Discovery of novel small-molecule aldehyde dehydrogenase 2 activators based on drug repurposing

Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the detoxification of reactive aldehydes under oxidative stress. Because an estimated 50% of East Asians carry a common ALDH2 deficient variant with decreased enzyme activity and are more susceptible to toxic aldehydes, more recent findings have highlighted the therapeutic potential of ALDH2 activators in aldehyde-related diseases such as cardiovascular injury. Drug repurposing has unique advantages in providing new lead compounds with good drug-like properties. Herein, we identified Tadalafil from DrugBank as a novel ALDH2 activator using a combination strategy of docking-based and pharmacophore-based virtual screening based on exploring the activation mechanism. Then a hit-based substructure search was completed and has led to the discovery of 5 hits, among which A1 showed better ALDH2 activation activity than Tadalafil. This study provides a good basis for the further research of ALDH2 activators

Native T1 Mapping and Magnetization Transfer Imaging in Grading Bowel Fibrosis in Crohn’s Disease: A Comparative Animal Study

In this study, we investigated the utility of native T1 mapping in differentiating between various grades of fibrosis and compared its diagnostic accuracy to magnetization transfer imaging (MTI) in a rat model of CD. Bowel specimens (64) from 46 CD model rats undergoing native T1 mapping and MTI were enrolled. The longitudinal relaxation time (T1 value) and normalized magnetization transfer ratio (MTR) were compared between none-to-mild and moderate-to-severe fibrotic bowel walls confirmed by pathological assessments. The results showed that the correlation between the T1 value and fibrosis (r = 0.438, p < 0.001) was lower than that between the normalized MTR and fibrosis (r = 0.623, p < 0.001). Overall, the T1 values (t = −3.066, p = 0.004) and normalized MTRs (z = 0.081, p < 0.001) in none-to-mild fibrotic bowel walls were lower than those in moderate-to-severe fibrotic bowel walls. The area under the curve (AUC) of the T1 value (AUC = 0.716, p = 0.004) was significantly lower than that of the normalized MTR (AUC = 0.881, p < 0.001) in differentiating moderate-to-severe fibrosis from none-to-mild fibrosis (z = −2.037, p = 0.042). Our results support the view that the T1 value could be a promising imaging biomarker in grading the fibrosis severity of CD. However, the diagnostic performance of native T1 mapping was not superior to MTI

CT Enterography score: a potential predictor for severity assessment of active ulcerative colitis

Abstract Background Evaluate the possibility of CT enterography (CTE) score system as a predictor in assessing active ulcerative colitis (UC) severity. Methods Forty-six patients with active UC with CTE and colonoscopy were enrolled. Based on modified Mayo score, patients were divided into three groups: mild (n = 10), moderate (n = 17) and severe (n = 19). A cumulative CTE score was calculated in each patient and its correlation with modified Mayo score was analyzed. The optimal cutoff values of CTE score were determined by receiver operating characteristic (ROC) curves analysis. Results Significant between-group differences were observed in CTE spectrums of mucosal bubbles, mural stratification, loss of haustration, enlarged mesenteric lymph nodes and engorged mesenteric vessels (P < 0.05). The cumulative CTE scores were significant difference between three groups (CTE score:4.9 ± 2.3, 7.6 ± 2.6, and 10.9 ± 2.0, respectively, P < 0.01). The cumulative CTE score showed a positive correlation with modified Mayo score (r = 0.835, P < 0.05). The optimal cut-off value for CTE score predicting moderate and severe UC was 9.5 (area under the curve [AUC]:0.847, sensitivity:78.9%, specificity:82.4%). Conclusion Disease severity assessment by CTE score demonstrates strong positive correlation with severity established modified Mayo score. CTE score system maybe a potential predictor for active UC severity assessment

Investigation of Pathogenesis of H1N1 Influenza Virus and Swine <i>Streptococcus suis</i> Serotype 2 Co-Infection in Pigs by Microarray Analysis

<div><p>Swine influenza virus and <i>Streptococcus suis</i> are two important contributors to the porcine respiratory disease complex, and both have significant economic impacts. Clinically, influenza virus and <i>Streptococcus suis</i> co-infections in pigs are very common, which often contribute to severe pneumonia and can increase the mortality. However, the co-infection pathogenesis in pigs is unclear. In the present study, co-infection experiments were performed using swine H1N1 influenza virus and <i>Streptococcus suis</i> serotype 2 (SS2). The H1N1-SS2 co-infected pigs exhibited more severe clinical symptoms, serious pathological changes, and robust apoptosis of lungs at 6 days post-infection compared with separate H1N1 and SS2 infections. A comprehensive gene expression profiling using a microarray approach was performed to investigate the global host responses of swine lungs against the swine H1N1 infection, SS2 infection, co-infection, and phosphate-buffered saline control. Results showed 457, 411, and 844 differentially expressed genes in the H1N1, SS2, and H1N1-SS2 groups, respectively, compared with the control. Noticeably, genes associated with the immune, inflammatory, and apoptosis responses were highly overexpressed in the co-infected group. Pathway analysis indicated that the cytokine–cytokine receptor interactions, MAPK, toll-like receptor, complement and coagulation cascades, antigen processing and presentation, and apoptosis pathway were significantly regulated in the co-infected group. However, the genes related to these were less regulated in the separate H1N1 and SS2 infection groups. This observation suggested that a certain level of synergy was induced by H1N1 and SS2 co-infection with significantly stronger inflammatory and apoptosis responses, which may lead to more serious respiratory disease syndrome and pulmonary pathological lesion.</p></div

Characterization of the differential expression of genes.

<p>(A) Categories of genes based on biological process GO term in each group. Only the top20 terms based on the gene numbers are showed. (B) Clustered pathways of the DE genes by KEGG analysis. Only the pathways containing more genes are presented. Many categories shared the same genes.</p

Clinical Outcome of Day-3 Cleavage Slow-Growing Embryos at Different Cleavage Rates after Overnight Culture: A Cohort Retrospective Study

Introduction: We explored the association between clinical outcomes and the cleavage rate of day-3 cleavage slow-growing embryos after overnight culture. Methods: The data collected from 303 frozen embryo transfer (FET) cycles with 606 4-cell or 5-cell embryos cultured overnight (18&ndash;22 h) after thawing were analyzed. Based on the growth rate after the overnight culture, the embryos were divided into three groups: no embryo reaching eight cells (Group I), either one of the two embryos reaching eight cells (Group II), and both two embryos reaching eight cells or more (Group III). A statistical analysis of the different clinical outcomes from the three groups was performed. Results: Biochemical pregnancy rate (OR 3.22; p = 0.001), implantation rate (OR 2.44; p = 0.002), clinical pregnancy rate (OR 3.04; p = 0.001), ongoing pregnancy rate (OR 3.14; p = 0.001), and live birth rate (OR 2.78; p = 0.004) were significantly higher in Group III as compared to Group I. Group II had a significantly higher biochemical pregnancy rate (OR 2.02; p = 0.013) and implantation rate (OR 1.77; p = 0.019) than Group I. Conclusions: The capability of day-3 cleavage slow-growing embryos to reach eight cells, especially that of two embryos reaching eight cells by overnight culture, appear to result in a better pregnancy outcome