Do matrix metalloproteinase and cathepsin K inhibitors work synergistically to reduce dentin erosion?

Objectives: To evaluate the effects of matrix metalloproteinase (MMP) and cathepsin K (catK) inhibitors on resistance to dentin erosion. Methodology: A total of 96 dentin specimens (3×3×2 mm) were prepared and randomly assigned into four groups (n=24): deionized water (DW); 1 µM odanacatib (ODN, catK inhibitor); 1 mM 1,10-phenanthroline (PHEN, MMP inhibitor); and 1 µM odanacatib + 1 mM 1,10-phenanthroline (COM). Each group was further divided into two subgroups for the application of treatment solutions before (PRE) and after erosive challenges (POST). All specimens were subjected to four daily erosive challenges for 5 d. For each erosive challenge, the specimens in subgroup PRE were immersed in the respective solutions before cola drinks, while the specimens in subgroup POST were immersed in the respective solutions after cola drinks (the immersion duration was 5 min in both cases). All specimens were stored in artificial saliva at 37°C between erosive challenges. The erosive dentin loss (EDL) was measured by profilometry. The residual demineralized organic matrix (DOM) of specimens was removed using type VII collagenase and evaluated by profilometry. Both the EDL and thickness of the residual DOM were statistically analyzed by two-way analysis of variance (ANOVA) and Bonferroni’s test (α=0.05). The surface topography and transverse sections of the specimens were observed using SEM. MMPs and catK were immunolabeled in the eroded dentin and in situ zymography was performed to evaluate the enzyme activity. Results: Significantly lower EDL was found in the groups ODN, PHEN, and COM than in the control group (all p<0.05), while no significant difference in EDL was found among the groups ODN, PHEN, and COM (all p>0.05). The application sequence showed no significant effect on the EDL of the tested groups (p=0.310). A significantly thicker DOM was observed in the group ODN than in the control group regardless of the application sequence (both p<0.05). The treatment with ODN, PHEN, and COM inhibited the gelatinolytic activity by approximately 46.32%, 58.6%, and 74.56%, respectively. Conclusions: The inhibition of endogenous dentinal MMPs and catK increases the acid resistance of human dentin but without an apparent synergistic effect. The inhibition of MMPs and catK is equally effective either before or after the acid challenge

Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitus

Leucine may function as a signaling molecule to regulate metabolism. We have previously shown that dietary leucine supplementation significantly improves glucose and energy metabolism in diet-induced obese mice, suggesting that leucine supplementation could potentially be a useful adjuvant therapy for obesity and type 2 diabetes. Since the underlying cause for obesity and type 2 diabetes is multifold, we further investigated metabolic effects of leucine supplementation in obese/diabetes mouse models with different etiologies, and explored the underlying molecular mechanisms. Leucine supplementation was carried out in NONcNZO10/LtJ (RCS10) - a polygenic model predisposed to beta cell failure and type 2 diabetes, and in B6.Cg-Ay/J (Aʸ) - a monogenic model for impaired central melanocortin receptor signaling, obesity, and severe insulin resistance. Mice in the treatment group received the drinking water containing 1.5% leucine for up to 8 months; control mice received the tap water. Body weight, body composition, blood HbA1c levels, and plasma glucose and insulin levels were monitored throughout and/or at the end of the study period. Indirect calorimetry, skeletal muscle gene expression, and adipose tissue inflammation were also assessed in Aʸ mice. Leucine supplementation significantly reduced HbA1c levels throughout the study period in both RCS10 and Aʸ mice. However, the treatment had no long term effect on body weight or adiposity. The improvement in glycemic control was associated with an increased insulin response to food challenge in RCS10 mice and decreased plasma insulin levels in Aʸ mice. In leucine-treated Aʸ mice, energy expenditure was increased by ~10% (p < 0.05) in both dark and light cycles while the physical activity level was unchanged. The expression levels of UCP3, CrAT, PPAR-alpha, and NRF-1, which are known to regulate mitochondrial oxidative function, were significantly increased in the soleus muscle of leucine-treated Ay mice whereas the expression levels of MCP-1 and TNF-alpha and macrophage infiltration in adipose tissue were significantly reduced. Chronic leucine supplementation significantly improves glycemic control in multiple mouse models of obesity and diabetes with distinct etiologies. The metabolic benefits of leucine supplementation are likely mediated via multiple mechanisms in different tissues, but are not necessarily dependent of weight reduction

LightBTSeg: A lightweight breast tumor segmentation model using ultrasound images via dual-path joint knowledge distillation

The accurate segmentation of breast tumors is an important prerequisite for lesion detection, which has significant clinical value for breast tumor research. The mainstream deep learning-based methods have achieved a breakthrough. However, these high-performance segmentation methods are formidable to implement in clinical scenarios since they always embrace high computation complexity, massive parameters, slow inference speed, and huge memory consumption. To tackle this problem, we propose LightBTSeg, a dual-path joint knowledge distillation framework, for lightweight breast tumor segmentation. Concretely, we design a double-teacher model to represent the fine-grained feature of breast ultrasound according to different semantic feature realignments of benign and malignant breast tumors. Specifically, we leverage the bottleneck architecture to reconstruct the original Attention U-Net. It is regarded as a lightweight student model named Simplified U-Net. Then, the prior knowledge of benign and malignant categories is utilized to design the teacher network combined dual-path joint knowledge distillation, which distills the knowledge from cumbersome benign and malignant teachers to a lightweight student model. Extensive experiments conducted on breast ultrasound images (Dataset BUSI) and Breast Ultrasound Dataset B (Dataset B) datasets demonstrate that LightBTSeg outperforms various counterparts.Comment: 7 pages, 7 figures, conferenc

C5aR antagonist inhibits LPS-induced inflammation in human gingival fibroblasts via NF-κB and MAPK signaling pathways

Objective: Abnormal complement activation is associated with periodontitis. W54011 is a novel non-peptide C5aR antagonist (C5aRA) that exhibits favorable anti-inflammatory effects in various inflammatory models. However, whether W54011 inhibits periodontitis has not yet been fully elucidated. To address this, we have investigated the probable anti-inflammatory mechanism of W54011 in LPS-treated inflammation in human gingival fibroblasts (HGFs). Methodology: HGFs were isolated from healthy gingival tissue samples using the tissue block method and were identified with immunofluorescence staining. The CCK8 assay and reverse transcription-PCR (RT-PCR) were used to select the optimal induction conditions for Lipopolysaccharide (LPS) and C5aRA (according to supplementary data S1, S2 and S3). The levels of inflammatory cytokines, C5aR, and the activation of NF-κB/MAPK signaling pathways were determined by RT-quantitative PCR (RT-qPCR) and Western blotting. Results: Immunofluorescence results showed that vimentin and FSP-1 were positive in HGFs and Keratin was negative in HGFs. Immunofluorescence staining demonstrated that C5aRA inhibited LPS-stimulated nuclear translocation of p-p65. RT-qPCR and Western blotting showed that C5aRA reduced the expression of IL-1β, IL-6, TNF-α, C5aR, p-p65, p-IκBα, p-JNK, p-c-JUN, and TLR4 in LPS-induced HGFs. Conclusion: These findings suggested that C5aRA attenuated the release of inflammatory cytokines in LPS-induced HGFs by blocking the activation of the NF-κB and MAPK signaling pathways

Predictors of failure of early neurological improvement in early time window following endovascular thrombectomy: a multi-center study

Background and objectiveEndovascular thrombectomy (EVT) has become the gold standard in the treatment of acute stroke patients. However, not all patients respond well to this treatment despite successful attempts. In this study, we aimed to identify variables associated with the failure of improvements following EVT.MethodsWe retrospectively analyzed prospectively collected data of 292 ischemic stroke patients with large vessel occlusion who underwent EVT at three academic stroke centers in China from January 2019 to February 2022. All patients were above 18 years old and had symptoms onset ≤6 h. A decrease of more than 4 points on the National Institute of Health Stroke Scale (NIHSS) after 24 h compared with admission or an NIHSS of 0 or 1 after 24 h was defined as early neurological improvement (ENI), whereas a lack of such improvement in the NIHSS was defined as a failure of early neurological improvement (FENI). A favorable outcome was defined as a modified Rankin scale (mRS) score of 0–2 after 90 days.ResultsA total of 183 patients were included in the final analyses, 126 of whom had FENI, while 57 had ENI. Favorable outcomes occurred in 80.7% of patients in the ENI group, in contrast to only 22.2% in the FENI group (p &lt; 0.001). Mortality was 7.0% in the ENI group in comparison to 42.1% in the FENI group (p &lt; 0.001). The multiple logistic regression model showed that diabetes mellitus [OR (95% CI), 2.985 (1.070–8.324), p = 0.037], pre-stroke mRS [OR (95% CI), 6.221 (1.421–27.248), p = 0.015], last known well to puncture time [OR (95% CI), 1.010 (1.003–1.016), p = 0.002], modified thrombolysis in cerebral infarction = 3 [OR (95% CI), 0.291 (0.122–0.692), p = 0.005], and number of mechanical thrombectomy passes [OR (95% CI), 1.582 (1.087–2.302), p = 0.017] were the predictors of FENI.ConclusionDiabetes mellitus history, pre-stroke mRS, longer last known well-to-puncture time, lack of modified thrombolysis in cerebral infarction = 3, and the number of mechanical thrombectomy passes are the predictors of FENI. Future large-scale studies are required to validate these findings

Protocol for a Single-Center Randomized Controlled Trial of Percutaneous Coronary Intervention Via Distal Transradial Access Versus Transradial Access

Background: Although transradial access (TRA) has become the main vascular access for coronary intervention, its high radial artery occlusion rate limits its application in some patients. Studies have shown that compared with TRA, distal transradial access (dTRA) with the snuffbox area or the Hegu acupoint area as the puncture point significantly decreases the incidence of radial artery occlusion. However, no randomized controlled study has confirmed the safety and efficacy of coronary artery intervention via dTRA in China. Methods and analyses: This single-center, prospective, randomized controlled, superiority open-label study will enroll 428 consecutive patients with coronary heart disease undergoing percutaneous coronary intervention as the study population. After preoperative evaluation, the participants will be randomly divided into a study group (dTRA) and control group (TRA) in a 1:1 ratio. The primary endpoint (radial artery occlusion at 24 hours after operation) and secondary endpoint events will be evaluated and recorded. Study registration: This study has been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2300073902)