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.

BMAL1-TTK-H2Bub1 loop deficiency contributes to impaired BM-MSC-mediated bone formation in senile osteoporosis.

During the aging process, the reduced osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) results in decreased bone formation, which contributes to senile osteoporosis. Previous studies have confirmed that interrupted circadian rhythm plays an indispensable role in age-related disease. However, the mechanism underlying the impaired osteogenic differentiation of BM-MSCs during aging and its relationship with interrupted circadian rhythm remains unclear. In this study, we confirmed that the circadian rhythm was interrupted in aging mouse skeletal systems. The level of the core rhythm component BMAL1 but not that of CLOCK in the osteoblast lineage was decreased in senile osteoporotic specimens from both human and mouse. BMAL1 targeted TTK as a circadian-controlled gene to phosphorylate MDM2 and regulate H2Bub1 level, while H2Bub1 in turn regulated the expression of BMAL1. The osteogenic capacity of BM-MSCs was maintained by a positive loop formed by BMAL1-TTK-MDM2-H2Bub1. Furthermore, we demonstrated that using bone-targeting recombinant adeno-associated virus 9 (rAAV9) to enhance Bmal1 or Ttk might have a therapeutic effect on senile osteoporosis and delays bone repair in aging mice. In summary, our study indicated that targeting the BMAL1-TTK-MDM2-H2Bub1 axis via bone-targeting rAAV9 might be a promising strategy for the treatment of senile osteoporosis.

Correlation Between Crohn's Disease Activity and Serum Selenium Concentration.

PURPOSE: Accurate and reliable evaluation of Crohn's disease (CD) activity is crucial for monitoring and treating the disease; however, it is challenging. There is a high demand for new, reliable, and noninvasive biomarkers for estimating CD activity. Selenium deficiency is common in patients with CD; however, its correlation with disease severity remains unclear. This study aimed to assess the feasibility of using serum selenium concentration as an additional biomarker for determining the severity of CD. METHODS: This retrospective study included consecutive Asian patients aged 18 to 60 years and hospitalized for CD between May 2020 and December 2020 at the Inflammatory Bowel Disease Center (Hangzhou, China). Patients with a history of extensive small intestinal surgery and/or short bowel syndrome were excluded from analysis. Serum selenium concentration was determined using inductively coupled plasma mass spectrometry. Disease severity was evaluated based on inflammatory markers (simple endoscopic score for CD, CD activity index, Harvey-Bradshaw index, serum C-reactive protein level, erythrocyte sedimentation rate, and platelet count) and markers of nutrition status (body mass index; blood hemoglobin and hematocrit; as well as serum levels of albumin, folic acid, and vitamin D). The correlations between serum selenium level and disease severity-related parameters were analyzed using univariate and multivariate analyses. FINDINGS: The study included 94 men and 41 women. Serum selenium level was significantly and inversely associated with all tested disease activity-related parameters by univariate analysis (all, P < 0.05). Further multivariate analysis showed that the simple endoscopic score for CD and serum levels of albumin and folic acid were significantly and independently correlated with serum selenium level (all, P < 0.05). IMPLICATIONS: Serum selenium concentration was inversely correlated with endoscopic disease severity in these Asian patients with CD. It is feasible to use serum selenium level as an additional biomarker for assessing and monitoring disease activity. The present results might have been influenced by geographic region, sample size, and/or dietary factors. Serum selenium level and other indicators of CD activity measured before and after treatment may provide more useful clinical information.

Minimally invasive perventricular device closure of an isolated perimembranous ventricular septal defect with a newly designed delivery system: preliminary experience.

OBJECTIVE: We sought to summarize the preliminary clinical experience of minimally invasive transthoracic device closure of perimembranous ventricular septal defects with a new delivery system without cardiopulmonary bypass. METHODS: Twenty-one patients aged 11 months to 12 years (median age, 3.6 years) with isolated perimembranous ventricular septal defects underwent minimally invasive device closure with an inferior sternotomy of 3 to 5 cm under transesophageal echocardiographic guidance. A single per-right ventricular U-like suture was established, and a new delivery system was introduced, aided by a 16-gauge trocar, including a guidewire, proper sheath, and loading sheath. The proper size of devices was determined by means of transesophageal echocardiographic analysis, and then the device was released under real-time transesophageal echocardiographic monitoring if no significant aortic regurgitation, abnormal atrioventricular valvular motion, or residual interventricular shunt appeared. RESULTS: All of the defects were successfully closed. No residual shunt, noticeable aortic or tricuspid regurgitation, or significant arrhythmias appeared during more than 5 months of follow-up. CONCLUSION: Minimally invasive transthoracic device closure of perimembranous ventricular septal defects with a new delivery system without cardiopulmonary bypass is feasible and safe under transesophageal echocardiographic guidance. However, it is necessary to evaluate the intermediate and long-term results.

Expression of matrix metalloproteinase-7 involving in growth, invasion, metastasis and angiogenesis of gastric cancer.

OBJECTIVE: To investigate the role of matrix metalloproteinase-7 (MMP-7) expression in caricinogenesis and progression of gastric cancer. METHODS: We studied MMP-7 expression and microvessel density (MVD) in adjacent mucosa and primary foci of 113 cases of gastric cancer by streptavidin-biotin-immunoperoxidase method using anti-MMP-7 and anti-CD34 antibodies. MMP-7 expression and mean MVD were compared with clinicopathological features of gastric cancer, with the relationship between MMP-7 expression and MVD concerned in gastric cancer. RESULTS: MMP-7 showed positive expression in adjacent mucosa of gastric cancer (29.20%, 33/113), less than that in gastric cancer (69.03%, 78/113). MMP-7 expression in primary foci of gastric cancer was positively correlated with tumor size, invasive depth, metastasis and TNM staging (P<0.05), but not with differentiation or growth pattern of gastric cancer (P>0.05). Positive correlation of mean MVD with tumor size, invasive depth, metastasis and TNM staging was found (P<0.05), despite no relationship between mean MVD and differentiation of gastric cancer (P>0.05). Mean MVD was dependent on MMP-7 expression in gastric cancer (P<0.05). CONCLUSION: Upregulated expression of MMP-7 played an important role in carcinogenesis and progression by participating in growth, invasion, metastasis and angiogenesis of gastric cancer. MMP-7 expression could be regarded as an effective and objective marker to reflect the biological behaviors of gastric cancer.