Polyprodrug nanomedicine for chemiexcitation-triggered self-augmented cancer chemotherapy and gas therapy.

Carbon monoxide (CO) has emerged as a potential antitumor agent by inducing the dysfunction of mitochondria and the apoptosis of cancer cells. However, it remains challenging to deliver appropriate amount of CO into tumor to ensure efficient tumor growth suppression with minimum side effects. Herein we developed a CO prodrug-loaded nanomedicine based on the self-assembly of camptothecin (CPT) polyprodrug amphiphiles. The polyprodrug nanoparticles readily dissociate upon exposure to endogenous H2O2 in the tumor, resulting in rapid release of CPT and generation of high-energy intermediate dioxetanedione. The latter can transfer the energy to neighboring CO prodrugs to activate CO production by chemiexcitation, while CPT promotes the generation of H2O2 in tumors, which in turn facilitates cascade CPT and CO release. As a result, the polyprodrug nanoparticles display remarkable tumor suppression in both subcutaneous and orthotopic breast tumor-bearing mice owing to the self-augmented CPT release and CO generation. In addition, no obvious systemic toxicity was observed in mice treated with the metal-free CO prodrug-loaded nanomedicine, suggesting the good biocompatibility of the polyprodrug nanoparticles. Our work provides new insights into the design and construction of polyprodrug nanomedicines for synergistic chemo/gas therapy.

Two new megastigmane glycosides from the leaves of Nicotiana tabacum and their anti-inflammatory activities.

Two new megastigmane glycosides, (6 R,7E,9R)-3-oxo-α-ionyl-9-O-α-L-rhamnopyranosyl-(1''→4')-ß-D-glucopyranoside (1) and (6 R,7E,9R)-3-oxo-α-ionyl-9-O-ß-D-glucopyranosyl-(1''→6')-ß-D-glucopyranoside (2), together with six known analogues (3-8) were isolated from the leaves of Nicotiana tabacum. The structures of all metabolites were determined by comprehensive analysis of NMR and MS spectroscopic data as well as by comparison with those of previously reported. The in vitro anti-inflammatory activity of all isolates was evaluated using a lipopolysaccharide (LPS)-induced RAW264.7 cell inflammatory model, and the compounds 1, 3, 7, and 8 exhibited inhibition of LPS-induced NO production in RAW264.7 macrophage cells with IC50 values of 42.3-61.7 µM (positive control, dexamethasone, IC50 = 21.3 ± 1.2 µM).

Targeted therapies of inflammatory diseases with intracellularly gelated macrophages in mice and rats.

Membrane-camouflaged nanomedicines often suffer from reduced efficacy caused by membrane protein disintegration and spatial disorder caused by separation and reassembly of membrane fragments during the coating process. Here we show that intracellularly gelated macrophages (GMs) preserve cell membrane structures, including protein content, integration and fluidity, as well as the membrane lipid order. Consequently, in our testing GMs act as cellular sponges to efficiently neutralize various inflammatory cytokines via receptor-ligand interactions, and serve as immune cell-like carriers to selectively bind inflammatory cells in culture medium, even under a flow condition. In a rat model of collagen-induced arthritis, GMs alleviate the joint injury, and suppress the overall arthritis severity. Upon intravenous injection, GMs efficiently accumulate in the inflammatory lungs of acute pneumonia mice for anti-inflammatory therapy. Conveniently, GMs are amenable to lyophilization and can be stored at ambient temperatures for at least 1 month without loss of integrity and bio-activity. This intracellular gelation technology provides a universal platform for targeted inflammation neutralization treatment.

Comparative clinical study of the modified Broström procedure for the treatment of the anterior talofibular ligament injury-outcomes of the open technique compared to the arthroscopic procedure.

PURPOSE: To observe the clinical efficacy and safety of arthroscopic-modified Broström surgery for the treatment of anterior talofibular ligament injury. METHODS: The clinical data of 51 cases with anterior talofibular ligament injury were retrospectively analyzed, in which 23 patients were treated by arthroscopic-modified Broström surgery (arthroscopic surgery group) and 28 patients were treated by open-modified Broström surgery (open surgery group). The time to surgery, hospital stay, visual analog scale (VAS) scores of ankle pain, American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot scores, and incidence rate of complications were compared between the two groups. RESULTS: (1) General results: compared with open surgery group, arthroscopic surgery group had shorter time to surgery and hospital stay ((33.8 ± 6.7) min, (42.1 ± 8.5) min, t = 1.468, P = 0.001; (2.2 ± 1.4) d, (5.8 ± 1.6) d, t = 1.975, P = 1.975, P = 0.002). (2) VAS scores of ankle pain: there was an interaction effect between the time and group factors (F = 0.378, P = 0.018); overall, there was no statistically significant difference in VAS scores of ankle pain between the two groups, i.e., there was no grouping effect (F = 1.865, P = 0.163); there was statistically significant difference in VAS score of ankle pain at different time points before and after operation, i.e., there was a time effect (F = 1.675, P = 0.000); the VAS scores of ankle pain showed a decreasing trend with time in both groups, but the decreasing trend was not completely consistent between the two groups ((7.78 ± 1.23), (1.23 ± 1.24), (1.03 ± 0.35), (1.01 ± 0.28), F = 0.568, P = 0.000. (7.45 ± 1.43), (1.45 ± 1.87), (1.23 ± 0.55), (1.04 ± 0.37), F = 1.358, P = 0.000); there was no statistically significant difference in VAS score of ankle joint pain between the two groups six and 12 months before and after surgery (t = 2.987, P = 0.055; t = 1.654, P = 2.542; t = 0.015, P = 0.078); the VAS scores of ankle pain in the arthroscopic surgery group was lower than that in the open surgery group three months after operation (t = 1.267, P = 0.023). (3) AOFAS ankle and hindfoot scores: there was an interaction effect between time and grouping factors (F = 2.693, P = 0.027); overall, there was no statistically significant difference in the AOFAS ankle and hindfoot scores between the two groups, i.e., there was no grouping effect (F = 1.983, P = 0.106); there was statistically significant difference in the AOFAS ankle and hindfoot scores at different time points before and after surgery, i.e., there was a time effect (F = 34.623, P = 0.000); the AOFAS ankle and hindfoot scores of the two groups showed an increasing trend with time, but the increasing trend of the two groups was not completely consistent ((48.19 ± 12.89), (89.20 ± 8.96), (90.24 ± 7.89), (91.34 ± 9.67), F = 25.623, P = 0.000; (49.35 ± 13.28), (86.78 ± 12.34), (88.78 ± 9.78),(91.43 ± 7.98), F = 33.275, P = 0.000); there was no statistically significant difference in the AOFAS ankle and hindfoot scores between the two groups 12 months before/after surgery (t = 2.145，P = 0.056；t = 2.879，P = 0.389); compared with open surgery group, the arthroscopic surgery group had higher AOFAS ankle and hindfoot scores 3/6 months after surgery (t = 1.346, P = 0.014; t = 1.874, P = 0.028). CONCLUSION: For the treatment of anterior talofibular ligament injury, arthroscopic surgery group is superior to open surgery group in ankle pain relief and functional recovery and has shorter operation time and hospital stay compared with open surgery group.

Paeoniflorin, the Main Monomer Component of Paeonia lactiflora, Exhibits Anti-inflammatory Properties in Osteoarthritis Synovial Inflammation.

OBJECTIVE: To explore the mechanism of paeoniflorin (PF) on osteoarthritis (OA) synovial inflammation from network pharmacology to experimental pharmacology. METHODS: Targets of OA were constructed by detecting the database of network database platforms (Therapeutic Target database, DrugBank and GeneCards), and the targets of PF were constructed by PubChem and Herbal Ingredients' Targets database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these co-targeted genes were conducted via Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, and protein-protein interaction (PPI) networks were conducted via the search tool for the retrieval of interacting genes (STRING) database. Cell counting kit-8 (CCK-8) assay was performed to assess the potential toxicity of PF on human OA fibroblast-like synoviocytes (FLS), quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) and Western blot were used to verify the potential mechanism of PF in synovial inflammation. RESULTS: Twenty-six co-targeted genes were identified. GO enrichment results showed that these co-targeted genes were most likely localized in the cytoplasm, and the biological processes mainly involved 'cellular response to hypoxia' 'lipopolysaccharide (LPS)-mediated signaling pathway' and 'positive regulation of gene expression'. KEGG pathway analysis indicated that these co-targeted genes may function through pathways associated with 'hypoxia-inducible factor-1 (HIF-1) signaling pathway' and 'tumor-necrosis factor (TNF) signaling pathway'. The PPI network showed that the top 3 hub genes were TP53, TNF, and CASP3. Molecular docking results showed that PF was well docking with TNF. CCK-8 showed no potential toxicity of 10, 20 and 50 µmol/L PF on human OA FLS. And PF significantly decreased the expression levels of interleukin-1 ß, interleukin-6, TNF-α matrix metalloproteinase 13 (MMP13), and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and TNF-α in LPS-induced OA FLS. CONCLUSION: PF exhibited potent anti-inflammatory effect in OA synovial inflammation.

ED90 of epidural esketamine with 0.075% ropivacaine for labor analgesia in nulliparous parturients: a prospective, randomized and dose-finding study.

Background: Because it has been reported that racemic ketamine had a local anesthetic-sparing effect when used for epidural analgesia this would suggest the likelihood of a potential advantage (less pruritus) over opioid drugs. Esketamine has greater analgesic efficacy than racemic ketamine, but the optimum dosage regimen for epidural use is undetermined. The aim of this study was to determine the ED90 of epidural esketamine when coadministered with 0.075% ropivacaine for labor analgesia. Methods: A total of 65 laboring nulliparous patients were enrolled in this study from 16 March 2022 to 15 October 2022. The patients were randomly assigned to receive 0, 0.25, 0.5, 0.75 or 1.0 mg/mL esketamine with 0.075% ropivacaine epidurally. An effective response to the epidural loading dose was defined as numerical rating scale pain score ≤3 at 30 min after the end of the epidural loading dose (10 mL of the ropivacaine 0.075% solution with the added esketamine). The ED90 of epidural esketamine coadministered with 0.075% ropivacaine with 95% confidence intervals for labor analgesia was determined using probit regression. Secondary outcomes and side effects were recorded. Results: The estimated value of ED90 with 95% CIs for epidural esketamine with 0.075% ropivacaine was 0.983 (0.704-2.468) mg/mL. The characteristics of sensory and motor block, consumption of ropivacaine per hour, duration of first or second stage, Apgar scores did not differ among the five groups. The incidence of mild dizziness in Group esketamine 1.0 mg/mL was significantly higher than that in other groups (p < 0.05). No statistical differences were found in other side effects among groups. Conclusion: The ED90 value of epidural esketamine coadministered with 0.075% ropivacaine for labor analgesia in nulliparous parturients was about 1.0 mg/mL. Furthermore, our results suggested that epidural esketamine would cause dose-dependent mild dizziness especially at doses up to 1.0 mg/mL. As a single epidural additive, esketamine may not be suitable for labor analgesia. Future studies may investigate the appropriate dosage of esketamine at slightly higher concentrations of local anesthetics or larger initial volume of analgesia, or explore other potential advantages of esketamine. Clinical Trial Registration: (https://www.chictr.org.cn/bin/project/edit?pid=159764), identifier (ChiCTR2200057662).

Exosome-Modified Liposomes Targeted Delivery of Thalidomide to Regulate Treg Cells for Antitumor Immunotherapy.

Thalidomide (THD), a synthetic derivative of glutamic acid, was initially used as a sedative and antiemetic until the 1960s, when it was found to cause devastating teratogenic effects. However, subsequent studies have clearly demonstrated the anti-inflammatory, anti-angiogenic, and immunomodulatory properties of thalidomide, thus providing a rationale for its current use in the treatment of various autoimmune diseases and cancers. Our group found that thalidomide can suppress the regulatory T cells (Tregs), a minor subset of CD4+ T cells (~10%) with unique immunosuppressive activity that have been shown to accumulate in the tumor microenvironment (TME) and represent a major mechanism of tumor immune evasion. Due to the low solubility of thalidomide in its present form of administration, coupled with its lack of specificity for targeted delivery and controlled drug release, it is an urgent need to find potent delivery methods that can significantly enhance its solubility, optimize the desired site of drug action, and mitigate its toxicity. In this study, the isolated exosomes were incubated with synthetic liposomes to form hybrid exosomes (HEs) that carried THD (HE-THD) with uniform size distribution. The results demonstrated that HE-THD could significantly abrogate the expansion and proliferation of Tregs induced by TNF, and this might result from blocking TNF-TNFR2 interaction. By encapsulating THD in hybrid exosomes, our drug delivery system successfully increased the solubility of THD, laying a foundation for future in vivo experiments that validate the antitumor activity of HE-THD by reducing the Treg frequency within the tumor microenvironment.

Conjugation of Macrophage-Mimetic Microalgae and Liposome for Antitumor Sonodynamic Immunotherapy via Hypoxia Alleviation and Autophagy Inhibition.

Sonodynamic therapy (SDT) is a noninvasive technique for local antitumor treatment; however, its clinical application is often limited by the low tumor accumulation of SDT agents, tumor's hypoxic microenvironment, and cytoprotective effects of autophagy. To address these issues, herein we developed surface-engineered chlorella (Chl, a green algae) as a targeted drug carrier and sustainable oxygen supplier (via photosynthesis) for significantly improved SDT via hypoxia alleviation as well as autophagy inhibition of chloroquine phosphate. In this design, the macrophage membrane was coated onto Chl to form macrophage-mimetic Chl (MChl) to increase its biocompatibility and targeted tumor accumulation driven by the inflammatory-homing effects of macrophage membranes. In addition, the membrane coating on Chl allowed lipid insertion to yield ß-cyclodextrin (ß-CD) modified MChl (CD-MChl). Subsequently, supramolecular conjugates of MChl-NP were constructed via host-guest interactions between CD-MChl and adamantane (ADA)-modified liposome (ADA-NP), and the anchored liposome went with CD-MChl hand-in-hand to the tumor tissues for co-delivery of Chl, hematoporphyrin, and chloroquine phosphate (loaded in ADA-NP). The synergistic therapy achieved via local oxygenation, SDT, and autophagy inhibition maximally improved the therapeutic efficacy of MChl-CQ-HP-NP against melanoma. Tumor rechallenging results revealed that the changes of tumor microenvironment including hypoxia alleviation, SDT induced immunogenic cell death, and autophagy inhibition collectively induced a strong antitumor immune response and memory.

Cyclodextrin-mediated conjugation of macrophage and liposomes for treatment of atherosclerosis.

Current pharmacological treatments of atherosclerosis often target either cholesterol control or inflammation management, to inhibit atherosclerotic progression, but cannot lead to direct plaque lysis and atherosclerotic regression, partly due to the poor accumulation of medicine in the atherosclerotic plaques. Due to enhanced macrophage recruitment during atheromatous plaque progression, a macrophage-liposome conjugate was facilely constructed for targeted anti-atherosclerosis therapy via synergistic plaque lysis and inflammation alleviation. Endogenous macrophage is utilized as drug-transporting cell, upon membrane-modification with a ß-cyclodextrin (ß-CD) derivative to form ß-CD decorated macrophage (CD-MP). Adamantane (ADA) modified quercetin (QT)-loaded liposome (QT-NP), can be conjugated to CD-MP via host-guest interactions between ß-CD and ADA to form macrophage-liposome conjugate (MP-QT-NP). Thus, macrophage carries liposome "hand-in-hand" to significantly increase the accumulation of anchored QT-NP in the aorta plaque in response to the plaque inflammation. In addition to anti-inflammation effects of QT, MP-QT-NP efficiently regresses atherosclerotic plaques from both murine aorta and human carotid arteries via CD-MP mediated cholesterol efflux, due to the binding of cholesterol by excess membrane ß-CD. Transcriptome analysis of atherosclerotic murine aorta and human carotid tissues reveal that MP-QT-NP may activate NRF2 pathway to inhibit plaque inflammation, and simultaneously upregulate liver X receptor to promote cholesterol efflux.

In vivo hitchhiking of immune cells by intracellular self-assembly of bacteria-mimetic nanomedicine for targeted therapy of melanoma.

Cell-based drug carriers are mostly prepared in vitro, which may negatively affect the physiological functions of cells, and induce possible immune rejections when applied to different individuals. In addition, the immunosuppressive tumor microenvironment limits immune cell-mediated delivery. Here, we report an in vivo strategy to construct cell-based nanomedicine carriers, where bacteria-mimetic gold nanoparticles (GNPs) are intravenously injected, selectively phagocytosed by phagocytic immune cells, and subsequently self-assemble into sizable intracellular aggregates via host-guest interactions. The intracellular aggregates minimize exocytosis of GNPs from immune cells and activate the photothermal property via plasmonic coupling effects. Phagocytic immune cells carry the intracellular GNP aggregates to melanoma tissue via inflammatory tropism. Moreover, an initial photothermal treatment (PTT) of the tumor induces tumor damage that subsequently provides positive feedback to recruit more immune cell-based carriers for enhanced targeting efficiency. The optimized secondary PTT notably improves antitumor immunotherapy, further strengthened by immune checkpoint blockade.

Mobile Bearing versus Fixed Bearing for Total Knee Arthroplasty: Meta-analysis of Randomized Controlled Trials at Minimum 10-Year Follow-up.

This meta-analysis aimed to compare the clinical and radiographic outcomes between mobile-bearing total knee arthroplasty (MB-TKA) and fixed-bearing total knee arthroplasty (FB-TKA) at a minimum 10-year follow-up. PubMed, EMBASE, and Cochrane databases were searched. All included articles were evaluated by two trained reviewers according to the guidelines of the Cochrane Collaboration Handbook for potential risk, and the Consolidated Standards on Reporting Trials (CONSORT) checklist and scoring system was also used to assess the methodological quality of each study. The extracted data included function scores, range of motion (ROM) of the knee, incidence of adverse events or revision, survivorship analysis, and radiographic outcomes. Seven randomized controlled trials (RCTs) were included in this meta-analysis, and all RCTs had a follow-up period longer than 10 years. This meta-analysis shows no significant difference between the two groups with respect to the Keen Society Score (KSS; p = 0.38), KSS function score (p = 0.30), the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC; p = 0.59), ROM (p = 0.71), radiolucent line (p = 0.45), femoral and tibial component positions in the coronal plane (p = 0.55 and 0.35, respectively), revision incidence (p = 0.77), and survivorship rates (p = 0.39). Meanwhile, it showed a slight difference between the two groups in the tibial component position in the sagittal plane (p = 0.003). According to this meta-analysis, the current best available evidence suggests no significant difference between the MB-TKA and FB-TKA groups with respect to the clinical outcomes, radiographic outcomes, revision, and survivorship at a minimum 10-year follow-up. This is a Level II, meta-analysis study.

Effect of Tai Chi exercise on lower limb function and balance ability in patients with knee osteoarthritis: A protocol of a randomized controlled trial.

BACKGROUND: Knee osteoarthritis (KOA) is a chronic degenerative joint disease commonly occurring in middle-aged and elderly people. The main clinical manifestations are joint pain, limited activity, and decreased muscle strength resulting in decreased motor control ability. Exercise therapy is an effective method to enhance muscle strength of lower limbs, while China's traditional skill Tai Chi (TC) is a combination of activity and inertia, internal and external exercise therapy. In recent years, scholars at home and abroad have found that regular TC can effectively improve patients' lower limb function and balance ability. The purpose of this study is to explore the effects of TC on lower limb function and balance ability in patients with KOA. METHODS: This is a prospective randomized controlled clinical trial. One hundred forty-six cases of KOA patients will be randomly divided into experimental group and control group according to 1:1 ratio, 73 cases in each group, the control group: sodium hyaluronate; experimental group: TC added on the basis of the control group. Both groups will receive standard treatment for 5 weeks and will be followed up for 3 months. Observation indicators include: the western Ontario and McMaster universities osteoarthritis index; hospital for special surgery knee score; balance stability index, liver and kidney function, adverse reaction rate, etc. SPSS 23.0 software will be used for data analysis. DISCUSSION: This study will evaluate the effects of TC on lower limb function and balance ability of patients with KOA. The results of this trial will provide a clinical basis for the selection of exercise therapy for patients with KOA.

Corrosion behavior of high nitrogen nickel-free austenitic stainless steel in the presence of artificial saliva and Streptococcus mutans.

High nitrogen nickel-free austenitic stainless steels (HNSs) have great potentials to be used in dentistry owing to its exceptional mechanical properties, high corrosion resistance, and biocompatibility. In this study, HNSs with nitrogen of 0.88 wt% and 1.08 wt% displayed much lower maximum pit depths than 316L stainless steel (SS) after 21 d of immersion in abiotic artificial saliva (2.2 µm and 1.7 µm vs. 4.5 µm). Microbiologically influenced corrosion (MIC) evaluations revealed that Streptococcus mutans biofilms led to much severer corrosion of 316L SS than HNSs. Corrosion current densities of HNSs were two orders of magnitude lower than that of 316L SS after incubation of 7 d (37.5 nA/cm2 and 29.9 nA/cm2 vs. 5.63 µA/cm2). The pitting potentials of HNSs were at least 550 mV higher than that of 316L SS in the presence of S. mutans, confirming the better MIC resistance of HNSs. Cytotoxicity assay confirmed that HNSs were not toxic to MC3T3-E1 cells and allowed better sessile cell growth on them than on 316L SS. It can be concluded that HNSs are more suitable dental materials than the conventional 316L SS.

Efficacy and Mechanism of Electroacupuncture Treatment of Rabbits With Different Degrees of Knee Osteoarthritis: A Study Based on Synovial Innate Immune Response.

Knee osteoarthritis (KOA) is a chronic degenerative bone and joint disease, which is often clinically manifested as pain, joint swelling, and deformity. Its pathological manifestations are mainly synovial inflammation and cartilage degeneration. This study aims to investigate the efficacy of electro-acupuncture (EA) on model rabbits with varying degrees of KOA and to study the mechanism of EA on KOA based on the innate immune response. Mild and moderate rabbit KOA models were established using a modified Hluth method, and EA was given to both the mild and moderate model groups. The Lequesne-MG index was used to evaluate the behavioral changes in the rabbits before and after EA treatment. Morphological changes in the synovial membrane and cartilage of each group were observed by H&E staining. The Mankin scoring standard and the Krenn scoring standard were used to score the pathology of the cartilage tissue and synovial tissue, respectively. The inflammatory factors and metalloproteinases were detected in the serum of each group by ELISA. The protein and messenger RNA (mRNA) expressions of important elements related to Toll-like receptors (TLRs)-mediated innate immune response in the synovial tissue were detected by Western blot and quantitative PCR (qPCR). The Lequesne-MG index score of the rabbits gradually increased with the modeling prolonged but decreased significantly after EA treatment, indicating that EA has a better effect on alleviating the pain and improving the dysfunction. The morphological analysis showed that the inflammation of and the damage to the synovial membrane and the cartilage tissue gradually deteriorated with the modeling prolonged. However, the synovial membrane inflammation was significantly relieved after EA treatment, and the cartilage injury showed signs of repair. The ELISA analysis showed that, with the modeling prolonged, the serum-related inflammatory factors and mechanism of metalloproteinases gradually increased but decreased after EA treatment. The tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and matrix metalloproteinase3 (MMP3) of EA1 group were significantly lower than those of EA2 group. Both Western blot and qPCR results showed that the protein and mRNA expressions of the elements related to the innate immune response in the synovial membrane increased gradually with the modeling prolonged, but decreased significantly after EA treatment. Additionally, the expression of some components in EA1 group was significantly lower than that in EA2 group. These results confirm that synovial inflammation gradually aggravated with time from the early to mid-stage of KOA. EA alleviated the inflammation and histological changes in KOA rabbits by inhibiting the TLRs-mediated innate synovial immune response. This suggests that using EA in the early stage of KOA may achieve a desirable efficacy.

Role of Dynamic Navigation Systems in Enhancing the Accuracy of Implant Placement: A Systematic Review and Meta-Analysis of Clinical Studies.

PURPOSE: This systematic review and meta-analysis aims to investigate the influence of dynamic navigation systems on accuracy (platform, apical and angular deviations) in clinical studies. METHODS: The research question was "Do dynamic navigation systems enhance the accuracy of implant placement?" The PubMed, Scopus and Embase databases were used to search the relevant studies up to January 2021. The role of dynamic navigation systems in enhancing the accuracy (platform, apical and angular deviations) of implant placement was then analyzed to conduct a systematic review and meta-analysis. RESULTS: Eight articles were analyzed in the systematic review and meta-analysis. The systematic review showed that the deviations in implant placement were significantly lower for dynamic navigation than for the freehand method, and there were no significant differences between the dynamic navigation and static guide methods. This meta-analysis showed that the dynamic navigation group exhibited less platform deviation, apical deviation and angular deviation than the control group. The results of subgroup analyses showed that the dynamic navigation group exhibited fewer deviations than the freehand group, and no significant differences were found between the dynamic navigation and static guide groups. CONCLUSIONS: Dynamic navigation resulted in higher accuracy than the freehand method, and similar accuracies were found between dynamic navigation and static guidance for platform deviation, apical deviation or angular deviations.

Cinnamic Aldehyde Inhibits Lipopolysaccharide-Induced Chondrocyte Inflammation and Reduces Cartilage Degeneration by Blocking the Nuclear Factor-Kappa B Signaling Pathway.

Osteoarthritis (OA), as one of the top 10 causes of physical disability, is characterized by inflammation of the synovial membrane and progressive destruction of the articular cartilage. Cinnamic aldehyde (CA), an α,ß-unsaturated aldehyde extracted from the traditional Chinese herbal medicine cinnamon (Cinnamomum verum J.Presl), has been reported to have anti-inflammatory, antioxidant, and anticancer properties. However, the anti-inflammatory effect of CA on OA remains unclear. The purpose of the present study was to investigate the effects of CA on inflammation, and cartilage degeneration in OA. A CCK-8 assay was performed to assess the potential toxicity of CA on cultured human OA chondrocytes. Following treatment with lipopolysaccharide (LPS) and CA, the expression of proinflammatory cytokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-alfa (TNF-α), was evaluated using quantitative real-time polymerase chain reaction (RT-qPCR) analysis, enzyme-linked immunosorbent assay, and Western blotting (WB). The production of matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) was also examined using RT-qPCR and WB. Furthermore, to investigate the potential anti-inflammatory mechanism of CA, biomarkers of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway (p65, IKB-α) were detected using WB. The results demonstrated that CA significantly inhibited the expressions of IL-1ß, IL-6, TNF-α, MMP-13, and ADAMTS-5 in LPS-induced OA chondrocytes. CA dramatically suppressed LPS-stimulated NF-κB activation. Collectively, these results suggest that CA treatment may effectively prevent OA.

[Effect of Tongluo Zhitong (, TLZT) gel preparation on p53 /miR-502-5p /NF-κBp65 in synovial tissue of knee osteoarthritis].

OBJECTIVE: To observe effects of Tongluo Zhitong (, TLZT) gel preparation on p53, miR-502-5p, NF-κBp65 in synovial tissue of knee osteoarthritis (KOA), and to explore mechanism of TLZT gel preparation in treating KOA. METHODS: Thirthy-six Wistar rats aged 8 weeks and weighed 200 to 220 g (meaned 208 g) were randomly divided into normal group, model group and traditional Chinese medicine (TCM) group, 12 rats in each group. KOA model was established by modified Hulth method. After 4 weeks of modeling, TCM group treated with TLZT gel preparation for external use, 3 times daily for 2 weeks;normal group and model group were fed normally without intervention. After treatment, morphological changes of specimens in each group were observed, changes of miR-502-5p in synovial tissue were detected by qPCR, and contents of p53, NF-κBp65, IL-1ß, TNF-α, MMP-13 in synovial tissue were detected by qPCR and Western Blot respectively. RESULTS: (1)Morphological observation of specimens showed that the articular cartilage in model group was hyaline and uneven, the synovial membranes were hypertrophic and proliferative with a large number of inflammatory cells infiltrating, the joint fluid was thicker in texture;the articular cartilage in TCM group was more transparent and smooth, synovial hyperplasia was mild with a small amount of inflammatory cell infiltration, the texture of articular fluid was clear and sparse. (2) Compared with normal group, content of miR-502-5p of synovial tissue in model and TCM group were increased, mRNA and expression of p53 decreased, expression of NF-κBp65, IL-1ß, TNF-α, MMP-13 increased. (3)Compared with model group, content of miR-502-5p in synovial tissue of TCM group decreased (P<0.05), mRNA and protein expression of p53 increased (P<0.05), mRNA and protein expression of NF-κBp65, IL-1ß, TNF-α, MMP-13 decreased (P<0.05). CONCLUSION: Expression of p53, miR-502 -5p, NF -κBp65 in synovial tissue is closely related to synovial hyperplasia and inflammatory reaction, TLZT gel preparation may reduce proliferation and inflammatory reaction of KOA synovium by regulating the expression of p53, miR- 502-5p, NF-κBp65 in synovial tissues.

Extraction and identification of synovial tissue-derived exosomes by different separation techniques.

OBJECTIVE: The aim of this study is to compare the efficiency of different separation techniques for extracting synovial tissue-derived exosomes. METHODS: The synovial tissue discarded during knee arthroscopy or total knee arthroplasty surgery was collected from the Third Affiliated Hospital of Beijing University of Chinese Medicine. Ultracentrifugation (UC), filtration combined with size exclusion chromatography (SECF), and 8% polyethylene glycol (PEG) were used to extract synovial tissue-derived exosomes. Transmission electron microscopy (TEM), nanoparticle tracer analysis (NTA), and Western Blot (WB) were used to detect the morphology, particle size, and biomarker proteins (CD9, CD63, Flotillin-1, and calnexin) of exosomes. RESULTS: The extracts of enriched round and discoid vesicles were successfully extracted with UC, SECF, and PEG. The results of TEM have shown that all three extraction methods can extract circular or elliptical vesicles with disc- and cup-shaped structures from the synovial tissue, with the diameter is about 30-150 nm. NTA suggested the main peaks of three groups of exosomes are around 100-120 nm, and the concentration of the three groups of exosomes was greater than 1 × 1010/ml. The results of WB showed that three positive protein markers (CD9, CD63, and Flotillin-1) were highly expressed in the suspension extracted by the three methods and low in the synovial tissue. However, the negative protein (calnexin) was highly expressed in synovial tissues and PEG group, while low in UC and SECF group. CONCLUSION: Morphology, particle size, and labeled protein marker detection confirmed that UC, SECF, and PEG can extract exosomes derived from synovial tissue; UC and SECF are more recommended for the extraction of synovial tissue-derived exosomes, which provides a methodological basis for studying the function and mechanism of synovial tissue exosomes in the future.

Intra-articular platelet-rich plasma injection for knee osteoarthritis: a summary of meta-analyses.

OBJECTIVE: The purpose of this study was (1) to perform a summary of meta-analyses comparing platelet-rich plasma (PRP) injection with hyaluronic acid (HA) and placebo injection for KOA patients, (2) to determine which meta-analysis provides the best available evidence to making proposals for the use of PRP in the treatment of KOA patients, and (3) to highlight gaps in the literature that require future investigation. MATERIAL AND METHODS: PubMed, EMBASE, and Cochrane databases search were performed for meta-analyses which compared PRP injection with HA or placebo. Clinical outcomes and adverse events were extracted from these meta-analyses. Meta-analysis quality was assessed using the Quality of Reporting of Meta-analyses (QUOROM) systems and the Oxman-Guyatt quality appraisal tool. The Jadad decision algorithm was also used to determine which meta-analysis provided the best available evidence. RESULTS: Four meta-analyses were included in our study, and all of these articles were Level I evidence. The QUOROM score of each included meta-analysis range from 14 to 17 points (mean score 15, maximum score 18), and the Oxman-Guyatt score range from 4 to 6 points (mean score 5, maximum score 7). Three meta-analyses indicated PRP showed more benefit in pain relief and functional improvement than the control group, and the other one suggested no difference between these groups. All included meta-analyses found no statistical difference in adverse events between these groups. In addition, a meta-analysis conducted by Shen et al. got the highest methodological quality score and suggested that PRP provided better pain relief and function improvement in the treatment of KOA. CONCLUSIONS: For short-term follow-up (≤1 year), intra-articular PRP injection is more effective in terms of pain relief and function improvement in the treatment of KOA patients than HA and placebo, and there is no difference in the risk of an adverse event between PRP and HA or placebo. LEVEL OF EVIDENCE: Level I evidence, a summary of meta-analyses TRIAL REGISTRATION: PROSPERO ID CRD42018116168.