[Association of ITGA4 and ICAM-1 gene polymorphisms with the risk and clinicopathological characteristics of Crohn's disease].

OBJECTIVE: To assess the association between the polymorphism of integral protein α4 (ITGA4) and intercellular adhesion molecule 1 (ICAM-1) genes and the risk and clinicopathological characteristics of Crohn's disease (CD) among Chinese patients. METHODS: From January 2010 to January 2021, a total of 215 CD patients and 529 gender- and age-matched healthy controls were enrolled from the Second Affiliated Hospital of Wenzhou Medical University as the study subjects. Genotypes of ITGA4 (rs6740847, rs7562325) and ICAM-1 (rs5498) were determined by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Harvey-Bradshaw Index (HBI) was applied to assess the disease activity of CD, and the patients were further divided into subgroups based on the Montreal Classification Criteria of CD. Unconditional logistic regression was employed to analyze the distribution of ITGA4 (rs6740847, rs7562325) and ICAM-1 (rs5498) polymorphisms between the patients and healthy controls and their association with the clinicopathological characteristics of the patients. RESULTS: The frequencies of T allele and CT+TT genotypes of ITGA4 (rs7562325) were higher in CD patients than the healthy controls (40.70% vs. 31.57%, P = 0.001; 62.79% vs. 54.36%, P = 0.042). The G variant and AG+GG genotypes of ITGA4 (rs6740847) were less common in patients with moderately to severely active CD compared with those with mildly active CD (31.18% vs. 51.72%, P = 0.002; 55.91% vs. 75.86%, P = 0.042). However, the opposite conclusion was drawn for the G allele (G) and AG+GG genotypes of ICAM-1 (rs5498) (31.45% vs. 17.24%, P = 0.027; 54.30% vs. 31.04%, P = 0.020). Compared with patients with terminal ileal or ileocolic CD, G allele and AG+GG genotypes of ITGA4 (rs6740847) were more prevalent in patients with colonic CD (55.26% vs. 29.38%, P < 0.001; 84.21% vs. 53.11%, P<0.001). The same conclusion could also be drawn for the G allele and AG+GG genotypes of ICAM-1 (rs5498) (42.11% vs. 26.84%, P = 0.008; 73.69% vs. 46.33%, P = 0.002). The frequency of homozygous GG genotype of ICAM-1 (rs5498) was lower in patients with stricturing and penetrating CD than those with non-stricturing and non-penetrating CD (0.00% vs. 12.32%, P = 0.001). The G allele and AG+GG genotypes of the ITGA4 (rs6740847) were more common in patients with perianal lesions than those without (40.28% vs. 30.77%, P = 0.049; 72.22% vs. 51.75%, P = 0.004). CONCLUSION: Variants of the ITGA4 (rs7562325) may be a risk factor for CD, whilst those of the ITGA4 (rs6740847) may be associated with the decline of disease activity and risk for colon involvement and perianal lesions. Variants of the ICAM-1 (rs5498) may increase the risk of disease activity and colonic involvement in CD patients, however, it may be a protective factor for stenosis and penetration. In addition, variants of the ITGA4 (rs6740847) and ICAM-1 (rs5498) may be associated with the early onset of CD.

Sec1 regulates intestinal mucosal immunity in a mouse model of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a common immune-mediated condition with its molecular pathogenesis remaining to be fully elucidated. This study aimed to deepen our understanding of the role of FUT2 in human IBD, by studying a new surrogate gene Sec1, a neighboring gene of Fut2 and Fut1 that co-encodes the α 1,2 fucosyltransferase in mice. CRISPR/Cas9 was used to prepare Sec1 knockout (Sec1-/-) mice. IBD was induced in mice using 3% w/v dextran sulphate sodium. Small interfering RNA (siRNA) was employed to silence Sec1 in murine colon cancer cell lines CT26.WT and CMT93. IBD-related symptoms, colonic immune responses, proliferation and apoptosis of colon epithelial cells were assessed respectively to determine the role of Sec1 in mouse IBD. Impact of Sec1 on the expression of death receptor 5 (DR5) and other apoptosis-associated proteins were determined. Sec1 knockout was found to be associated with deterioration of IBD in mice and elevated immune responses in the colonic mucosa. Silencing Sec1 in CT26.WT and CMT93 cells led to greater secretion of inflammatory cytokines IL-1ß, IL-6 and TNF-α. Cell counting kit 8 (CCK8) assay, flow cytometry and TUNEL detection suggested that Sec1 expression promoted the proliferation of colon epithelial cells, inhibited cell apoptosis, reduced cell arrest in G0/G1 phase and facilitated repair of inflammatory injury. Over-expression of DR5 and several apoptosis-related effector proteins was noticed in Sec1-/- mice and Sec1-silenced CT26.WT and CMT93 cells, supporting a suppressive role of Sec1 in cell apoptosis. Our results depicted important regulatory roles of Sec1 in mouse IBD, further reflecting the importance of FUT2 in the pathogenesis of human IBD.

Phloroglucinol derivatives with α-glucosidase inhibitory activities from Syzygium fluviatile.

Four new phloroglucinol derivatives (1 - 4) were isolated from the leaves of Syzygium fluviatile. Their structures were elucidated by means of extensive spectroscopic data. Among them, compounds 1 and 3 showed significant inhibitory activity against α-glucosidase with IC50 values of 10.60 and 5.07 µM, respectively. The structure-activity relationship was also discussed briefly.

Ameliorative effects of different doses of selenium against fluoride-triggered apoptosis and oxidative stress-mediated renal injury in rats through the activation of Nrf2/HO-1/NQO1 signaling pathway.

Excess fluoride (F) exposure can cause oxidative stress in the kidney. As an antioxidant, selenium (Se) can potentially protect the kidney from F-induced injury in rats. Hence, the histopathological, renal biochemical, oxidative stress, and apoptotic-related indices upon exposure to 100 mg/L sodium fluoride (NaF) and various doses of sodium selenite (Na2SeO3; 0.5, 1, and 2 mg/L) were assessed. Our results demonstrated that F-mediated renal structural damage and apoptosis elevated the content of serum creatinine (SCr), inhibited the activity of catalase (CAT) in serum, and increased the production of reactive oxygen species (ROS) in kidney and malondialdehyde (MDA) in serum. Interestingly, 1 mg/L dietary supplementation of Se tangibly mitigated these injuries. Furthermore, F could also change the gene and protein expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase1 (NQO1). Concomitantly, the different concentrations of Se notably alleviated their expression. Taken together, 1-2 mg/L Se ameliorated F-induced renal injury through oxidative stress and apoptosis-related routes. The recorded ameliorative effects might be related to the activation of the Nrf2/HO-1/NQO1 signaling pathway.

Linc00852 from cisplatin-resistant gastric cancer cell-derived exosomes regulates COMMD7 to promote cisplatin resistance of recipient cells through microRNA-514a-5p.

OBJECTIVE: Cisplatin (DDP)-based chemotherapy is commonly referred to as advanced gastric cancer (GC). The purpose of this study was to unravel whether Linc00852 from DDP-resistant tumor cell-derived exosomes (Exos) promotes DDP resistance of GC cells. METHODS: Reverse transcription quantitative polymerase chain reaction was used to detect the expression of Linc00852, miR-514a-5p, COMM domain protein 7 (COMMD7) mRNA, Bax mRNA, and Bcl-2 mRNA. Western blot was used to measure the expression of COMMD7 protein. The IC50 value of DDP is determined by MTT assay. The cell proliferation ability was measured by colony formation test. The apoptosis ability was measured by flow cytometry. The interaction between Linc00852, miR-514a-5p, and COMMD7 was confirmed by luciferase reporter gene assay and RNA pull-down assay. Xenograft tumor model was used to study the effect of Linc00852 on DDP resistance in vivo. RESULTS: Linc00852 was up-regulated in DDP-resistant GC cells and their secreted exosomes. Down-regulating Linc00852 facilitated the sensitivity of DDP-resistant GC cells to DDP. Linc00852 bound to miR-514a-5p and COMMD7 was a target of miR-514a-5p. Linc00852 could regulate COMMD7 expression via targeting miR-514a-5p. Exosomes from DDP-resistant GC cells enhanced the resistance of recipient GC cells to DDP via exosomal delivery of Linc00852. Depletion of Linc00852 repressed the growth and DDP resistance of GC cells in vivo. CONCLUSION: Linc00852 from DDP-resistant tumor cell-derived Exos regulates COMMD7 to promote drug resistance of GC cells through miR-514a-5p.