ROS-sensitive PD-L1 siRNA cationic selenide nanogels for self-inhibition of autophagy and prevention of immune escape.

In the field of cancer therapy, inhibiting autophagy has emerged as a promising strategy. However, pharmacological disruption of autophagy can lead to the upregulation of programmed death-ligand 1 (PD-L1), enabling tumor immune evasion. To address this issue, we developed innovative ROS-responsive cationic poly(ethylene imine) (PEI) nanogels using selenol chemistry-mediated multicomponent reaction (MCR) technology. This procedure involved simple mixing of low-molecular-weight PEI (LMW PEI), γ-selenobutylacetone (γ-SBL), and poly(ethylene glycol) methacrylate (PEGMA). Through high-throughput screening, we constructed a library of AxSeyOz nanogels and identified the optimized A1.8Se3O0.5/siPD-L1 nanogels, which exhibited a size of approximately 200 nm, excellent colloidal stability, and the most effective PD-L1 silencing efficacy. These nanogels demonstrated enhanced uptake by tumor cells, excellent oxidative degradation ability, and inhibited autophagy by alkalinizing lysosomes. The A1.8Se3O0.5/siPD-L1 nanogels significantly downregulated PD-L1 expression and increased the expression of major histocompatibility complex class I (MHC-I), resulting in robust proliferation of specific CD8+ T cells and a decrease in MC38 tumor growth. As a result, the A1.8Se3O0.5/siPD-L1 nanogels inhibited tumor growth through self-inhibition of autophagy, upregulation of MHC-I, and downregulation of PD-L1. Designed with dynamic diselenide bonds, the A1.8Se3O0.5/siPD-L1 nanogels showed synergistic antitumor efficacy through self-inhibition of autophagy and prevention of immune escape.

The effectiveness of home rehabilitation based on BPMpathway exercise rehabilitation system for patients after total knee arthroplasty in China.

BACKGROUND: There is significant interest in the use of web-based technologies for rehabilitation of patients after total knee arthroplasty (TKA). BPMpathway is a combination of a wireless BPMpro sensor and mobile app to provide a personalized post-operative support programme for TKA patients. OBJECTIVE: To investigate the impact of the BPMpathway exercise rehabilitation system on home rehabilitation for TKA patients. METHODS: This study had a quasi-experimental design and was conducted with 42 inpatients after TKA. Patients were divided into a control group (n = 21) and an intervention group (n = 21) according to sequence of hospitalization. After discharge, patients in the control group received routine follow-up outside the hospital, while the intervention group, underwent out-of-hospital transitional care utilizing the BPMpathway exercise rehabilitation system. Knee function scores (HSS), quality of life scores (SF-36), and functional exercise compliance scores were compared between the two groups at 1, 3, and 6 months after TKA. RESULTS: The between-group differences in knee function were statistically significant at 1, 3, and 6 months post-operation (t = 6.299, 10.021, 13.064, all P < 0.05). There were between-group significant differences observed in functional exercise compliance and quality of life at 1 and 3 months (t = 7.166, 2.435, both P < 0.05; t = 2.879, 3.117, both P < 0.05). However, there were no significant differences at 6 months in these two respects (t = 0.167, 0.901, both P > 0.05). CONCLUSIONS: The BPMpathway exercise rehabilitation system seems to be potential effective in improving knee function, early compliance with functional exercise and quality of life in TKA patients.

Feasibility of the modified inverted L-shaped approach for posterolateral tibial plateau fracture: A retrospective study.

Approaches for treating posterolateral tibial plateau fractures vary among surgeons, and the inverted L-shaped approach is a known option. This article aims to introduce a new modified posterolateral inverted L-shaped approach for isolated posterolateral tibial plateau fractures and study its feasibility. Medical records of patients with posterolateral tibial plateau fractures were reviewed. Plain radiographs were obtained during the follow-up period, and the hospital for special surgery (HSS) score was used to assess the function of the injured limb. Perioperative complications were recorded and followed-up. In total, 32 patients with posterolateral tibial plateau fractures were treated using a modified posterolateral approach. The mean age of the patients was 44 ± 11 years (28-64 years). All patients successfully underwent surgery and were followed-up for a mean duration of 13 ± 2 months (10-16 months). On plain radiographs, fracture lines were fuzzy 3 months after surgery and disappeared 12 months after surgery. No perioperative complications occurred during the follow-up period. The HSS score was evaluated 12 months after surgery, and the mean score was 91 ± 5 points (81-97 points), including 25 excellent cases and 7 good cases. The modified posterolateral inverted L-shaped approach has the advantages of small soft tissue dissection, fracture reduction under direct vision, easy internal fixation, and a lower risk of neurovascular injury. This approach is feasible for the treatment of isolated posterolateral tibial plateau fractures, and further high-quality randomized control trials are required to confirm its clinical efficacy.

Analysis of Bone Loss around Cemented and Biologic Prostheses after Hemiarthroplasty.

Objective: To perform hemiarthroplasty (HA) on elderly patients with femoral neck fractures using cemented and biologic prostheses and then compare the bone loss around the two types of prostheses after surgery. Methods: A total of 60 patients aged over 75 years (with a mean age of 83.5 years) and suffering from femoral neck fracture (Garden types III and IV) from January 2018 to December 2020 were selected; they were randomly divided into group A (n = 30, cemented prostheses) and group B (n = 30, biologic prostheses) and received HA. At 1 month, 6 months, and 12 months after surgery, Harris Hip Scale (HHS) was adopted for patient evaluation, and patients' bone mineral density (BMD) of the 7 Gruen zones around the prostheses was measured by dual-energy X-ray absorptiometry (DEXA scan). Results: Both groups achieved satisfactory results postoperatively, and the Harris scores of the hips increased gradually over time, which were better in group A than in group B. Gruen zones in group A showed a slower trend of decreasing BMD than group B, and the differences were significant at zones 2, 3, and 4 (P < 0.05). Conclusion: For elderly patients with femoral neck fractures, selecting cemented prosthesis for HA better recovers the hip function and has a low rate of bone loss around the prosthesis.

Thermally Driven Diselenide Metathesis: Polarization Process vs Radical Process.

Diselenide, as a dynamic covalent bond, has been widely applied in functional materials due to its response to light, heat, sonication, pH, and other stimuli. Herein, a polarization-induced metathesis mechanism for diselenides under heating conditions in the dark is proposed. First, a radical trap experiment is used to prove that the exchange reaction of diselenides in the dark does not involve any radicals. Second, the dynamic exchange reaction of diselenides is found to be affected not only by the polarity of the solvent but also by the introduction of polar groups into the molecular skeleton. Furthermore, DFT calculations also support the notion that polarity has a large effect on the heterolytic rather than homolytic bond dissociation energies. The experimental results for allyl selenide small molecules, polymers, and polymer materials catalyzed by diselenide all support the polarization-induced metathesis mechanism. In short, we successfully enhanced the understanding of the mechanism for diselenide metathesis.

Estrogen-induced Tgfbr1 and Bmpr1a Expression Repressed via Estrogen Receptor Beta in MC3T3-E1 Cells.

BACKGROUND: Estrogen, as an important hormone in human physiological process, is closely related to bone metabolism. The aim of this study was to investigate the mechanism of estrogen on osteoblasts metabolism in MC3T3-E1 cells. METHODS: We treated the MC3T3-E1 cells with different concentrations of ß-estradiol (0.01, 0.1, 1, and 10 nmol/L), observed the morphological changes of the cells, and detected the cell's proliferation and apoptosis of MC3T3-E1 cells. Two transcriptome libraries were constructed and sequenced. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to confirm the differentially expressed genes (DEGs), and then treated the MC3T3-E1 cells with estrogen receptor (ER) inhibitors α and ß, respectively, and then examined the expression of Tgfbr1 and Bmpr1a genes. The promoter of Tgfbr1 and Bmpr1a gene was analyzed, and the ER response elements were identified. Finally, ChIP was used to verify the binding of ER to Tgfbr1 and Bmpr1a promoter. RESULTS: In the high-concentration ß-estradiol treatment group (1 nmol/L and 10 nmol/L), there was no significant difference in the morphology of the cells under the microscope, 1 nmol/L and 10 nmol/L treated group appeared statistically significant difference in cell apoptosis and proliferation (P < 0.05 and P < 0.01, respectively). We found 460 DEGs compared with the control group. Among the DEGs, there were 66 upregulated genes and 394 downregulated genes. Gene ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that many bone metabolism-related biological processes and cell signaling pathways were disordered. The qRT-PCR verification showed that the expressions of Tgfbr1- and Bmpr1a-related genes in bone metabolism pathway in the 10 nmol/L treatment group were significantly decreased (P < 0.05). ER ß was involved in the inhibitory effect of Tgfbr1 and Bmpr1a genes. The bioinformatics of the promoter found that there were three ER response elements in the promoter of Tgfbr1, and there were two ER response elements in Bmpr1a promoter regions. ChIP experiments showed that estrogen could enhance the binding of ERs to Tgfbr1 and Bmpr1a genes. CONCLUSIONS: Estrogen can promote the apoptosis and proliferation of osteoblasts simultaneously, and the mechanism may be the joint action of transforming growth factor-beta, Wnt, mitogen-activated protein kinase, and nuclear factor-kappaB bone metabolism-related signaling pathway. Estrogen inhibits the expression of Tgfbr1 and Bmpr1a genes through ER ß and affects the metabolism of MC3T3-E1 osteoblasts.

Possible mechanisms of prednisolone-induced osteoporosis in zebrafish larva.

Glucocorticoid-induced osteoporosis (GIOP) is a serious clinical bone disease that results from the long-term consumption of glucocorticoids or glucocorticoid-like drugs. Although many studies have attempted to determine the mechanisms of GIOP, they are still unclear. In this study, we established a zebrafish model of glucocorticoid-like drug-induced osteoporosis by treating larvae with prednisolone. We then quantified the expression of a selection of extracellular matrix (ECM)-, osteoblast-, and osteoclast-related genes. Our results showed that at 15 days post fertilization, zebrafish larvae treated with 25 µM prednisolone are a suitable model for GIOP, not only owing to the decrease in robust bone mass but also because of significant alterations in gene expression. The quantification of the expression of ECM-, osteoblast-, and osteoclast- related genes revealed that mmp9 and mmp13 were significantly upregulated and entpd5a, acp5a, and sost were significantly downregulated. These genes may be a target for future research into GIOP. Our study thus provides new insights into GIOP.

Elucidation of possible molecular mechanisms underlying the estrogen-induced disruption of cartilage development in zebrafish larvae.

Estrogen can affect the cartilage development of zebrafish; however, the mechanism underlying its effects is not completely understood. Four-day-old zebrafish larvae were treated with 0.8 µM estrogen, the 5 days post fertilization (dpf) zebrafish larvae did not demonstrate obvious abnormalities during development; however, the 6 dpf and 7 dpf larvae exhibited abnormal craniofacial bone development along with craniofacial bone degradation. RNA deep sequencing was performed to elucidate the mechanism involved. Gene Ontology functional and KEGG pathway enrichment analysis of differentially expressed genes (DEGs) showed that the extracellular matrix (ECM), extracellular region, ECM-interaction receptor, focal adhesion, cell cycle, apoptosis, and bone-related signaling pathways were disrupted. In these signaling pathways, the expressions of key genes, such as collagen encoded (col19a1a, col7a1, col7al, col18a1, and col9a3), MAPK signaling pathway (fgf19, fgf6a), TGF-beta signaling pathway (tgfbr1), and cell cycle (cdnk1a) genes were altered. The qRT-PCR results showed that after treatment with 0.8 µM 17-ß estradiol (E2), col19a1a, col7a1, col7al, col18a1, col9a3, fgf6a, cdkn1a were downregulated, and fgf19, tgfr1 were upregulated, which were consistent with deep sequencing analysis. Therefore, the effect of estrogen on cartilage development might occur via multiple mechanisms. The study results demonstrate the mechanism underlying the effect of estrogen on cartilage development.

Reduced miR-144-3p expression in serum and bone mediates osteoporosis pathogenesis by targeting RANK.

Osteoblasts and osteoclasts are responsible for the formation and resorption of bone, respectively. An imbalance between these two processes results in a disease called osteoporosis, in which a decreased level of bone strength increases the risk of a bone fracture. MicroRNAs (miRNAs) are small non-coding RNA molecules of 18-25 nucleotides that have been previously shown to control bone metabolism by regulating osteoblast and osteoclast differentiation. In this study, we detected the expression pattern of 10 miRNAs in serum samples from patients with osteoporosis, and identified the altered expression of 6 miRNAs by comparison with patients without osteoporosis. We selected miR-144-3p for further investigation, and showed that it regulates osteoclastogenesis by targeting RANK, and that it is conserved amongst vertebrates. Disrupted expression of miR-144-3p in CD14+ peripheral blood mononuclear cells changed TRAP activity and the osteoclast-specific genes TRAP, cathepsin K (CTSK), and NFATC. TRAP staining, CCK-8, and flow cytometry analyses revealed that miR-144-3p also affects osteoclast formation, proliferation, and apoptosis. Together, these results indicate that miR-144-3p critically mediates bone homeostasis, and thus, represents a promising novel therapeutic candidate for the treatment of this disease.