Background Pouchitis is the most common long-term complication after restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) for ulcerative colitis (UC) or familial adenomatous polyposis (FAP), which can eventually progress to pouch failure, necessitating permanent stoma construction. Hypoxia-inducible transcription factor prolyl hydroxylase–containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors that control adaptive gene expression through hypoxia-inducible factor (HIF). Emerging evidence supports PHDs as being therapeutic targets in intestinal inflammation. However, pharmacological inhibition of PHDs has not been validated as a treatment strategy in pouchitis. Methods PHD1-3 mRNA and protein expression were analyzed in mucosal pouch and prepouch ileal patient biopsies. After establishment of a preclinical IPAA model in rats, the impact of the pan-PHD small-molecule inhibitor dimethyloxalylglycine (DMOG) on dextran sulfate sodium (DSS)–induced pouchitis was studied. Clinical and molecular parameters were investigated. Results PHD1, but not PHD2 or PHD3, was overexpressed in pouchitis in biopsies of patients with IPAA for UC but not FAP. In addition, PHD1 expression correlated with disease activity. DMOG treatment profoundly mitigated DSS-induced pouchitis in a rodent IPAA model. Mechanistically, DMOG restored intestinal epithelial barrier function by induction of tight junction proteins zona occludens-1 and claudin-1 and alleviation of intestinal epithelial cell apoptosis, thus attenuating pouch inflammation. Conclusions Together, these results establish a strong therapeutic rationale for targeting PHD1 with small-molecule inhibitors in pouchitis after IPAA for UC.

BackgroundThis study aimed to investigate the course of tricuspid annulus dilation in functional tricuspid regurgitation with varied severities by direct intraoperative assessment.MethodsA total of 317 patients who underwent left heart surgery and concomitant tricuspid repair were divided into three groups according to the severity of the functional tricuspid regurgitation (mild, moderate and severe). Demographic and echocardiographic data were collected. The length of each tricuspid annulus segment was measured intraoperatively. The risk factors for preoperative severe functional tricuspid regurgitation and its postoperative recurrence were identified, and the impact of each tricuspid annulus segment on postoperative recurrence was compared.ResultsIn the course of tricuspid annulus dilation, the posterior annulus dilated 17% (group 1: 33.31 ± 6.94 mm vs. group 2: 35.56 ± 7.63 vs. group 3: 38.98 ± 8.70, p < 0.01), the anterior annulus dilated 13.4% (group 1: 36.71 ± 6.30 mm vs. group 2: 38.21 ± 8.35 vs. group 3: 41.63 ± 9.20, p < 0.01), and the septal annulus dilated 11.4% (group 1: 38.11 ± 5.28 mm vs. group 2: 39.76 ± 6.90 vs. group 3: 42.46 ± 7.50, p < 0.01). Tricuspid annulus circumference index (p < 0.01) independently correlated with preoperative severe tricuspid regurgitation and postoperative recurrence. When patients were grouped based on the length of each segment, the septal annulus demonstrated significantly higher sensitivity (p < 0.001) to postoperative recurrence than the anterior (p = 0.085) or posterior annulus (p = 0.262).ConclusionsThis study revealed that each segment of tricuspid annulus could dilate in functional tricuspid regurgitation and highlighted the potential benefits of septal annulus plication in tricuspid annuloplasty, which may aid in the development of a methodology for prosthetic ring annuloplasty.

Background. Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. We sought to investigate the effect of cilengitide on the neovascularization of abdominal aortic plaques in rabbits and explore its underlying antiangiogenic mechanism on human umbilical vein endothelial cells (HUVECs). Materials and Methods. For the in vivo experiment, the abdominal aortic plaque model of rabbits was established and injected with different doses of cilengitide or saline for 14 consecutive days. Conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) were applied to measure the vascular structure and blood flow parameters. CD31 immunofluorescence staining was performed for examining neovascularization. Relative expressions of vascular endothelial growth factor (VEGF) and integrin of the plaque were determined. For in vitro experiments, HUVECs were tested for proliferation, migration, apoptosis, and tube formation in the presence of different doses of cilengitide. Relative expressions of VEGF, integrin, and Ras/ERK/AKT signaling pathways were determined for the exploration of underlying mechanism. Results. CEUS showed modestly increased size and eccentricity index (EI) of plaques in the control group. Different degrees of reduced size and EI of plaques were observed in two cilengitide treatment groups. The expressions of VEGF and integrin in the plaque were inhibited after 14 days of cilengitide treatment. The neovascularization and apoptosis of the abdominal aorta were also significantly alleviated by cilengitide treatment. For in vitro experiments, cilengitide treatment was found to inhibit the proliferation, migration, and tube formation of HUVECs. However, cilengitide did not induce the apoptosis of HUVECs. A higher dose of cilengitide inhibited the mRNA expression of VEGF-A, β3, and β5, but not αV. Lastly, cilengitide treatment significantly inhibited the Ras/ERK/AKT pathway in the HUVECs. Conclusions. This study showed that cilengitide effectively inhibited the growth of plaque size by inhibiting the angiogenesis of the abdominal aortic plaques and blocking the VEGF-mediated angiogenic effect on HUVECs.

BackgroundMyocardial injury is the main manifestation of cardiovascular diseases, and previous studies have shown that propofol (PPF) regulates myocardial injury. However, the mechanism of PPF in regulating myocardial injury remains to be further explored. This work aims to analyze the effects of PPF on human cardiomyocyte injury and the underlying mechanism.MethodsThe regulatory and functional role of PPF and circAPBB2 in human cardiomyocyte injury were analyzed using an in vitro hypoxia/reoxygenation (H/R) cell model, which was established by treating human cardiomyocytes (AC16 cells) with H/R. The study evaluated AC16 cell injury by analyzing cytotoxicity, oxidative stress, inflammation and apoptosis of H/R‐induced AC16 cells. Quantitative real‐time polymerase chain reaction was performed to detect circAPBB2, miR‐18a‐5p and dual specificity phosphatase 14 (DUSP14) expression. Protein expression was analyzed by Western blot analysis assay. Dual‐luciferase reporter assay, RNA pull‐down assay and RNA immunoprecipitation assay were performed to identify the associations among circAPBB2, miR‐18a‐5p and DUSP14. Cytotoxicity was investigated by cell counting kit‐8 assay and lactate dehydrogenase activity detection kit. Oxidative stress was evaluated by cellular reactive oxygen species assay kit and superoxide dismutase activity assay kit. The production of tumor necrosis factor‐α and interleukin‐1β was evaluated by enzyme‐linked immunosorbent assays.ResultsThe expression of circAPBB2 and DUSP14 was significantly decreased, while miR‐18a‐5p was increased in H/R‐induced AC16 cells when compared with controls. H/R treatment‐induced cytotoxicity, oxidative stress, inflammation and cell apoptosis were attenuated after circAPBB2 overexpression or PPF treatment, whereas these effects were restored by increasing miR‐18a‐5p expression. PPF treatment improved the inhibitory effect of ectopic circAPBB2 expression on H/R‐induced cell injury. MiR‐18a‐5p silencing ameliorated H/R‐induced AC16 damage by interacting with DUSP14. Mechanically, circAPBB2 acted as a miR‐18a‐5p sponge, and miR‐18a‐5p targeted DUSP14 in AC16 cells.ConclusionPPF synergized with circAPBB2 to protect AC16 cells against H/R‐induced oxidative stress, inflammation and apoptosis through the miR‐18a‐5p/DUSP14 pathway.