Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy.

Tumor metastases and reoccurrence are considered the leading causes of cancer-associated deaths. As an emerging therapeutic method, increasing research efforts have been devoted to immunogenic cell death (ICD)-inducing compounds to solve the challenge. The clinically approved chemotherapeutic Pt complexes are not or are only poorly able to trigger ICD. Herein, the axial functionalization of the Pt(II) complex cisplatin with perfluorocarbon chains into ICD-inducing Pt(IV) prodrugs is reported. Strikingly, while the Pt(II) complex as well as the perfluorocarbon ligands did not induce ICD, the Pt(IV) prodrug demonstrated unexpectantly the induction of ICD through accumulation in the endoplasmic reticulum and generation of reactive oxygen species in this organelle. To enhance the pharmacological properties, the compound was encapsulated with human serum albumin into nanoparticles. While selectively accumulating in the tumorous tissue, the nanoparticles demonstrated a strong tumor growth inhibitory effect against osteosarcoma inside a mouse model. In vivo tumor vaccine analysis also demonstrated the ability of Pt(IV) to be an ideal ICD inducer. Overall, this study reports on axially perfluorocarbon chain-modified Pt(IV) complexes for ICD induction and chemoimmunotherapy in osteosarcoma.

Is it reasonable to shorten the length of cemented stems? A finite element analysis and biomechanical experiment.

Background: Uncemented short stems have been shown to optimize load distribution on the proximal femur, reducing stress shielding and preserving bone mass. However, they may adversely affect the initial stability of the stems. To date, most research conducted on short stems has predominantly centered on uncemented stems, leaving a notable dearth of investigations encompassing cemented stems. Therefore, this study aimed to investigate the length of cemented stems on the transmission of femoral load patterns and assess the initial stability of cemented short stems. Method: A series of finite element models were created by gradient truncation on identical cemented stem. The impact of varying lengths of the cemented stem on both the peak stress of the femur and the stress distribution in the proximal femur (specifically Gruen zones 1 and 7) were assessed. In addition, an experimental biomechanical model for cemented short stem was established, and the initial stability was measured by evaluating the axial irreversible displacement of the stem relative to the cement. Result: The maximum von-Mises stress of the femur was 58.170 MPa. Spearman correlation analysis on the shortened length and von-Mises stress of all nodes in each region showed that the p-values for all regions were less than 0.0001, and the correlation coefficients (r) for each region were 0.092 (Gruen Zone 1) and 0.366 (Gruen Zone 7). The result of the biomechanical experiment showed that the irreversible axial displacement of the stem relative to cement was -870 µm (SD 430 µm). Conclusion: Reducing the length of a cemented stem can effectively enhance the proximal load of the femur without posing additional fracture risk. Moreover, the biomechanical experiment demonstrated favorable initial stabilities of cemented short stems.

Both Acetabular and Femoral Reconstructions With Impaction Bone Grafting in Revision Total Hip Arthroplasty: Case Series and Literature Review.

Background: Extensive bone loss on femur and acetabulum posed a big challenge to orthopedists in total hip revision surgeries. Impaction bone grafting (IBG) as a valuable bone preservation technique could effectively address this problem. Either IBG revision on the femoral or acetabular side was well studied, while its use on both sides in one operation was not. The aim of this study is to present the outcomes of IBG on both femoral and acetabular sides at first-time hip revision. Methods: We retrospectively reviewed 8 patients (mean follow-up of 5.8 years) undergoing first-time revision with IBG on both acetabular and femoral sides at our institution. The Paprosky classification system was used to classify bone defects. Freeze-dried allografts and cemented prostheses were used in all patients. Postoperative complications and rerevision rates were reported. Results: Five patients presented a Paprosky type IIC acetabular defect, 3 with a type IIIB, IIIA, and IIC defect, respectively. Three patients presented with a type IV femoral defect, 3 with a type IIIB defect, and 2 with a type II defect. Two patients developed complications, while one had an intraoperative femoral fracture and one had delayed wound healing. At the latest follow-up, no patient had rerevisions or operations related to the prosthesis. Conclusions: IBG in combination with cemented prosthesis is a profitable biological reconstruction revision technique that could provide satisfying midterm outcomes. We first propose the use of blood clots mixed with bone grafts for potential bone incorporation enhancement, while its specific effects need to be verified in further studies.

Mesenchymal stem cells in osteoarthritis: The need for translation into clinical therapy.

Widely used for cell-based therapy in various medical fields, mesenchymal stem cells (MSCs) show capacity for anti-inflammatory effects, anti-apoptotic activity, immunomodulation, and tissue repair and regeneration. As such, they can potentially be used to treat osteoarthritis (OA). However, MSCs from different sources have distinct advantages and disadvantages, and various animal models and clinical trials using different sources of MSCs are being conducted in OA regenerative medicine. It is now widely believed that the primary tissue regeneration impact of MSCs is via paracrine effects, rather than direct differentiation and replacement. Cytokines and molecules produced by MSCs, including extracellular vesicles with mRNAs, microRNAs, and bioactive substances, play a significant role in OA repair. This chapter outlines the properties of MSCs and recent animal models and clinical trials involving MSCs-based OA therapy, as well as how the paracrine effect of MSCs acts in OA cartilage repair. Additionally, it discusses challenges and controversies in MSCs-based OA therapy. Despite its limits and unanticipated hazards, MSCs have the potential to be translated into therapeutic therapy for future OA treatment.

Inhibition of Leukotriene A4 Hydrolase Suppressed Cartilage Degradation and Synovial Inflammation in a Mouse Model of Experimental Osteoarthritis.

OBJECTIVE: Chronic inflammation plays an important role in the osteoarthritis (OA) pathology but how this influence OA disease progression is unclear. Leukotriene B4 (LTB4) is a potent proinflammatory lipid mediator generated from arachidonic acid through the sequential activities of 5-lipoxygenase, 5-lipoxygenase-activating protein, Leukotriene A4 hydrolase (LTA4H) and its downstream product LTB4. The aim of this study is to investigate the involvement and the potential therapeutic target of the LTB4 pathway in OA disease progression. DESIGN: Both clinical human cartilage samples (n = 7) and mice experimental OA models (n = 6) were used. The levels of LTA4H and leukotriene B4 receptor 1 were first examined using immunostaining in human OA/non-OA cartilage and mice experimental OA models. We also determined whether the LTA4H pathway was associated with cartilage degeneration and synovitis inflammation in OA mice models and human articular chondrocytes. RESULTS: We found that both LTA4H and LTB4 receptor (BLT1) were highly expressed in human and mice OA cartilage. Inhibition of LTA4H suppressed cartilage degeneration and synovitis in OA mice model. Furthermore, inhibition of LTA4H promoted cartilage regeneration by upregulating chondrogenic genes expression such as aggrecan (ACAN), collagen 2A1 (COL2A1), and SRY-Box transcription factor 9 (SOX9). CONCLUSIONS: Our results indicate that the LTA4H pathway is a crucial regulator of OA pathogenesis and suggest that LTA4H could be a therapeutic target in combat OA.

Impaction Bone Grafting with Low Dose Irradiated Freeze-Dried Allograft Bone for Acetabular Reconstruction.

OBJECTIVE: Reconstruction of acetabular defects has been extremely challenging in both primary and revision total hip arthroplasty (THA). Impaction bone grafting (IBG) can restore the acetabulum bone mass and anatomically reconstruct the acetabulum. Our study aimed to report the short and medium-term clinical and radiographic outcomes of IBG for acetabular reconstruction in the cemented THA in the Chinese population. METHODS: This was a single-center retrospective review enrolling 57 patients between May 2013 and July 2019. The patients with acetabular defects were treated with IBG, using low dose irradiated freeze-dried allograft bone with or without autograft bone, in the cemented THA performed by one senior surgeon. Harris hip score (HHS), standard pelvis anterior-posterior radiograph and lateral hip radiograph were obtained before operation and at 1 week, 3 months, 12 months, and yearly. Graft osteointegration was evaluated by Oswestry's criteria, and complication was documented at the last follow-up. Independent sample ANOVA test and Pearson chi-square tests are used for statistical analysis. RESULTS: There were 61 hips in 57 patients. The average follow-up time was 35.59 months (5-77 months). According to AAOS classification, a total of 18 hips were identified as segmental bone deficiency (type I), with 21 and 22 hips for cavitary bone deficiency (type II) and the combined bone deficiency (type III), respectively. The average HHS was improved from 44.49 (range: 32-58) preoperatively to 86.98 (range: 78-93) postoperatively. Graft osteointegration was satisfactory (Oswestry score ≥2) in all patients. No dislocation occurred in the 57 patients (61 hips) during follow-up. Although one cup migrated, no revision, re-revision, radiographic loosening, graft bone lysis, or postoperative complications were detected at the final follow-up. CONCLUSIONS: IBG with low-dose irradiated freeze-dried allograft bone in acetabular bone defect reconstruction is a reliable technique for restoring acetabular bone defects in THA.

Arthroscopic Management of Giant Meniscal Cysts Among Young Patients: An Average Three-Year MRI Follow-Up.

OBJECTIVE: To describe an arthroscopic technique for giant meniscal cyst excision with preservation of the functional meniscus, report the short- and medium-term outcomes, and assess magnetic resonance imaging (MRI) for follow-up imaging evaluations. METHODS: A total of 54 consecutive patients with symptomatic meniscal cysts were admitted to the Second Xiangya Hospital of Central South University between 2014 and 2019. Nine patients with giant meniscus cysts (six females and three males) were included in this study. The age range of the patients was 6-34 years. All patients underwent a complete physical examination, X-ray, Doppler ultrasound, and MRI of the knee preoperatively. After an arthroscopic diagnosis of a meniscal rupture with a giant meniscal cyst, partial meniscectomy, ablation of the cyst, and suturing of the retainable meniscus were performed. Lysholm and International Knee Documentation Committee (IKDC) scores were used preoperatively and at the most recent follow-up. Clinical outcomes were classified into four categories: excellent, good, fair, and poor. During the last visit, all patients underwent MRI to assess the recurrence of the cyst and meniscal suture healing. RESULTS: Preoperative MRI and arthroscopic examination revealed giant meniscal cysts combined with meniscal tears and congenital discoid meniscus, and all giant meniscal cysts occurred in the lateral meniscus. The main types of meniscal tears were horizontal and complex tears. The cysts were unicystic in one case and multicystic in eight cases. The mean size of the cysts on the MRI was 5.86 cm × 2.24 cm × 2.48 cm. The mean follow-up periods were 37.5 (19-60) months. Clinical outcomes were excellent in six patients and good in three patients. The postoperative scores were significantly improved compared to the preoperative scores (Lysholm: 90.78 ± 4.60 vs. 54.56 ± 7.25; IKDC: 96.2 ± 3.46 vs. 61.69 ± 3.36; p <0.01). No recurrence of the cyst was indicated on the MRI, and there was good healing of the torn meniscus. CONCLUSIONS: Arthroscopic cystectomy combined with the meniscus suture technique was effective to eradicate residual cyst cavities, and traffic orifices be highly recommended.

Nanoparticle delivery of a triple-action Pt(IV) prodrug to overcome cisplatin resistance via synergistic effect.

Cisplatin is the most widely used chemotherapeutic agent due to its efficacy in the treatment of a broad range of cancer types; while the side effects and drug resistance of cisplatin limit its clincial application. Combination therapy, which contains several types of free drugs, exhibits promising potential in clinical practice. Nevertheless, current combination chemotherapy cannot accurately deliver different drug components into a single tumor cell at the same time. Herein, we report a triple-action nanoplatinum drug based on artesunate and cantharidin to overcome the influence of pharmacokinetics and distribution variation in different drugs. The results show that the triple action nanoplatinum drug enhances ROS generation, leads to DNA damage, and inhibits DNA repair. Therefore, a high-efficiency killing effect is achieved with a triple-action platinum drug in a single tumor cell.

Nanoparticle-based drug delivery systems with platinum drugs for overcoming cancer drug resistance.

Platinum drugs are commonly used in cancer therapy, but their therapeutic outcomes have been significantly compromised by the drug resistance of cancer cells. To this end, intensive efforts have been made to develop nanoparticle-based drug delivery systems for platinum drugs, due to their multifunctionality in delivering drugs, in modulating the tumor microenvironment, and in integrating additional genes, proteins, and small molecules to overcome chemoresistance in cancers. To facilitate the clinical application of these promising nanoparticle-based platinum drug delivery systems, this paper summarizes the common mechanisms for chemoresistance towards platinum drugs, the advantages of nanoparticles in drug delivery, and recent strategies of nanoparticle-based platinum drug delivery. Furthermore, we discuss how to design delivery platforms more effectively to overcome chemoresistance in cancers, thereby improving the efficacy of platinum-based chemotherapy.

Identification of KIF4A as a pan-cancer diagnostic and prognostic biomarker via bioinformatics analysis and validation in osteosarcoma cell lines.

BACKGROUND: Cancer is a disease of abnormal cell proliferation caused by abnormal expression of cancer-related genes. However, it is still difficult to distinguish benign and malignant lesions in many cases. KIF4A has been reported to be associated with a variety of cancer lesions. We aimed to explore whether KIF4A could be used as a biomarker of pan-cancer diagnostic. METHODS: We identified twenty-eight cell cycle-related genes that were overexpressed in no less than ten types of cancer. We determined KIF4A mRNA and protein expression in osteosarcoma (OS) cells. Furthermore, to determine the effect of KIF4A in OS, we silenced KIF4A in OS cells and detected cell viability, colony formation, invasion, migration, apoptosis and cell cycle parameters. RESULTS: KIF4A exhibited upregulated expression in eleven types of cancer. Cell cycle-related genes are extensively overexpressed in various types of cancers. KIF4A overexpression can serve as a diagnostic and prognostic marker in various cancers. Silencing KIF4A inhibited the viability, colony formation, invasion and migration and induced apoptosis and cell cycle arrest of OS cells. Our findings revealed that high expression of KIF4A could serve as a diagnostic and prognostic marker in OS cancers. CONCLUSION: KIF4A could serve as a pan-cancer diagnostic and prognostic marker. KIF4A could be used as a novel therapeutic target for OS.

Effects of Judet Quadricepsplasty in the Treatment of Post-traumatic Extension Contracture of the Knee.

OBJECTIVE: To investigate the clinical outcomes and the affecting factors of Judet's quadricepsplasty on the stiffness of post-traumatic knee flexion. METHODS: A retrospective survey was analyzed from June 2015 to October 2018. A total of 15 patients (eight males, seven females; mean age, 48.27 years) with extension contracture of the knee were treated by Judet's quadricepsplasty. All cases were injuries induced by fracture trauma. The mean interval between the initial procedure and quadricepsplasty was 56.2 months (range, 13-276 months). The knee range of motion (ROM) was assessed with a goniometer. The results of the procedure were analyzed by measuring the degrees of flexion of the operated knees at different time points (before, immediately after, and late postoperatively). We evaluated Hospital for Special Surgery (HSS) score, Judet's criteria, change in the degree of knee flexion, and complications. RESULTS: All patients were followed up for 14 to 47 months, with an average of 31.53 months. The degree of flexion increased from 23.33° (range, 10°-50°) preoperatively to 107.33° (range, 100°-125°) intraoperatively, followed by a slight fall in the range of flexion in the late postoperative period, which reached an average of 95.33° (range, 60°-115°) in the last follow-up. The knee joint function was assessed according to the Judet's criteria, eight cases (53.33%) achieved excellent results, six (40%) good, one (6.67%) fair, and zero (0.00%) poor results at final follow-up. The long-term excellent and good rate was 93.33%. The range of flexion of the knee during operation and at the last time of follow-up was better than that before surgery (P < 0.001). The final flexion was significantly lower than that measured at immediate postoperative (P < 0.001). The mean postoperative HSS score for the entire group was 93.73 (range, 89-96). Fifteen excellent results were obtained according to the HSS knee score. Skin infection was seen in one patient (6.67%). There were no complications such as deep sepsis, intraoperative rupture of the quadriceps tendon, fracture of the lateral femoral condyle, skin dehiscence. CONCLUSION: Judet quadricepsplasty is an effective method to treat knee extension contracture and improve knee range of motion (ROM). It should be performed by an experienced orthopaedic surgeon and followed by physiotherapy with continuous passive motion (CPM). The knee ROM obtained with the surgery has an excellent long-term effect.

Effects of Diet Induced Weight Reduction on Cartilage Pathology and Inflammatory Mediators in the Joint Tissues.

Obesogenic diets contribute to the pathology of osteoarthritis (OA) by altering systemic and local metabolic inflammation. Yet, it remains unclear how quickly and reproducibly the body responds to weight loss strategies and improve OA. In this study we tested whether switching obese diet to a normal chow diet can mitigate the detrimental effects of inflammatory pathways that contribute to OA pathology. Male C57BL/6 mice were first fed with obesogenic diet (high fat diet) and switched to normal chow diet (obese diet → normal diet) or continued obese diet or normal diet throughout the experiment. A mouse model of OA was induced by surgical destabilization of the medial meniscus (DMM) model into the knee joint. Outcome measures included changes in metabolic factors such as glucose, insulin, lipid, and serum cytokines levels. Inflammation in synovial biopsies was scored and inflammation was determined using FACs sorted macrophages. Cartilage degeneration was monitored using histopathology. Our results indicate, dietary switching (obese diet → normal diet) reduced body weight and restored metabolic parameters and showed less synovial tissue inflammation. Systemic blood concentrations of pro-inflammatory cytokines IL-1α, IL-6, IL-12p40, and IL-17 were decreased, and anti-inflammatory cytokines IL-4 and IL-13 were increased in dietary switch group compared to mice that were fed with obesogenic diet continuously. Although obese diet worsens the cartilage degeneration in DMM OA model, weight loss induced by dietary switch does not promote the histopathological changes of OA during this study period. Collectively, these data demonstrate that switching obesogenic diet to normal improved metabolic syndrome symptoms and can modulate both systemic and synovium inflammation levels.

Osteoarthritic Subchondral Bone Release Exosomes That Promote Cartilage Degeneration.

Altered subchondral bone and articular cartilage interactions have been implicated in the pathogenesis of osteoarthritis (OA); however, the mechanisms remain unknown. Exosomes are membrane-derived vesicles that have recently been recognized as important mediators of intercellular communication. Herein, we investigated if OA subchondral bone derived exosomes alter transcriptional and bioenergetic signatures of chondrocytes. Exosomes were isolated and purified from osteoblasts of nonsclerotic or sclerotic zones of human OA subchondral bone and their role on the articular cartilage chondrocytes was evaluated by measuring the extent of extracellular matrix production, cellular bioenergetics, and the expression of chondrocyte activity associated marker genes. Exosomal microRNAs were analyzed using RNA sequencing and validated by quantitative real-time PCR and loss-of-function. In coculture studies, chondrocytes internalized OA sclerotic subchondral bone osteoblast derived exosomes and triggered catabolic gene expression and reduced chondrocyte-specific marker expression a phenomenon that is often observed in OA cartilage. RNA sequencing and miRNA profiling have identified miR-210-5p, which is highly enriched in OA sclerotic subchondral bone osteoblast exosomes, triggered the catabolic gene expression in articular cartilage chondrocytes. Importantly, we demonstrate that miR-210-5p suppresses the oxygen consumption rate of chondrocytes, altering their bioenergetic state that is often observed in OA conditions. These effects were markedly inhibited by the addition of a miR-210-5p inhibitor. Our study indicates that exosomes released by OA sclerotic subchondral bone osteoblasts plays a critical role in progression of cartilage degeneration and might be a potential target for therapeutic intervention in OA.

Mesenchymal Stem Cell-Derived Exosomes Modulate Chondrocyte Glutamine Metabolism to Alleviate Osteoarthritis Progression.

Osteoarthritis (OA) had a high incidence in people over 65 years old, and there is currently no drug that could completely cure it. This study is aimed at studying the role of exosomes in regulating glutamine metabolism in the treatment of OA. First, we identified the exosomes extracted from the mouse OA model's bone marrow mesenchymal stem cells (MSC). In vitro, compared with the control group, the cell apoptosis in the OA group increased, while the cell proliferation of the OA group was suppressed. After exosomal treatment, cell apoptosis and cell proliferation were reversed. Inflammatory factors (TNFα, IL-6), glutamine metabolic activity-related proteins (c-MYC, GLS1), glutamine, and GSH/GSSG were increased in the OA group. The overexpression of c-MYC reduced the therapeutic effect of exosomes. At the same time, we found that chondrocyte functional factors (collagen II, Aggrecan) were improved under the treatment of exosomes. However, oe-c-MYC reversed the therapeutic effect of exosomes. In vivo, we found that the running capacity of the mice in the OA group was reduced, and the cartilage tissue was severely damaged. In addition, TNFα, IL-6, and chondrocyte apoptosis increased, while the metabolism of collagen II, Aggrecan, and glutamate decreased in the OA group. After exosomal treatment, the mice's exercise capacity, tissue damage, inflammation, and chondrocyte function were improved, and glutamate metabolism was increased. This study showed that exosomes regulated the level of chondrocyte glutamine metabolism by regulating c-MYC, thereby alleviating OA.

Efficacy and safety of tranexamic acid in unilateral major revision total hip arthroplasty.

BACKGROUND: The risk of blood loss differs among subtypes of revision total hip arthroplasty (THA), and different tranexamic acid (TXA) protocols have rarely been studied in those conditions. The present study aimed to evaluate the efficacy and safety of intravenous and intravenous plus topical TXA in a subtype of revision THA. METHODS: We retrospectively reviewed 91 patients who underwent unilateral major revision THA from 2010 to 2018. The major revision was defined as a subtype of revision THA, which included concomitant femoral and acetabular components revision, revision for periprosthetic femoral fracture (PFF), and one-stage revision for periprosthetic joint infection (PJI). In the intravenous group, 23 patients received intravenously 1 g of TXA 30 minutes before the incision with the second dose 3 hours later. In the combined group, 20 patients received intravenously 1 g of TXA 30 minutes before the incision with the second dose 3 hours later, and 2 g of TXA was topically injected around the joint capsule when the fascia layer was closed. Forty-eight patients who underwent revision procedures without TXA constituted the control group. Within the three groups, we compared demographic variables, operation-related data, transfusion volume, transfusion rate, calculated blood loss, postoperative drainage volume, and venous thromboembolism (VTE) risk. RESULTS: Compared with the control group, both intravenous and combined TXA significantly reduced intraoperative transfusion volume (3.43±2.32 vs. 4.68±2.63 units, P=0.044; 2.78±1.91 vs. 4.68±2.63 units, P=0.004; respectively) and total transfusion volume (4.16±2.73 vs. 5.73±3.05 units, P=0.036; 3.50±2.74 vs. 5.73±3.05 units, P=0.005; respectively), and there were significant reductions of postoperative drainage volume (250.87±204.54 vs. 455.73±303.93 mL, P=0.003; 285.00±218.14 vs. 455.73±303.93 mL, P=0.017; respectively) and calculated blood loss (1,322.49±656.13 vs. 1,698.66±728.39 mL, P=0.031; 1,237.13±545.32 vs. 1,698.66±728.39 mL, P=0.012; respectively). One patient had a symptomatic pulmonary embolism, and two patients had calf muscular vein thrombosis in the control group. There were two patients and one patient with calf muscular vein thrombosis in the intravenous group and the combined group, respectively. Perioperative transfusion volume, transfusion rate, and calculated blood loss were comparable between the intravenous group and the combined group. CONCLUSIONS: Both intravenous TXA and combined TXA significantly reduced perioperative transfusion volume and calculated blood loss in unilateral major revision THA with comparable perioperative transfusion rate and risk of VTE. More researches are required to explore the optimal TXA administration protocol in subtypes of revision THA.

TNF-α regulates the early development of avascular necrosis of the femoral head by mediating osteoblast autophagy and apoptosis via the p38 MAPK/NF-κB signaling pathway.

Previous studies have shown that the tumor necrosis factor-α (TNF-α) levels in serum and bone tissues formed in avascular necrosis of femoral head (ANFH) patients were higher than those of normal individuals, indicating TNF-α might play a role in the pathogenesis of ANFH. However, the underlying mechanisms remain unclear. Hematoxylin and eosin staining was performed to show the pathological changes of ANFH bone tissues. TNF-α expression in normal and ANFH tissues was examined by quantitative real-time polymerase chain reaction and western blot analyses. Osteoblast autophagy and apoptosis, as well as signaling pathways activation, were measured by their corresponding marker proteins. Osteoblast proliferation, autophagy, and apoptosis were evaluated using cell counting kit-8, transmission electron microscopy, and flow cytometry. The structures of bone tissues of ANFH were obviously damaged. TNF-α expression was significantly upregulated in ANFH bone tissues compared to normal tissues. Autophagy and apoptosis were remarkably promoted, and p38 mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signaling pathways were markedly activated in ANFH. Suppression of the p38 MAPK/NF-κB pathway significantly attenuated the TNF-α-induced autophagy, however, enhanced the TNF-α-induced apoptosis in osteoblasts. Increased TNF-α in ANFH regulated osteoblast autophagy and apoptosis by p38 MAPK/NF-κB signaling pathways, blocking the pathway by inhibitors exacerbated TNF-α-induced apoptosis through impairing autophagy flux.

MicroRNA-375 exacerbates knee osteoarthritis through repressing chondrocyte autophagy by targeting ATG2B.

OBJECTIVE: This study aimed to explore the underlying mechanism of miR-375 in exacerbating osteoarthritis (OA). RESULTS: MiR-375 expression were upregulated in OA cartilage tissues, whereas ATG2B expression was decreased. MiR-375 targeted ATG2B 3' UTR and inhibited its expression in the chondrocytes, and then suppressed autophagy and promoted endoplasmic reticulum stress (ERs). The apoptosis rate of chondrocytes was increased after being transfected with miR-375 mimics. In vivo results further verified that inhibition of miR-375 could relieve OA-related symptoms. CONCLUSION: miR-375 can inhibit the expression of ATG2B in chondrocytes, suppress autophagy and promote the ERs. It suggests that miR-375 could be considered to be a key therapy target for OA. METHODS: Differential expression analyses for mRNA and miRNA microarray datasets from ArrayExpress were performed. MiR-375 and ATG2B expressions in cartilage tissues were detected by qRT-PCR. Dual luciferase assay was applied to verify the targeting relationship between ATG2B and miR-375. In vitro, the role of miR-375 on chondrocyte autophagy and ERs was investigated by western blot and immunofluorescence. The apoptotic rate was quantified by flow cytometry. In vivo, OA mice model was established, HE and Safranin O and Fast Green staining, as well as the OARSI and modified Mankin scores, were applied to measure the OA cartilage damage severity.

Extracellular vesicles: Potential role in osteoarthritis regenerative medicine.

Osteoarthritis (OA) is a prevalent whole joint disease characterised by cartilage degradation, subchondral bone sclerosis and bone remodelling, and synovium inflammation, leading to pain, deformity, and cartilage dysfunction. Currently, there is no appropriate therapy for OA, and available treatments simply aim to reduce pain and swelling. Exosomes are membrane-bound extracellular vesicles secreted by almost all cells, receiving increasing interest because of their effect in cell-to-cell communication. Increasing evidence suggests that exosomes play an important role in cartilage physiological and pathological effects. This article reviews the potential role of exosomes in OA regenerative medicine. Special attention is given to mesenchymal stem cells-derived exosomes due to the extensive research on their cartilage repair property and their function as miRNA cargo. More investigations are needed for the effects of exosomes from synovial fluid and chondrocytes in joints. A better understanding of the mechanisms will contribute to a novel and promising therapy for OA patients. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: A better understanding of the role of extracellular vesicles in regenerative medicine will contribute to a novel and promising therapy for OA patients.

Oxygen embolism after hydrogen peroxide irrigation during hip arthroscopy: a case report.

BACKGROUND: Hydrogen peroxide has been widely used in Orthopaedics including Orthopaedic oncology, trauma and joint surgeries. However, we encountered an oxygen embolism and myoglobinuria after hydrogen peroxide was used to irrigate a septic hip arthroscopically. CASE PRESENTATION: A 61-year-old male patient with right hip septic arthritis underwent an arthroscopic hip washout and debridement. During the operation, the surgeon used 100 ml of 3% hydrogen peroxide to irrigate the joint cavity. Two minutes after irrigation, there was a transient decrease in oxygen saturation, heart rate and blood pressure, with significant subcutaneous emphysema around the wound. Concentrated urine was drained out 8 h after operation which resolved the following day. Post-operatively, the patient was managed in the intensive care unit for a pulmonary embolism and discharged without further complications. CONCLUSION: Medical staff should be aware of the risk of oxygen embolism and be extremely careful when using hydrogen peroxide in patient care. Oxygen embolism following hydrogen peroxide use is rare, however, once encountered, it may bring serious consequences. Therefore, the use of hydrogen peroxide in closed spaces or arthroscopic procedures should be discontinued.

Association of global DNA hypomethylation with post-operative cognitive dysfunction in elderly patients undergoing hip surgery.

BACKGROUND: Post-operative cognitive dysfunction (POCD) is a decline of cognitive status that commonly occurs after surgery in elderly patients. Whether DNA methylation is associated with the development of POCD remains unclear. METHODS: Subjects (N = 124) older than 65 years-of-age undergoing hip replacement surgery were enrolled. A battery of neuropsychiatric tests was used to examine the perioperative cognitive function of the patients. Early POCD was analyzed using the reliable change index (RCI), and subjects were diagnosed with POCD if RCI < -1.96. Peripheral leukocyte DNA was isolated, and DNA methylation was measured via 5-methylcytosine (mC) using Elisa. RESULTS: Twenty-four patients (19.4%) developed early POCD. There was no difference in baseline 5-mC levels by POCD status. The 5-mC levels significantly decreased on day 7 after surgery in patients who developed early POCD (P = .004), but did not change in non-POCD patients. Moreover, post-operative 5-mC levels were significantly lower in POCD patients than those in non-POCD patients (P = .003). Bivariate logistic models adjusted for age, gender, BMI, duration of anesthesia, and education level clearly demonstrated an independent association between post-operative 5-mC level and early POCD. CONCLUSIONS: Post-operative global hypomethylation of leukocyte DNA was associated with the development of early POCD. TRIAL REGISTRATION: ClinicalTrial, NCT02965235. Registered 16 November 2016, https://www.clinicaltrials.gov/ct2/results?term=NCT02965235&rank=1#rowId0.