The major brassinosteroid (BR) receptor of Arabidopsis BRASSINOSTEROID INSENSITIVE1 (BRI1) plays fundamental roles in BR signaling, but the molecular mechanisms underlying the effects of BR on BRI1 internalization and assembly state remain unclear. Here, we applied variable angle total internal reflection fluorescence microscopy and fluorescence cross-correlation spectroscopy to analyze the dynamics of GFP-tagged BRI1. We found that, in response to BR, the degree of co-localization of BRI1-GFP with AtFlot1-mCherry increased, and especially BR stimulated the membrane microdomain-associated pathway of BRI1 internalization. We also verified these observations in endocytosis-defective chc2-1 mutants and the AtFlot1 amiRNA 15-5 lines. Furthermore, examination of the phosphorylation status of bri1-EMS-suppressor 1 and measurement of BR-responsive gene expression revealed that membrane microdomains affect BR signaling. These results suggest that BR promotes the partitioning of BRI1 into functional membrane microdomains to activate BR signaling.
BackgroundDiabetic complications may be associated with impaired time-dependent glycemic control. Therefore, long-term glycemic variability, assessed by variations in haemoglobin A1c (HbA1c), may be a potential risk factor for microvascular complications, such as diabetic peripheral neuropathy (DPN). We investigated the association of HbA1c variability with DPN in patients with type 2 diabetes.MethodsIn this cross-sectional study, 563 type 2 diabetic patients who had been screened for DPN and undergone quarterly HbA1c measurements during the year preceding enrolment were recruited. DPN was confirmed in patients displaying both clinical manifestations of neuropathy and abnormalities in a nerve conduction evaluation. HbA1c variability was assessed by the coefficient of variation of HbA1c (CV-HbA1c), and the mean of HbA1c (M-HbA1c) was calculated. In addition, medical history and clinical data were collected.ResultsAmong the recruited patients, 18.1% (n = 102) were found to have DPN, and these patients also presented with a higher CV-HbA1c than the patients without DPN (p < 0.001). The proportion of patients with DPN increased significantly from 6.9% in the first to 19.1% in the second and 28.5% in the third tertile of CV-HbA1c (p for trend < 0.001). After adjusting for initial HbA1c, M-HbA1c and other clinical factors via multiple logistic regression analysis, the odds ratios (ORs) for DPN in the second and third versus those in the first CV-HbA1c tertile were 3.61 (95% CI 1.62–8.04) and 6.48 (2.86–14.72), respectively. The area under the receiver operating characteristic (ROC) curve of CV-HbA1c was larger than that of M-HbA1c, at 0.711 (95% CI 0.659–0.763) and 0.662 (0.604–0.721), respectively. ROC analysis also revealed that the optimal cutoff value of CV-HbA1c to indicate DPN was 15.15%, and its corresponding sensitivity and specificity were 66.67% and 65.73%, respectively.ConclusionsIncreased HbA1c variability is closely associated with DPN in type 2 diabetic patients and could be considered as a potent indicator for DPN in these patients.
Dysplasia is a histologic precursor of esophageal squamous cell carcinoma (SCC). We previously showed that dietary freeze-dried, or lyophilized, strawberry powder inhibits N-nitrosomethylbenzylamine-induced SCC in the rat esophagus. On the basis of this observation, we conducted a randomized (noncomparative) phase II trial in China to investigate the effects of two doses of freeze-dried strawberries in patients with esophageal dysplastic lesions in a high-risk area for esophageal cancer. We randomly assigned 75 patients identified by endoscopy to have dysplastic esophageal premalignant lesions to receive freeze-dried strawberry powder at either 30 g/d (37 patients) or 60 g/d (38 patients) for six months; the powder was mixed with water and drunk. After six months, we assessed the changes in histologic grade of these lesions (primary endpoint) in a blinded fashion. The dose of 30 g/d, did not significantly affect histology or any other measured parameter. The dose of 60 g/d, however, reduced the histologic grade of dysplastic premalignant lesions in 29 (80.6%) of the 36 patients at this dose who were evaluated for histology (P < 0.0001). The strawberry powder was well tolerated, with no toxic effects or serious adverse events. Strawberries (60 g/d) also reduced protein expression levels of inducible nitric oxide synthase (iNOS) by 79.5% (P < 0.001), cyclooxygenase-2 (COX-2) by 62.9% (P < 0.001), phospho-nuclear factor kappa B (NFκB)-p65 (pNFκB-p65) by 62.6% (P < 0.001), and phospho-S6 (pS6) by 73.2% (P < 0.001). Freeze-dried strawberries (60 g/d) also significantly inhibited the Ki-67 labeling index by 37.9% (P = 0.023). Our present results indicate the potential of freeze-dried strawberry powder for preventing human esophageal cancer, supporting further clinical testing of this natural agent in this setting.
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