Infliximab modifies CD74-mediated lymphatic abnormalities and adipose tissue alterations in creeping fat of Crohn's disease.

BACKGROUND: Lymphatic abnormalities are essential for pathophysiologic changes of creeping fat (CrF) in Crohn's disease (CD). Anti-tumor necrosis factor (TNF) therapy has been proved to alleviate CrF lesions, however, whether it achieves these by remodeling lymphatics is unknown. METHODS: CD74 expression was detected in CrF and uninvolved mesentery of CD patients. Lymphatic functions in vitro were evaluated and lymphatic endothelium barrier were checked by transendothelial electrical resistance (TEER) and FITC-Dextran permeability. Protein level of tight junction and signaling pathways were detected by western blotting. RESULTS: CD74 was upregulated in LECs of CrF and positively correlated with TNF-α synthesis. This was suppressed by IFX administration. In vitro, TNF-α stimulated LECs to express CD74 through NF-κB signaling pathway, and this was rescued by IFX. CD74 downregulation suppressed the abilities of LECs in proliferation, migration and tube formation. Interaction of CD74-MIF impaired LECs' barrier via reducing tight junction proteins in an ERK1/2-dependent manner, which was reversed by CD74 downregulation. Consistently, the CD patients receiving IFX therapy displayed decreased lymphangiogenesis and improved mesenteric lymphatic endothelium barrier, companied with reduced adipocyte size and adipokine levels in CrF. CONCLUSIONS: Anti-TNF therapy could modify pathological changes in CrF by alleviating CD74-mediated lymphatic abnormalities.

Endoscopic purse-string suture and naso-jejunal tube feeding for duodenal cutaneous fistula and gastric cutaneous fistula.

BACKGROUND: The Endoscopic Purse-string Suture (EPSS) technique has gained attention for its potential in closing large defects following gastrointestinal procedures. However, its application in fistula closure is not as widely reported. This study aims to evaluate the safety and efficacy of EPSS and naso-jejunal tube feeding in the closure of duodenal cutaneous fistulas and gastric cutaneous fistulas. METHODS: This single-center retrospective study, conducted from September 2020 to September 2023 at Tongji University in Shanghai, China, examined the outcomes of EPPS and nasojejunal feeding for patients with gastric and duodenal cutaneous fistulas (n = 10). Demographic data, fistula characteristics, procedure technique and outcomes were evaluated. RESULTS: In this study, the average size of a fistula opening was 7.9 ± 4.6 mm. The operations took an average of 25.8 ± 5.6 min. Patients typically needed naso-jejunal tube feeding for a median of 14.0 days, with an interquartile range (IQR) of 7.7-19.0 days. The median duration of hospital stay post-operation was 16.5 days, with an IQR of 7.0-25.0 days. Nine patients were successful in their initial fistula closure using the EPSS technique. The other patient underwent a second EPSS and, ultimately, all patients experienced complete healing and fully recovered. There were no major adverse events reported. CONCLUSIONS: EPSS and naso-jejunal tube feeding are a safe and effective treatment option for duodenal and gastric cutaneous fistulas. Larger, prospective studies are needed to validate these findings and establish the long-term safety and efficacy of this approach.

Integrated Analysis of Colorectal Cancer Reveals Cross-Cohort Gut Microbial Signatures and Associated Serum Metabolites.

BACKGROUND & AIMS: Studies have reported abnormal gut microbiota or circulating metabolome associated with colorectal cancer (CRC), but it remains a challenge to capture the CRC-relevant features consistent across geographic regions. This is particularly the problem for metabolic traits of CRC because the analyses generally use different platforms and laboratory methods, which poses a barrier to cross-dataset examination. In light of this, we sought to elucidate the microbial and metabolic signatures of CRC with broad population relevance. METHODS: In this integrated metagenomic (healthy controls [HC], n = 91; colorectal adenoma [CRA], n = 63; CRC, n = 71) and metabolomic (HC, n = 34; CRA, n = 31; CRC, n = 35) analysis, CRC-associated features and microbe-metabolite correlations were first identified from a Shanghai cohort. A gut microbial panel was trained in the in-house cohort and cross-validated in 7 published metagenomic datasets of CRC. The in-house metabolic connections to the cross-cohort microbial signatures were used as evidence to infer serum metabolites with potentially external relevance. In addition, a combined microbe-metabolite panel was produced for diagnosing CRC or adenoma. RESULTS: CRC-associated alterations were identified in the gut microbiome and serum metabolome. A composite microbe-metabolite diagnostic panel was developed and yielded an area under the curve of 0.912 for adenoma and 0.994 for CRC. We showed that many CRC-associated metabolites were linked to cross-cohort gut microbiome signatures of the disease, including CRC-enriched leucylalanine, serotonin, and imidazole propionate; and CRC-depleted perfluorooctane sulfonate, 2-linoleoylglycerol (18:2), and sphingadienine. CONCLUSIONS: We generated cross-cohort metagenomic signatures of CRC, some of which linked to in-house CRC-associated serum metabolites. The microbial and metabolic shifts may have wide population relevance.

Transformation of colitis and colorectal cancer: a tale of gut microbiota.

Intestinal inflammation modifies host physiology to promote the occurrence of colorectal cancer (CRC), as seen in colitis-associated CRC. Gut microbiota is crucial in cancer progression, primarily by inducing intestinal chronic inflammatory microenvironment, leading to DNA damage, chromosomal mutation, and alterations in specific metabolite production. Therefore, there is an increasing interest in microbiota-based prevention and treatment strategies, such as probiotics, prebiotics, microbiota-derived metabolites, and fecal microbiota transplantation. This review aims to provide valuable insights into the potential correlations between gut microbiota and colitis-associated CRC, as well as the promising microbiota-based strategies for colitis-associated CRC.

Site-Specific Incorporation of Multiple Thioamide Substitutions into a Peptide Backbone via Solid Phase Peptide Synthesis.

Among various peptide modification strategies, thioamide substitution by replacing the carbonyl oxygen atom of an amide bond with a sulfur atom constitutes an invaluable tool for chemical biology, for use in peptide drug discovery and protein structure-function studies. However, the thioamide substitution effect has not been well studied because of the lack of synthetic methods for site-specifically incorporating a thioamide bond into a peptide backbone, particularly introducing multiple thioamide substitutions into peptide on a solid support. Herein, we report a highly efficient method for incorporating a thioamide bond into the peptide backbone in a site-specific manner by employing α-thioacyloxyenamides, which are formed from the addition of N-protected monothioamino acids and ynamides, as novel thioacylating reagents in solid phase peptide synthesis. This method is amenable for 19 of 20 proteinogenic amino acids, His being the exception. One to multiple thioamide substitutions could be incorporated into a growing peptide with no epimerization or a low level of epimerization. By using this method, a fully thioamide-substituted hexapeptide containing up to five continuous thioamide bonds could be synthesized smoothly. This synthetic methodology will spur the application of the thioamide substitution tool for protein engineering and peptide drug discovery.

Misdiagnosis of multiple synchronous small bowel adenocarcinomas as intestinal tuberculosis: a case report.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare malignancy that primarily occurs in the duodenum. Multiple synchronous SBA is unique rare and difficult to diagnose due to non-specific disease presentation. Protocols to identify multiple synchronous SBA during early disease stages are urgently required. CASE PRESENTATION: An elderly man experienced left lower abdominal pain and melena for 3 months. Abdominal CT showed thickening of the multiple segmental small intestinal walls. As the patient had pulmonary tuberculosis simultaneously, he was misdiagnosis as intestinal tuberculosis and received anti-spasm therapy. The treatment delayed radical resection surgery and the patient underwent palliative segmental resection of the jejunum after 4 months due to intestinal obstruction. Resected specimens showed multiple synchronous SBA (five tumors). The patient accepted chemotherapy postoperatively. Six months postoperatively, the patient died of brain metastasis. CONCLUSIONS: We highlight how multiple synchronous SBA is rare and easily misdiagnosed. We should rule out multiple synchronous SBA when diagnosing intestinal diseases (e.g. inflammatory bowel disease, IBS). Intestinal tuberculosis may also be one of the risk factors for multiple synchronous SBA. High-risk patients should be assessed for known tumor makers, and receive gastroscopy, enteroscopy or capsule endoscopy. Doctors should obtain the pathology under endoscopy to the greatest possible degree. For suspected patients, laparotomy should be performed.

Minimally invasive treatment of mid-low rectovaginal fistula: a transanal endoscopic surgery study.

BACKGROUND: Treatment of rectovaginal fistulas (RVFs) is extremely difficult. No standard surgical procedure is accepted worldwide. The aim of this article was to evaluate a minimally invasive procedure for the repair of mid-low rectovaginal fistula. METHODS: This is a retrospective review of 17 patients who underwent minimally invasive surgery for the repair of mid-low rectovaginal fistulas (located in the lower or middle one-third of the vaginal wall) at our center between August 2016 and October 2018. The anal approach was adopted for 12 patients: 6 patients were treated directly by rectal mucosal advancement flap (RMAF) with transanal endoscopic surgery (TES), while the other 6 patients underwent initial TES exploration followed by RMAF procedure under direct vision. The vaginal approach was adopted for 5 patients: 3 patients were treated under TES directly and the other 2 were treated under direct vision after initial TES exploration. A total of 9 (52.94%) patients received diverting ileostomy-5 anal approach patients and 4 vaginal approach patients. RESULTS: Median age of the patients was 46 years (range 10-76 years), and median BMI was 21.9 (range 17.9-28.1). Median operative time was 75 min (range 60-120 min), and median duration of postoperative hospital stay was 8 days (range 6-15 days). Recurrence was seen in 3/12 anal approach patients vs. 0/5 vaginal approach patients. Both the median preoperative and the median postoperative Wexner score were 0 (range 0-2). The median follow-up time was 8 months (range 2-24). No severe complications occurred in any patient. CONCLUSION: The TES procedure for the treatment of mid-low rectovaginal fistulas avoids any incision of the abdomen and perineal area and appears to be a safe and feasible procedure. This minimally invasive technique is still evolving and is likely to gain wide acceptance in the near future.

Using GRGDSPC peptides to improve re-endothelialization of decellularized pancreatic scaffolds.

Engineering of functional vascularized pancreatic tissues offers an alternative way to solve the perpetual shortage of organs for transplantation. However, revascularization remains a major bottleneck in biological engineering, which limited the further clinical applications of this strategy. In this study, an efficient approach for enhancing re-endothelialization of rat decellularized pancreatic scaffolds (DPS) was presented, by conjugating with GRGDSPC peptide to maximize coverage of the vessel walls with human umbilical vein endothelial cells (HUVECs). First, pancreas was perfused with 1% Triton X-100 and 0.1% ammonium hydroxide to remove the cellular components. Subsequently, GRGDSPC was covalently coupled to the vasculature of DPS and re-seeded with HUVECs via perfusion of the portal vein in the bioreactor. After the re-endothelialized scaffolds were created, in vitro and in vivo experiments were undertaken to evaluate the angiogenesis. Our results demonstrated that GRGDSPC-conjugated scaffolds could support the survival and accelerated the proliferation of HUVECs; angiogenesis was also significantly improved over untreated scaffolds. In conclusion, GRGDSPC-conjugated scaffolds showed great potential for the generation of functional bioengineered pancreatic tissue suitable for long-term transplantation.

CD177+ neutrophils suppress epithelial cell tumourigenesis in colitis-associated cancer and predict good prognosis in colorectal cancer.

Neutrophils are found to be infiltrated in tumour tissues of patients with colitis-associated cancer (CAC) and colorectal cancer (CRC), and CD177 is mainly expressed in neutrophils. In our study, expression of CD177 in tumour tissues from patients with CAC or CRC was analysed byquantitative real-time polymerase chain reaction, flow cytometry and immunohistochemistry. We recruited 378 patients with CRC, determined CD177 expression in tumours and examined its correlation with clinicopathological features. Moreover, CAC model was induced in wild-type and CD177-/- mice by azoxymethane/dextran sodium sulphate. CD177+ neutrophils were significantly increased in colon tumour tissues from patients with CRC or CAC compared with controls. Expression of CD177 mRNA and percentages of CD177+ neutrophils were also markedly increased in tumour tissues from CRC patients compared with controls. Patients with high density of CD177+ neutrophils had better overall survival and disease-free survival compared with controls. Multivariate analyses revealed that the density of CD177+ neutrophils was an independent factor in predicting overall survival and disease-free survival. Consistently, CD177 depletion aggravated azoxymethane/dextran sodium sulphate-induced CAC in mice. Expression of Ki67 and proliferating cell nuclear antigen was increased in tumour tissues from CD177-/- mice compared with wild-type counterparts. Moreover, CD177-/- neutrophils failed to migrate in response to fMLP[AU: Please expand fMLP, DN, TNM and HIF-1α.] stimulation compared with wild-type controls. Our data indicate that CD177+ neutrophils suppress epithelial cell tumourigenesis and act as an independent factor in predicting the prognosis in patients with CRC. CD177+ neutrophils may serve as a novel therapeutic target in the treatment and predict the prognosis of CAC and CRC.

Absorbable Versus Nonabsorbable Sutures for Skin Closure: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Prior studies focused on skin closure using absorbable or nonabsorbable sutures involved small samples and produced conflicting results. The optimal method of skin closure still remains unclear. OBJECTIVE: This study aimed to compare the outcomes of absorbable versus nonabsorbable sutures for skin closure. METHODS: A meta-analysis was performed in randomized controlled trials (RCTs) that compared outcomes of absorbable versus nonabsorbable sutures for skin closure. RESULTS: A total of 1748 patients in 19 RCTs were analyzed. There was no significant difference between absorbable sutures and nonabsorbable sutures in the incidence of wound infections, cosmetic outcomes, scar formation, wound dehiscence, and patients' or patient caregivers' satisfaction. Better cosmetic results were achieved by using intradermal absorbable sutures compared with nonabsorbable sutures in subgroup analysis, but this result might be affected by insufficient follow-ups. CONCLUSIONS: Absorbable sutures for skin closure were not inferior to nonabsorbable sutures. It should be recommended due to its great cost and time savings. Well-designed RCTs with sufficient follow-ups are needed to adequately clarify whether better cosmetic results can be achieved using intradermal absorbable sutures.

A Randomized Clinical Trial of Berberine Hydrochloride in Patients with Diarrhea-Predominant Irritable Bowel Syndrome.

We aimed to evaluate clinical symptoms in diarrhea predominant irritable bowel syndrome (IBS-D) receiving berberine hydrochloride in a randomized double-blind placebo-controlled clinical trial. Overall, 196 patients with IBS-D were recruited for this study; consequently, 132 patients randomized to receive daily 400 mg of berberine hydrochloride, delivered twice daily or placebo for 8 weeks followed by a 4-week washout period. After a 2-week run-in period, diarrhea, abdominal pain, urgent need for defecation frequency and any adverse events were recorded daily. Prior to administration of the medication and after completing the treatment, assessment of IBS symptom scores, depression and anxiety scale scores and the IBS scale for quality of life (QOL) was carried out. The effects of berberine hydrochloride on IBS-D, defined by a reduction of diarrhea frequency (P = 0.032), abdominal pain frequency (P < 0.01) and urgent need for defecation frequency (P < 0.01), were significantly more pronounced in the berberine group than the placebo group in the 8 weeks of treatment. A trend of improvement (P < 0.05) was observed with berberine hydrochloride for IBS symptom score, depression score and anxiety score and the IBSQOL, compared with placebo. At last, berberine hydrochloride was well tolerated. So we concluded that berberine hydrochloride is well tolerated and reduces IBS-D symptoms, which effectively improved patients QOL.

p38 MAPK inhibition alleviates experimental acute pancreatitis in mice.

BACKGROUND: The mitogen-activated protein kinases (MAPKs) signaling pathway is involved in inflammatory process. However, the mechanism is not clear. The present study was to investigate the role of p38 MAPK in acute pancreatitis in mice. METHODS: Mice were divided into 4 groups: saline control; acute pancreatitis induced with repeated injections of cerulein; control plus p38 MAPK inhibitor SB203580; and acute pancreatitis plus SB203580. The pancreatic histology, pancreatic enzymes, cytokines, myeloperoxidase activity, p38 MAPK and heat shock protein (HSP) 60 and 70 were evaluated. RESULTS: Repeated injections of cerulein resulted in acute pancreatitis in mice, accompanying with the activation of p38 MAPK and overexpression of HSP60 and HSP70 in the pancreatic tissues. Treatment with SB203580 significantly inhibited the activation of p38 MAPK, and furthermore, inhibited the expression of HSP60 and HSP70 in the pancreas, the inflammatory cytokines in the serum, and myeloperoxidase activity in the lung. CONCLUSION: The p38 MAPK signaling pathway is involved in the regulation of inflammatory response and the expression of HSP60 and HSP70 in acute pancreatitis.

Chinese herbal medicines in the treatment of IBD and colorectal cancer: a review.

OPINION STATEMENT: Inflammatory bowel diseases (IBD) are a group of chronic inflammatory gastrointestinal (GI) disorders, mainly represented by Crohn's disease and ulcerative colitis. Although the etiology of IBD is not fully understood, there is substantial evidence that immunologic, genetic, and environmental factors are the main contributors in IBD pathogenesis. Conventional therapies for IBD include anti-inflammatory and immunosuppressive drugs, such as 5-aminosalicylic acid, corticosteroids, antibiotics, and biologicals, such as anti-TNFα antibodies. However, because of low efficacy and high risk of side effects, there is a clear need for the development of novel and efficient pharmacologic strategies in IBD treatment. Among various complementary and alternative medicine (CAM) approaches, which are used for the treatment of gastrointestinal (GI) disorders, traditional Chinese medicine (TCM) is one of the most developed and diversified. TCM encompasses methods and therapies that emerged over centuries and is based mostly on ethnic wisdom and observations transmitted from generation to generation. In the recent years, the efficacy of TCM as treatment of IBD has been extensively characterized in preclinical and clinical studies, which resulted in a significant number of research reports. Moreover, the popularity of TCM among patients with IBD has rapidly increased not only in Asia, but also in the Western hemisphere.

The role of the CXCR6/CXCL16 axis in the pathogenesis of fibrotic disease.

CXC chemokine receptor 6 (CXCR6), a seven-transmembrane domain G-protein-coupled receptor, plays a pivotal regulatory role in inflammation and tissue damage through its interaction with CXC chemokine ligand 16 (CXCL16). This axis is implicated in the pathogenesis of various fibrotic diseases and correlates with clinical parameters that indicate disease severity, activity, and prognosis in organ fibrosis, including afflictions of the liver, kidney, lung, cardiovascular system, skin, and intestines. Soluble CXCL16 (sCXCL16) serves as a chemokine, facilitating the migration and recruitment of CXCR6-expressing cells, while membrane-bound CXCL16 (mCXCL16) functions as a transmembrane protein with adhesion properties, facilitating intercellular interactions by binding to CXCR6. The CXCR6/CXCL16 axis is established to regulate the cycle of damage and repair during chronic inflammation, either through modulating immune cell-mediated intercellular communication or by independently influencing fibroblast homing, proliferation, and activation, with each pathway potentially culminating in the onset and progression of fibrotic diseases. However, clinically exploiting the targeting of the CXCR6/CXCL16 axis requires further elucidation of the intricate chemokine interactions within fibrosis pathogenesis. This review explores the biology of CXCR6/CXCL16, its multifaceted effects contributing to fibrosis in various organs, and the prospective clinical implications of these insights.

Predicting short-term major postoperative complications in intestinal resection for Crohn's disease: A machine learning-based study.

BACKGROUND: Due to the complexity and numerous comorbidities associated with Crohn's disease (CD), the incidence of postoperative complications is high, significantly impacting the recovery and prognosis of patients. Consequently, additional studies are required to precisely predict short-term major complications following intestinal resection (IR), aiding surgical decision-making and optimizing patient care. AIM: To construct novel models based on machine learning (ML) to predict short-term major postoperative complications in patients with CD following IR. METHODS: A retrospective analysis was performed on clinical data derived from a patient cohort that underwent IR for CD from January 2017 to December 2022. The study participants were randomly allocated to either a training cohort or a validation cohort. The logistic regression and random forest (RF) were applied to construct models in the training cohort, with model discrimination evaluated using the area under the curves (AUC). The validation cohort assessed the performance of the constructed models. RESULTS: Out of the 259 patients encompassed in the study, 5.0% encountered major postoperative complications (Clavien-Dindo ≥ III) within 30 d following IR for CD. The AUC for the logistic model was 0.916, significantly lower than the AUC of 0.965 for the RF model. The logistic model incorporated a preoperative CD activity index (CDAI) of ≥ 220, a diminished preoperative serum albumin level, conversion to laparotomy surgery, and an extended operation time. A nomogram for the logistic model was plotted. Except for the surgical approach, the other three variables ranked among the top four important variables in the novel ML model. CONCLUSION: Both the nomogram and RF exhibited good performance in predicting short-term major postoperative complications in patients with CD, with the RF model showing more superiority. A preoperative CDAI of ≥ 220, a diminished preoperative serum albumin level, and an extended operation time might be the most crucial variables. The findings of this study can assist clinicians in identifying patients at a higher risk for complications and offering personalized perioperative management to enhance patient outcomes.

Gastrointestinal Dysmotility Predisposes to Colitis through Regulation of Gut Microbial Composition and Linoleic Acid Metabolism.

Disrupted gastrointestinal (GI) motility is highly prevalent in patients with inflammatory bowel disease (IBD), but its potential causative role remains unknown. Herein, the role and the mechanism of impaired GI motility in colitis pathogenesis are investigated. Increased colonic mucosal inflammation is found in patients with chronic constipation (CC). Mice with GI dysmotility induced by genetic mutation or chemical insult exhibit increased susceptibility to colitis, dependent on the gut microbiota. GI dysmotility markedly decreases the abundance of Lactobacillus animlalis and increases the abundance of Akkermansia muciniphila. The reduction in L. animlalis, leads to the accumulation of linoleic acid due to compromised conversion to conjugated linoleic acid. The accumulation of linoleic acid inhibits Treg cell differentiation and increases colitis susceptibility via inducing macrophage infiltration and proinflammatory cytokine expression in macrophage. Lactobacillus and A. muciniphila abnormalities are also observed in CC and IBD patients, and mice receiving fecal microbiota from CC patients displayed an increased susceptibility to colitis. These findings suggest that GI dysmotility predisposes host to colitis development by modulating the composition of microbiota and facilitating linoleic acid accumulation. Targeted modulation of microbiota and linoleic acid metabolism may be promising to protect patients with motility disorder from intestinal inflammation.

Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration.

We report the synthesis and pharmacological characterization of a novel glycosylated analog of a potent and selective endogenous µ-opioid receptor (MOP) agonist, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2), obtained by the introduction in position 3 of the tyrosine residue possessing the glucose moiety attached to the phenolic function via a ß-glycosidic bond. The improved blood-brain barrier permeability and enhanced antinociceptive effect of the novel glycosylated analog suggest that it may be a promising template for design of potent analgesics. Furthermore, the described methodology may be useful for increasing the bioavailability and delivery of opioid peptides to the CNS.

Inhibiting roles of berberine in gut movement of rodents are related to activation of the endogenous opioid system.

Although Berberine (BER) is popular in treating gastrointestinal (GI) disorders, its mechanisms are not clear yet. In order to investigate the effects and possible mechanism of BER on GI motility in rodents, we first explored GI motility by recording the myoelectrical activity of jejunum and colon in rats, and upper GI transit with a charcoal marker in mice. Then, the plasma levels of gastrin, motilin, somatostatin and glucagon-like-peptide-1 (Glp-1) were measured by ELISA or radioimmunoassay (RIA). Furthermore, endogenous opioid-peptides (ß-endorphin, dynorphin-A, met-enkephalin) were detected by RIA after treatment with BER. Our results showed that BER concentration-dependently inhibited myoelectrical activity and GI transit, which can be antagonized by opioid-receptor antagonists to different extents. The elevated somatostatin and Glp-1, and decreased gastrin and motilin in plasma, which were caused by BER application, also could be antagonized by the opioid-receptor antagonists. Additionally, plasma level of ß-endorphin, but not dynorphin-A and met-enkephalin, was increased by applying BER. Taken together, these studies show that BER plays inhibiting roles on GI motility and up-regulating roles on somatostatin, Glp-1 and down-regulating roles on gastrin, motilin. The pharmacological mechanisms of BER on GI motility and plasma levels of GI hormones were discovered to be closely related to endogenous opioid system.

Single-cell Expression Atlas Reveals Cell Heterogeneity in the Creeping Fat of Crohn's Disease.

BACKGROUND: Creeping fat (CrF) has been recognized to play a positive role in Crohn's disease (CD) progression, yet the cellular compositions within mesenteric adipose tissue (MAT) and their potential mechanism in CrF formation are poorly understood. METHODS: Analysis of 10X single-cell RNA sequencing was performed on 67 064 cells from 3 pairs of surgically resected samples of CrF and their uninvolved MAT. The results were validated in another cohort with 6 paired MAT samples by immunofluorescence. RESULTS: All samples manifested excellent consistency and repeatability in our study, and 10 cell types from the transcriptome atlas, including 20 clusters, were identified. In CrF, a specific vascular endothelial cell subpopulation highly expressing lipoprotein lipase was first identified, with a significantly increased proportion. This vascular endothelial cell subpopulation manifested robust peroxisome proliferator-activated receptor γ (PPARγ) transcription activity and an upregulated PPAR signaling pathway and was involved in lipid metabolism and the antibacterial response. A novel fibroblast subpopulation (FC3) with remarkable GREM1 and RFLNB expression was identified and validated to predominantly accumulate in the CrF. The FC3 was annotated as inflammation-associated fibroblasts, which are characterized by inflammatory responses and the regulation of Smad phosphorylation related to intestinal fibrosis. The trajectory of fibroblasts revealed their pro-inflammatory and profibrotic conversion tendency during CrF formation with corresponding gene dynamics. Additionally, we unprecedently dissected the different origins and functions of 6 macrophage subclusters within the myeloid compartment. CONCLUSIONS: Our results uncover the cellular heterogeneity in the MAT of CD and the role of these various cellular compositions in CrF development. This comprehensive understanding of CrF provides future directions for in-depth research on and potential targets for MAT-based treatment.

This is the first study that provides a comprehensive single-cell transcriptomic atlas in mesenteric adipose tissue (MAT) of Crohn's disease and elaborates the functional diversity and dynamic changes of the cellular components during creeping fat (CrF) formation.

Nodal promotes colorectal cancer survival and metastasis through regulating SCD1-mediated ferroptosis resistance.

Re-expression of an embryonic morphogen, Nodal, has been seen in several types of malignant tumours. By far, studies about Nodal's role in colorectal cancer (CRC) remain limited. Ferroptosis is essential for CRC progression, which is caused by cellular redox imbalance and characterized by lipid peroxidation. Herein, we observed that Nodal enhanced CRC cell's proliferative rate, motility, invasiveness, and epithelial-mesenchymal transition (EMT) in vivo and in vitro. Notably, Nodal overexpression induced monounsaturated fatty acids synthesis and increased the lipid unsaturation level. Nodal knockdown resulted in increased CRC cell lipid peroxidation. Stearoyl-coenzyme A desaturase 1 (SCD1) inhibition at least partially abolished the resistance of Nodal-overexpressing cells to RSL3-induced ferroptosis. Mechanistically, SCD1 was transcriptionally up-regulated by Smad2/3 pathway activation in response to Nodal overexpression. Significant Nodal and SCD1 up-regulation were observed in CRC tissues and were associated with CRC metastasis and poor clinical outcomes. Furthermore, bovine serum albumin nanoparticles/si-Nodal nanocomplexes targeting Nodal had anti-tumour effects on CRC progression and metastasis. This research elucidated the role of Nodal in CRC development and revealed a potential gene-based therapeutic strategy targeting Nodal for improving CRC treatment.