IL6ST: A Novel Therapeutic Target for Managing and Treating Colorectal Cancer Via Ferroptosis.

Inflammation is an essential driver of colorectal cancer (CRC). Identifying phenotypes and targets associated with inflammation and cancer may be an effective way to treat CRC. R was used to analyze interleukin 6 cytokine family signal transducer (IL6ST) expression in The Cancer Genome Atlas Colon Adenocarcinoma database. Immunohistochemistry, western blotting, and quantitative PCR were used to detect IL6ST and ferroptosis-related genes expression in our cohort. Receiver operating characteristic curves evaluated the specificity and sensitivity of IL6ST to predict CRC. Cell counting kit-8 investigated cell viability. Mitochondrial morphology, total iron, and reactive oxygen species (ROS) levels were evaluated to assess cell ferroptosis. The correlation of IL6ST and immune cells filtration were also analyzed based on R. IL6ST was significantly upregulated in CRC tissues (P < .05). The specificity and sensitivity of IL6ST for predicting CRC were high (area under the curve (AUC): 0.919, CI: 0.896-0.942). IL6ST was significantly associated with ferroptosis-related genes. IL6ST knockdown decreased SW480 cells viability (knockdown vs. vector, P = .004), promoted the ferroptosis phenotype, and increased iron accumulation (knockdown vs. vector P = .014) and ROS production (knockdown vs. vector P = .005). IL6ST upregulation increased SW620 cells viability (overexpression vs. blank, P = .001), inhibited the ferroptosis phenotype, and decreased iron accumulation (overexpression vs. vector P = 0.006) and ROS production (overexpression vs. vector P = .05). IL6ST increased FTH1 and GPX4 expression and reduced PTGS2, NOX1, and ACSL4 expression (P < .01). Additionally, IL6ST level is linked to immune cell infiltration. A higher enrichment score of T cells was observed in IL6ST up-regulated group. IL6ST inhibits ferroptosis and may be a potential novel therapeutic target in CRC via the modulation of ferroptosis.

Development and validation of multiparametric models based on computed tomography enterography to determine endoscopic activity and surgical risk in patients with Crohn's disease: A multi-center study.

Objective: To develop novel multiparametric models based on computed tomography enterography (CTE) scores to identify endoscopic activity and surgical risk in patients with Crohn's disease (CD). Methods: We analyzed 171 patients from 3 hospitals. Correlations between CTE outcomes and endoscopic scores were assessed using Spearman's rank correlation analysis. Predictive models for moderate to severe CD were developed, and receiver operating characteristic (ROC) curves were constructed to determine the area under the ROC curve (AUC). A combined nomogram based on CTE scores and clinical variables was also developed for predicting moderate to severe CD and surgery. Results: CTE scores were significantly correlated with endoscopy scores at the segment level. The global CTE score was an independent predictor of severe (HR = 1.231, 95% CI: 1.048-1.446, p = 0.012) and moderate-to-severe Simplified Endoscopic Scores for Crohn's Disease (SES-CD) (HR = 1.202, 95% CI: 1.090-1.325, p < 0.001). The nomogram integrating CTE and clinical data predicted moderate to severe SES-CD and severe SES-CD scores in the validation cohort with AUCs of 0.837 and 0.807, respectively. The CTE score (HR = 1.18; 95% CI: 1.103-1.262; p = 0.001) and SES-CD score (HR = 3.125, 95% CI: 1.542-6.33; p = 0.001) were independent prognostic factors for surgery-free survival. A prognostic nomogram incorporating CTE scores, SES-CD and C-reactive protein (CRP) accurately predicted the risk of surgery in patients with CD. Conclusion: The newly developed CTE score and multiparametric models displayed high accuracy in predicting moderate to severe CD and surgical risk for CD patients.

Body Composition in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is associated with body composition changes, which are associated with clinical prognosis, response to therapy, and quality of life in IBD patients. Therefore, it is critical to review the body composition distribution in IBD, summarize the potential factors affecting body composition distribution, and take steps to improve the body composition distribution of IBD patients as early as possible. In the current review, we searched PubMed via keywords 'inflammatory bowel disease', or 'IBD', or 'Crohn's disease', or 'CD', or 'ulcerative colitis', or 'UC', and 'body composition'. Malnutrition and sarcopenia are common in IBD patients and are associated with the clinical course, prognosis, and need for surgery. Disease activity, reduced nutrition intake, vitamin D deficiency, and intestinal dysbiosis are factors contributing to changed body composition. Early use of biological agents to induce remission is critical to improving body composition distribution in IBD patients, supplementation of vitamin D is also important, and moderate physical activity is recommended in IBD patients with clinical remission.

Titin as a potential novel therapeutic target in colorectal cancer.

Colorectal cancer (CRC) is identified as a primary cause of death around the world. The current chemotherapies are not cost-effective. Therefore, finding novel potential therapeutic target is urgent. Titin (TTN) is a muscle protein that is critical in hypertrophic cardiomyopathy. However, its role in CRC is not well understood. The study focused on exploring the possible role of TTN in CRC carcinogenesis. TTN mRNA and protein expression levels presented an obvious downregulation in CRC tissue samples, relative to normal control (p < 0.05). TTN expression significantly correlated with the clinical stage (normal vs. Stage 1, p < 0.05; normal vs. Stage 4, p < 0.05), node metastasis (normal vs. N1, p < 0.05; N1 vs. N2, p < 0.05), histological type (normal vs. adenocarcinoma, p < 0.05), race (Caucasian vs. Asian, p < 0.05; African-American vs. Asian, p < 0.05) and TP53 mutation (normal vs. TP53 mutation, p < 0.05), considering The Cancer Genome Atlas database. However, for patients who had higher TTN expression, the overall survival was remarkably shorter than patients who had low TTN expression. Furthermore, TTN was lowly expressed in four CRC cell lines. TTN overexpression facilitated CRC cells in terms of the proliferation, metastasis and invasion. Based on gene set enrichment analysis, the ERB pathway might be responsible for TTN-related CRC. Besides, TTN was involved in the response to azacitidine. Overall, TTN might serve as a potential novel therapeutic target for treating and overcoming chemotherapy resistance in CRC.

The Novel LncRNA WASH5P Inhibits Colorectal Cancer Carcinogenesis via Targeting AKT Signaling Pathway.

Emerging evidence has shown that long non-coding RNAs (lncRNAs) play an important role in colorectal cancer (CRC) carcinogenesis, so more specific mechanisms of key lncRNAs in CRC initiation and development are needed. Here, we evaluated the expression profiles of lncRNAs in CRC tissues and identified a novel lncRNA generated from the pseudogene Wiskott-Aldrich syndrome protein (WASP) family homolog 5, termed lncRNA WASH5P. However, the role and potential molecular mechanism of this novel lncRNA in diseases, including CRC carcinogenesis, is unknown. Our present study found that WASH5P was significantly downregulated in CRC cell lines and tissues compared with normal controls. The ectopic expression of WASH5P in CRC cells could significantly inhibit CRC cell proliferation, invasion, and migration. In addition, WASH5P could increase the expression of E-cadherin and decrease Vimentin expression. WASH5P-overexpressing CRC cells developed tumors more slowly in different mouse models. Meanwhile, the overexpression of WASH5P could significantly inhibit AKT activation via suppressing AKT phosphorylation. The treatment of PI3K/AKT (phosphatidlinositol 3-kinase /protein kinase B) signaling agonist 740Y-P rescued WASH5P-reduced AKT phosphorylation and abolished the inhibitory effects of WASH5P on cell viability, migration, and invasion. Moreover, 740Y-P restored the WASH5P-induced downregulation of p-AKT and vimentin and the upregulation of E-cadherin via Western blot. In summary, our findings suggested that the novel lncRNA WASH5P might be a potential candidate biomarker and therapeutic target that could inhibit CRC by repressing the AKT signaling pathway.

Status of Gene Methylation and Polymorphism in Different Courses of Ulcerative Colitis and Their Comparison with Sporadic Colorectal Cancer.

BACKGROUND: The objective of this study is to explore the common genetic and epigenetic mechanism of ulcerative colitis (UC) and sporadic colorectal cancer (SCRC) by observing genes methylation level and single nucleotide polymorphisms (SNPs) of different disease courses in UC and SCRC. METHODS: Two hundred subjects were enrolled, including 40 in the healthy control (HC) group, 50 in the short disease course UC group (SUC), 52 in the long disease course UC group (LUC), and 58 in the SCRC group. Methylation-specific polymerase chain reaction was used to detect the methylation of MINT1 and cyclooxygenase 2 (COX-2) gene. Single nucleotide polymorphisms of interleukin (IL)-23R rs10889677 and IL-1ß rs1143627 were detected by Sanger sequencing. RESULTS: Compared with HCs (32.5%), methylation level of MINT1 was significantly increased in SCRC (67.2%; P = 0.001) and was a risk factor for CRC (odds ratio, [OR] 4.26). The methylation ratios of COX-2 were 95.0%, 58.0%, 23.1%, and 24.1% in HC, SUC, LUC, and SCRC, respectively, which were negatively correlated with the disease course of UC (r = -0.290). Hypermethylation of COX-2 was a protective factor for SUC (OR, 0.11), LUC (OR, 0.02), and SCRC (OR, 0.03; P < 0.05). Compared with HCs, rs10889677 allele A was a risk factor for SUC and LUC, and rs1143627 allele T was a protective factor for SUC and LUC. Genotype TT was a protective factor for SUC. CONCLUSION: The hypomethylation of COX-2 gene was a common risk factor and epigenetic modification for UC and SCRC, which might be one of the mechanisms through which UC patients were susceptible to CRC. The hypermethylation of MINT1 was a risk factor for SCRC but not for UC; alleles of IL-23Rrs10889677 and IL-1ßrs1143627 were related to UC but not to SCRC.

Effects of Post-Surgical Parenteral Nutrition on Patients with Gastric Cancer.

BACKGROUND/AIMS: In this study, we investigated the effect of post-surgical parenteral nutrition on patients with gastric cancer (GC) and its possible mechanism. METHODS: A total of 108 patients were invited to assess for eligibility and 28 patients were excluded. The eighty patients were randomized to either a study group (1 L peripheral intravenous nutrition, 700 kcal) or a control group (1 L isotonic electrolyte solution). Parenteral nutrition was started on day 1 post-surgery and maintained for 4-8 days. Levels of albumin (ALB), prealbumin (PAB), hemoglobin (Hb) were measured before and after treatment. Self-rating Scale of Life Quality (SSLQ) and Quality of life (QoL) was assessed to analyze the patients' quality of life. Psychological status was evaluated using both the Hospital Anxiety and Depression Scale (HADS-A/D) and the Patient Health Questionnaire-9 (PHQ-9). Immune function was evaluated by flow cytometric analysis of the levels of CD3+, CD4+, and CD8+ cells. RESULTS: Following post-surgical parenteral nutrition, the levels of ALB, PAB and Hb were significantly higher in the study group than those in the control group. QoL and SSLQ scores were also significantly increased, while HAD-A/D and PHQ-9 scores were significantly reduced. Furthermore, the percentages of CD3+ and CD4+ cells, but not CD8+ cells, as well as the CD4+/CD8+ ratio were significantly increased in the study group. There were no significant differences in these parameters between the control and study group prior to surgery. CONCLUSION: The results suggest that post-surgical parenteral nutrition can significantly improve the nutritional and psychological status, QoL, and immune function of patients treated surgically for GC.

TNF-α inhibits SCF, ghrelin, and substance P expressions through the NF-κB pathway activation in interstitial cells of Cajal.

Ulcerative colitis is a chronic inflammatory disease of the colon where intestinal motility is disturbed. Interstitial cells of Cajal (ICC) are required to maintain normal intestinal motility. In the present study, we assessed the effect of tumor necrosis factor-alpha (TNF-α) on viability and apoptosis of ICC, as well as on the expression of stem cell factor (SCF), ghrelin, and substance P. ICC were derived from the small intestines of Swiss albino mice. Cell viability and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. ELISA was used to measure the concentrations of IL-1ß, IL-6, ghrelin, substance P, and endothelin-1. Quantitative RT-PCR was used to measure the expression of SCF. Western blotting was used to measure the expression of apoptosis-related proteins, interleukins, SCF, and NF-κB signaling pathway proteins. TNF-α induced inflammatory injury in ICC by decreasing cell viability and increasing apoptosis and levels of IL-1ß and IL-6. TNF-α decreased the levels of SCF, ghrelin, and substance P, but had no effect on endothelin-1. TNF-α down-regulated expressions of SCF, ghrelin, and substance P by activating the NF-κB pathway in ICC. In conclusion, TNF-α down-regulated the expressions of SCF, ghrelin, and substance P via the activation of the NF-κB pathway in ICC.

Involvement of NLRP3 inflammasome in the impacts of sodium and potassium on insulin resistance in normotensive Asians.

Salt, promoting oxidative stress, contributes to insulin resistance, whereas K, inhibiting oxidative stress, improves insulin sensitivity. Oxidative stress activation of NLRP3 inflammasome is a central player in the induction of insulin resistance. Therefore, we hypothesised that NLRP3 inflammasome may mediate the effects of salt and K on insulin resistance. In all, fifty normotensive subjects were recruited from a rural community of Northern China. The protocol included a low-salt diet for 7 d, then a high-salt diet for 7 d and a high-salt diet with K supplementation for another 7 d. In addition, THP-1 cells were cultured in different levels of Na with and without K. The results showed that salt loading elevated fasting blood glucose, insulin and C-peptide levels, as well as insulin resistance, whereas K supplementation reversed them. Meanwhile, additional K reversed the active effects of high salt on NLRP3 inflammasome in both the subjects and THP-1 cells, and the change of insulin resistance index notably related with the alteration of plasma IL-1ß, the index of NLRP3 inflammasome activation, during intervention in the subjects. Additional K ameliorated oxidative stress induced by high salt in both the subjects and cultured THP-1 cells, and the change of oxidative stress related with the alteration of plasma IL-1ß during intervention in the subjects. In vitro, antioxidant N-acetyl-l-cysteine significantly prevented the active effects of high Na or oxidant Rosup on NLRP3 inflammasome, so did K. Our study indicates that oxidative stress modulation of NLRP3 inflammasome may be involved in the impacts of Na and K on insulin resistance.

Suppression of TGF-ß1 enhances chemosensitivity of cisplatin-resistant lung cancer cells through the inhibition of drug-resistant proteins.

Cisplatin-based chemotherapy is the first-line treatment for non-small cell lung cancer (NSCLC), but drug resistance occurs in most patients, leading to treatment failure. Recent studies have shown that epithelial-mesenchymal transition (EMT) is associated with drug resistance. However, the underlying mechanism is not entirely clear. In this study, first we showed significant positive correlation between the expression of ERCCl and vimentin, and significant negative correlation between the ERCCl and E-cadherin in the neoadjuvant chemotherapy group and the simple surgery group. Second, we showed that cisplatin-resistant A549 cells (A549/DDP) acquire EMT phenotype with high expression of drug-resistant proteins, P-gp and ERCC1. Knockdown of TGF-ß1 may reverse EMT and significantly reduce the expression of P-gp and ERCC1. Moreover, A549/DDP cells become more sensitive to cisplatin. In summary, our results globally confirm a molecular and phenotypic association between chemoresistance and EMT of resistant tumour cells under a histological and cellular level. More importantly, silence of TGF-ß1 may enhance sensitivity to cisplatin of A549/DDP through inducing the reversal of EMT and inhibiting the expression of resistance-associated proteins. Hence, inhibition of TGF-ß1 could be considered as an effective strategy for eliminating resistant lung cancer.

TNF-α inhibits SCF, ghrelin, and substance P expressions through the NF-κB pathway activation in interstitial cells of Cajal

Ulcerative colitis is a chronic inflammatory disease of the colon where intestinal motility is disturbed. Interstitial cells of Cajal (ICC) are required to maintain normal intestinal motility. In the present study, we assessed the effect of tumor necrosis factor-alpha (TNF-α) on viability and apoptosis of ICC, as well as on the expression of stem cell factor (SCF), ghrelin, and substance P. ICC were derived from the small intestines of Swiss albino mice. Cell viability and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. ELISA was used to measure the concentrations of IL-1β, IL-6, ghrelin, substance P, and endothelin-1. Quantitative RT-PCR was used to measure the expression of SCF. Western blotting was used to measure the expression of apoptosis-related proteins, interleukins, SCF, and NF-κB signaling pathway proteins. TNF-α induced inflammatory injury in ICC by decreasing cell viability and increasing apoptosis and levels of IL-1β and IL-6. TNF-α decreased the levels of SCF, ghrelin, and substance P, but had no effect on endothelin-1. TNF-α down-regulated expressions of SCF, ghrelin, and substance P by activating the NF-κB pathway in ICC. In conclusion, TNF-α down-regulated the expressions of SCF, ghrelin, and substance P via the activation of the NF-κB pathway in ICC.

Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity?

Overweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death. Several epidemiological studies have demonstrated a clear relationship between salt intake and obesity, but the pathophysiologic mechanisms remain unknown. We hypothesized that ghrelin, which regulates appetite, food intake, and fat deposition, becomes elevated when one consumes a high-salt diet, contributing to the progression of obesity. We, therefore, investigated fasting ghrelin concentrations during a high-salt diet. Thirty-eight non-obese and normotensive subjects (aged 25 to 50 years) were selected from a rural community in Northern China. They were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for seven days (3 g/day, NaCl), then a high-salt diet for seven days (18 g/day). The concentration of plasma ghrelin was measured using an immunoenzyme method (ELISA). High-salt intake significantly increased fasting ghrelin levels, which were higher during the high-salt diet (320.7 ± 30.6 pg/mL) than during the low-salt diet (172.9 ± 8.9 pg/mL). The comparison of ghrelin levels between the different salt diets was statistically-significantly different (p < 0.01). A positive correlation between 24-h urinary sodium excretion and fasting ghrelin levels was demonstrated. Our data indicate that a high-salt diet elevates fasting ghrelin in healthy human subjects, which may be a novel underlying mechanism of obesity.

Effect of active Notch signaling system on the early repair of rat sciatic nerve injury.

It is all known that dedifferentiated Schwann cells (SCs) play an important role in neural regeneration, and Notch signaling has complex and extensive regulatory functions in dedifferentiated SCs. So studies have focused on how to improve peripheral nerve repair by regulating proliferation and dedifferentiation in SCs with Notch signaling meloculars.We have found SCs can be activated when adding Recombinant rat jagged1/FC chimera (an activator of the Notch signaling system) in vivo. Compared with that of the control groups, at 4 weeks post-surgery nerve regeneration and functional rehabilitation in the Recombinant rat jagged1/FC chimera group were advanced significantly, and the expression of neurotrophic factors in the regenerated nerves was elevated largely. These results indicated that SCs activated by Notch signaling could promote nerve repair effectively in the early regenerative stage, suggesting the possible clinical application for the treatment of peripheral nerve defects.

High salt intake fails to enhance plasma adiponectin in normotensive salt-sensitive subjects.

OBJECTIVE: Evidence shows that salt can modulate adiponectin and inflammation levels in normal individuals. Therefore, we hypothesized that abnormalities in adiponectin and inflammation might be the potential mechanism of salt sensitivity. The aim of this study was to investigate whether different alterations of adiponectin and inflammation levels in response to a high-salt intake were exhibited between normotensive salt-sensitive and salt-resistant subjects. METHODS: Thirty normotensive subjects (25 to 50 y old) were selected from a rural community of northern China. They were sequentially maintained on a normal diet for 3 d at baseline, a low-salt diet for 7 d (NaCl 3 g/d), and then a high-salt diet for 7 d (18 g/d). RESULTS: Salt sensitivity was diagnosed in 10 subjects who exhibited an increase of at least 10% in mean blood pressure from the low-salt to the high-salt periods. Plasma adiponectin was significantly higher with the high-salt intake than with the low-salt intake (6.1 ± 1.3 versus 7.1 ± 1.7 µg/mL, P = 0.047) in normotensive salt-resistant subjects but not in the normotensive salt-sensitive subjects (6.4 ± 2 versus 5.9 ± 2.1 µg/mL, P = 0.481). The high-salt intake markedly increased plasma tumor necrosis factor-α (P < 0.0001) and monocyte chemoattractant protein-1 (P < 0.0001) in normotensive salt-sensitive and salt-resistant subjects. No significant change in plasma high-sensitivity C-reactive protein was observed. CONCLUSIONS: Our data indicate that the disturbance of adiponectin exists in normotensive salt-sensitive subjects during a high-salt diet, which may be a novel underlying mechanism of salt sensitivity.