs), steroids, biologic medications, and novel small molecule drugs [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation

Salla

Guo

Joshi

et al. 2023

IJMS

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Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC: Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.

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Tackling Inflammatory Bowel Diseases: Targeting Proinflammatory Cytokines and Lymphocyte Homing

Cited by 19 publications

References 162 publications

A novel oral formulation of the melanocortin-1 receptor agonist PL8177 resolves inflammation in preclinical studies of inflammatory bowel disease and is gut restricted in rats, dogs, and humans

A novel oral formulation of the melanocortin-1 receptor agonist PL8177 resolves inflammation in preclinical studies of inflammatory bowel disease and is gut restricted in rats, dogs, and humans

The Chromatin Landscape of Pathogenic Transcriptional Cell States in Rheumatoid Arthritis

Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation

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