Dysregulation of the ubiquitin-proteasomal system (UPS) enables pathogenic accumulation of disease-driving proteins in neurons across a host of neurological disorders. However, whether and how the ...UPS contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI) remains undefined. Here we show that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates oligodendrocyte differentiation during development. Using proteomic analysis of the Daam2-VHL complex coupled with conditional genetic knockout mouse models, we further discovered that the E3 ubiquitin ligase
is required for developmental myelination through stabilization of VHL via K63-linked ubiquitination. Furthermore, studies in mouse demyelination models and white matter lesions from patients with multiple sclerosis corroborate the function of this pathway during remyelination after WMI. Overall, these studies provide evidence that a signaling axis involving key UPS components contributes to oligodendrocyte development and repair and reveal a new role for
in glial biology.
Gastric carcinoma is one of the most common cancers and lethal malignancies worldwide. Thus far, the regulatory mechanisms of its aggressiveness are still poorly understood. To understand the ...pathogenesis and to develop new therapeutic strategies, it is essential to dissect the molecular mechanisms that regulate progression of gastric cancer. Herein, we sought to address whether Notch1 signal pathway is involved in the control of progression in gastric cancer. We found that expression of Notch ligand Jagged1 was correlated with aggressiveness of human gastric cancer. Patients with Jagged1 expression in gastric cancer tissues had a poor survival rate compared with those without Jagged1 expression. The Notch1 receptor intracellular domain (N1IC), the activated form of Notch1 receptor, promoted the colony-forming ability and xenografted tumor growth of human stomach adenocarcinoma SC-M1 cells. Migration and invasion abilities of SC-M1 cells were enhanced by N1IC. Furthermore, N1IC and C promoter-binding factor 1 (CBF1) bound to cyclooxygenase-2 (COX-2) promoter and elevated COX-2 expression in SC-M1 cells through a CBF1-dependent manner. The colony-forming, migration, and invasion abilities enhanced by N1IC were suppressed in SC-M1 cells after treatment with the COX-2 inhibitor NS-398 or knockdown of COX-2. These cellular processes inhibited by Notch1 knockdown were restored by prostaglandin E(2) or exogenous COX-2. Taken together, these results suggest that activation of Notch1 signal pathway promotes progression of gastric cancer, at least in part through COX-2.
Histone deacetylase 6 (HDAC6) uniquely serves as a tumor suppressor in hepatocellular carcinogenesis, but the underlying mechanisms leading to tumor suppression are not fully understood. To identify ...comprehensive microRNAs (miRNAs) regulated by HDAC6 in hepatocellular carcinogenesis, differential miRNA expression analysis of HDAC6‐transfected Hep3B cells was performed. Using integrative analyses of publicly available transcriptome data and miRNA target prediction, we selected five candidate miRNAs and, through in vitro functional validation, showed that let‐7i‐5p specifically suppressed thrombospondin‐1 (TSP1) in hepatocellular carcinoma (HCC). Ectopic expression of antisense let‐7i‐5p (AS‐let‐7i‐5p) inhibited in vitro tumorigenesis of HCC cells. In addition, treatments of partially purified TSP1 from culture cell media (ppTSP1) and recombinant TSP1 (rTSP1) exhibited similar effects with AS‐let‐7i‐5p treatment on the same HCC cells, whereas TSP1 neutralizing antibody treatment significantly attenuated these effects. Notably, treatments of HDAC6 plasmid, AS‐let‐7i‐5p, ppTSP1, and rTSP1 significantly suppressed in vitro angiogenesis and metastatic potential of HCC cells, but the co‐treatment of TSP1 antibody specific to cluster of differentiation 47 (CD47) binding domain successfully blocked these effects in the same cells. Furthermore, we demonstrated that recovery of HDAC6 elicited let‐7i‐5p suppression to de‐repress TSP1 expression; therefore, it occupied the CD47 receptor to block CD47‐SIRPα‐mediated anti‐phagocytosis of macrophage in HCC. We also observed that HCC‐derived exosomal let‐7i‐5p suppressed TSP1 of recipient hepatocyte cells. Treatments of HDAC6 plasmid, AS‐let‐7i‐5p, and rTSP1 suppressed tumor incidence as well as tumor growth rates in a spontaneous mouse HCC model. Conclusion: Our findings suggest that the HDAC6–let‐7i‐5p–TSP1 regulatory pathway suppresses neoplastic and antiphagocytic behaviors of HCC by interacting with cell surface receptor CD47 in HCC and neighboring cells of tumor microenvironment, providing a therapeutic target for the treatment of liver malignancy and metastasis.
Proton pump inhibitors (PPIs) have been reported to increase the risk of acute and chronic renal disease. However, the data are unclear in patients with acute kidney injury (AKI) requiring dialysis ...(AKI‐D) who are often candidates for PPIs. To investigate this important issue, we identified 26,052 AKI‐D patients from Taiwan’s National Health Insurance Research Database weaning from dialysis. During a mean follow‐up period of 3.52 years, the PPI users had a higher incidence of end‐stage renal disease (ESRD) than the PPI nonusers (P < 0.001). After propensity score matching and treating mortality as a competing risk factor, the PPI users had a higher risk of ESRD (subhazard ratio (sHR) 1.40; 95% confidence interval (CI), 1.31–1.50) and major adverse cardiac events (MACE, sHR 1.53; 95% CI, 1.37–1.71) compared with the PPI nonusers with AKI‐D survivors. In conclusion, the use of PPIs was associated with a higher risk of ESRD and MACE, compared with the PPI nonusers in AKI‐D patients who weaned from dialysis.
The world is aging, and hemophilia patients are as well. The association between patients with hemophilia (PWH) and low bone mineral density is clear. However, the incidence of fractures in patients ...with hemophilia is inconclusive, and no research has yet explored repeated fractures among PWH. In this study, we investigated the incidence of all-site fractures, repeated fractures and osteoporotic fractures amongst PWH. The study compared the incidence of all-site fractures, repeated fractures and osteoporotic fractures occurring in all PWH who were enrolled in Taiwan's National Health Insurance Research Database between 1997 and 2013 with an age- and gender-matched group from the general population. Eight-hundred thirty-two PWH, along with 8320 members of the general population, were included in the final analysis. After multivariate COX regression analysis with an adjustment for confounding factors, it was found that PWH experienced a higher risk of osteoporotic fracture (HR: 1.25 with 95% CI of 1.03-2.52) but only saw a neutral effect with regards to both all-sites of fracture (HR: 1.00 with 95% CI of 0.92-1.09) and repeated fractures (HR: 1.01 with 95% CI of 0.92-1.10), when compared with the general population. This 14-year population-based cohort study showed that PWH had a higher risk of osteoporotic fracture, but that hemophilia only had a neutral effect in all-sites of fracture and repeated fractures. Screening, prevention and treatment for osteoporosis and further osteoporotic fractures among PWH, in order to improve quality of life and achieve healthy aging in this particular population, remain essential.
In tomato cultivation, a rare natural mutation in the flowering repressor antiflorigen gene SELF-PRUNING (sp-classic) induces precocious shoot termination and is the foundation in determinate tomato ...breeding for open field production. Heterozygous single flower truss (sft) mutants in the florigen SFT gene in the background of sp-classic provide a heterosis-like effect by delaying shoot termination, suggesting the subtle suppression of determinacy by genetic modification of the florigen–antiflorigen balance could improve yield. Here, we isolated three new sp alleles from the tomato germplasm that show modified determinate growth compared to sp-classic, including one allele that mimics the effect of sft heterozygosity. Two deletion alleles eliminated functional transcripts and showed similar shoot termination, determinate growth, and yields as sp-classic. In contrast, amino acid substitution allele sp-5732 showed semi-determinate growth with more leaves and sympodial shoots on all shoots. This translated to greater yield compared to the other stronger alleles by up to 42%. Transcriptome profiling of axillary (sympodial) shoot meristems (SYM) from sp-classic and wild type plants revealed six mis-regulated genes related to the floral transition, which were used as biomarkers to show that the maturation of SYMs in the weaker sp-5732 genotype is delayed compared to sp-classic, consistent with delayed shoot termination and semi-determinate growth. Assessing sp allele frequencies from over 500 accessions indicated that one of the strong sp alleles (sp-2798) arose in early breeding cultivars but was not selected. The newly discovered sp alleles are potentially valuable resources to quantitatively manipulate shoot growth and yield in determinate breeding programs, with sp-5732 providing an opportunity to develop semi-determinate field varieties with higher yields.
Endoscopic submucosal dissection is minimal invasive endoscopic procedure to deal with gastric tumor. Initially, it was developed to resect mucosal neoplasm since 2000 and extended its application to ...submucosal tumor in the following years. Although the basic ESD skills are similar in gastric mucosal tumor and subepithelial tumor, the success rate, complication may be different between the two types of gastric tumor resection. This retrospective study is conducted to analyze the ESD procedure in gastric mucosal tumor and subepithelial tumor.
From 2007 to 2016, we reviewed all patients who underwent endoscopic submucosal dissection for gastric mucosal tumor and subepithelial tumor in Kaohsiung Medical University Hospital.
Totally, 35 patients with gastric subepithelial tumor and 41 patients with gastric mucosal tumor received endoscopic submucosal dissection are enrolled. Among 35 patients with subepithelial tumor, 32 (91.4%) patients achieved curative treatment. 1 patient received emergent operation and 2 patients received salvage operation to complete tumor resection. 8 patients (22.9%) occurred perforation and no delay bleeding was found. Among 41 patients with mucosal neoplasm, 30 (71.4%) patients achieved curative treatment. 2 patients received emergent operation and 9 patients received salvage operation to complete tumor resection. 9 patients (21.9%) occurred complication, 6 patients occurred delay bleeding and 3 patients had perforation.
Comparing ESD between gastric mucosal tumor and subepithelial tumor, ESD had similar efficiency in curative treatment. However, ESD in subepethelial tumor encountered higher perforation and lesser delay bleeding.
Limited evidence concerns fine particulate matter (with aerodynamic diameter ≤ 2.5μm PM2.5) exposure and the risk for kidney failure with replacement therapy (KFRT). This study assessed whether PM2.5 ...exposure was associated with progression of chronic kidney disease (CKD) to KFRT.
Prospective cohort study.
6,628 adult patients with CKD were recruited from the Advanced CKD Program in Taiwan between 2003 and 2015.
Satellite-based spatiotemporal models were used to calculate each individual’s 1-year PM2.5 exposure before the date of enrollment into the Advanced CKD Program.
Time to KFRT (defined as initiation of maintenance hemodialysis, peritoneal dialysis, or kidney transplantation) and time to all-cause mortality.
Multivariable proportional hazard regression analyses were used to estimate the association of PM2.5 with KFRT and all-cause mortality. Restricted cubic splines were used to explore dose-response relationships.
The study population included 6,628 adult patients with CKD who were aged 20 to 90 years. 941 KFRT events and 1,653 deaths occurred during follow-up. The adjusted HR for progression to KFRT was 1.19 (95% CI, 1.08-1.31) per 7.8μg/m3 greater PM2.5, an amount spanning the interquartile range. There was evidence of a dose-response relationship (adjusted HRs of 1.16 95% CI, 0.90-1.51, 1.19 95% CI, 0.94-1.52, and 1.42 95% CI, 1.12-1.80 for low, medium, and high PM2.5 levels). There was no significant association between PM2.5 and all-cause mortality (adjusted HR, 1.01 95% CI, 0.95-1.08).
Misclassification of PM2.5 exposure assessment and the potential for residual confounding.
Our findings suggest that long-term exposure to PM2.5 is associated with increased risk for progression to KFRT in patients with CKD.
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Here, we present a mouse brain protein atlas that covers 17 surgically distinct neuroanatomical regions of the adult mouse brain, each less than 1 mm3 in size. The protein expression levels are ...determined for 6,500 to 7,500 gene protein products from each region and over 12,000 gene protein products for the entire brain, documenting the physiological repertoire of mouse brain proteins in an anatomically resolved and comprehensive manner. We explored the utility of our spatially defined protein profiling methods in a mouse model of Parkinson's disease. We compared the proteome from a vulnerable region (substantia nigra pars compacta) of wild type and parkinsonian mice with that of an adjacent, less vulnerable, region (ventral tegmental area) and identified several proteins that exhibited both spatiotemporal- and genotype-restricted changes. We validated the most robustly altered proteins using an alternative profiling method and found that these modifications may highlight potential new pathways for future studies. This proteomic atlas is a valuable resource that offers a practical framework for investigating the molecular intricacies of normal brain function as well as regional vulnerability in neurological diseases. All of the mouse regional proteome profiling data are published on line at http://mbpa.bprc.ac.cn/.
Endoscopic submucosal dissection (ESD) is a minimally invasive endoscopic procedure to deal with local early esophageal neoplasm, although post-ESD esophageal stricture is a major delayed ...complication of esophageal ESD greatly influencing the patient's quality of life. This retrospective study was conducted to analyze the esophageal stricture after esophageal ESD while determining further treatment and outcome of stricture management.
From 2009 to 2021, we reviewed all patients who underwent ESD for esophageal squamous cell neoplasia in Kaohsiung Medical University Hospital.
Totally, 133 patients with esophageal squamous cell neoplasm were enrolled. Among these 133 patients, 108 patients had lesions less than three-fourths in circumferential and 25 patients had lesions in excess of three-fourths circumferentially. Totally, 18 patients (13.5%) had symptomatic esophageal stricture and 17 patients (94.4%) had stricture existing over the upper or middle esophagus. The most important risk factor of esophageal stricture was the extent of resection of esophageal circumference, especially whole circumferential resection. Although oral steroid prevention medication was prescribed for high-risk patients with lesions more than three-fourth circumferential ESD, the stricture rate was still up to 40% (10/25). Endoscopic/luminal management with balloon dilation, radial incision and self-bougination achieved 83% (15/18) symptom remission. Three patients received surgical intervention with esophagectomy or jejunostomy.
Esophageal stricture is frequently encountered in esophageal ESD. Aggressive preventative strategy is warranted for the high-risk group. Endoscopy/luminal management has high efficacy for post-ESD esophageal stricture.
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