Decision tree models for the estimation of geo-polymer concrete compressive strength.

The green concretes industry benefits from utilizing gel to replace parts of the cement in concretes. However, measuring the compressive strength of geo-polymer concretes (CSGPoC) needs a significant amount of work and expenditure. Therefore, the best idea is predicting CSGPoC with a high level of accuracy. To do this, the base learner and super learner machine learning models were proposed in this study to anticipate CSGPoC. The decision tree (DT) is applied as base learner, and the random forest and extreme gradient boosting (XGBoost) techniques are used as super learner system. In this regard, a database was provided involving 259 CSGPoC data samples, of which four-fifths of is considered for the training model and one-fifth is selected for the testing models. The values of fly ash, ground-granulated blast-furnace slag (GGBS), Na2SiO3, NaOH, fine aggregate, gravel 4/10 mm, gravel 10/20 mm, water/solids ratio, and NaOH molarity were considered as input of the models to estimate CSGPoC. To evaluate the reliability and performance of the decision tree (DT), XGBoost, and random forest (RF) models, 12 performance evaluation metrics were determined. Based on the obtained results, the highest degree of accuracy is achieved by the XGBoost model with mean absolute error (MAE) of 2.073, mean absolute percentage error (MAPE) of 5.547, Nash-Sutcliffe (NS) of 0.981, correlation coefficient (R) of 0.991, R2 of 0.982, root mean square error (RMSE) of 2.458, Willmott's index (WI) of 0.795, weighted mean absolute percentage error (WMAPE) of 0.046, Bias of 2.073, square index (SI) of 0.054, p of 0.027, mean relative error (MRE) of -0.014, and a20 of 0.983 for the training model and MAE of 2.06, MAPE of 6.553, NS of 0.985, R of 0.993, R2 of 0.986, RMSE of 2.307, WI of 0.818, WMAPE of 0.05, Bias of 2.06, SI of 0.056, p of 0.028, MRE of -0.015, and a20 of 0.949 for the testing model. By importing the testing set into trained models, values of 0.8969, 0.9857, and 0.9424 for R2 were obtained for DT, XGBoost, and RF, respectively, which show the superiority of the XGBoost model in CSGPoC estimation. In conclusion, the XGBoost model is capable of more accurately predicting CSGPoC than DT and RF models.

WTAP-mediated m6A modification of FRZB triggers the inflammatory response via the Wnt signaling pathway in osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis. However, the exact pathogenesis remains unclear. Emerging evidence shows that N6-methyladenosine (m6A) modification may have an important role in OA pathogenesis. This study aimed to investigate the role of m6A writers and the underlying mechanisms in osteoarthritic cartilage. Among m6A methyltransferases, Wilms tumor 1-associated protein (WTAP) expression most significantly differed in clinical osteoarthritic cartilage. WTAP regulated extracellular matrix (ECM) degradation, inflammation and antioxidation in human chondrocytes. Mechanistically, the m6A modification and relative downstream targets in osteoarthritic cartilage were assessed by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing, which indicated that the expression of frizzled-related protein (FRZB), a secreted Wnt antagonist, was abnormally decreased and accompanied by high m6A modification in osteoarthritic cartilage. In vitro dysregulated WTAP had positive effects on ß-catenin expression by targeting FRZB, which finally contributed to the cartilage injury phenotype in chondrocytes. Intra-articular injection of adeno-associated virus-WTAP alleviated OA progression in a mouse model, while this protective effect could be reversed by the application of a Wnt/ß-catenin activator. In summary, this study revealed that WTAP-dependent RNA m6A modification contributed to Wnt/ß-catenin pathway activation and OA progression through post-transcriptional regulation of FRZB mRNA, thus providing a potentially effective therapeutic strategy for OA treatment.

Doxorubicin-Loaded Microalgal Delivery System for Combined Chemotherapy and Enhanced Photodynamic Therapy of Osteosarcoma.

Osteosarcoma (OS) is considered the most frequent type of primary malignant bone tumor. Currently, radiotherapy, photodynamic (PDT), and other therapies for osteosarcoma are limited by tumor hypoxia and single efficacy and serve side-effects. Herein, we reported a microalgal drug delivery system (SpiD), doxorubicin (DOX)-loaded Spirulina platensis (Spi) for OS therapy. The specific surface of Spirulina platensis allowed for effective loading of DOX via surface channels and electrostatic interactions. Under 650 nm laser irradiation, SpiD enabled high oxygen production by photosynthesis and enhanced reactive oxygen species (ROS) generation via chlorophyll-assisted photosensitization, synergistically killing tumor cells with the released DOX. Combined chemotherapy and enhanced PDT mediated by SpiD exerted synergic antitumor effects and resulted in potent therapeutic efficacy in orthotopic osteosarcoma mice. Furthermore, SpiD could reduce the side-effects of chemotherapy, showing excellent blood and tissue safety. Taken together, this microalgal drug delivery system provided a natural, efficient, safe, and inexpensive strategy for OS treatment.

Impact of spinal Anaesthesia versus general Anaesthesia on the incidence of surgical site infections after knee or hip arthroplasty: A meta-analysis.

Postoperative Surgical Site Infections (SSIs) pose significant challenges to recovery after joint arthroplasty. This systematic review and meta-analysis aim to compare the incidence of SSIs after knee or hip arthroplasty under Spinal Anaesthesia (SA) versus general anaesthesia (GA). We conducted the systematic review and meta-analysis following the PRISMA guidelines, analysing data from 15 studies selected from PubMed, Embase, Web of Science, and Cochrane Library up to May 16, 2023. The analysis included studies comparing SSIs incidence in patients aged 18 years and above who underwent knee or hip arthroplasty under SA or GA. Quality assessment was performed using the Cochrane Collaboration's risk of bias tool. The effect size was calculated using random or fixed-effects models based on the observed heterogeneity. We assessed the heterogeneity between studies and conducted a sensitivity analysis. Of 1651 initially identified studies, 15 articles encompassing 353 169 patients were included in the final analysis. A total of 156 405 patients were under SA, while 196 764 received GA. The studies demonstrated substantial heterogeneity (p = 0.007, I2 = 53.7%), resulting in a random-effects model being employed. Patients receiving SA showed a 23% lower likelihood of developing SSIs postoperatively compared to GA patients (OR: 0.77, 95% CI: 0.70-0.86, p < 0.001). Sub-group analysis further confirmed these findings regardless of the type of joint arthroplasty. This meta-analysis indicated a significantly lower incidence of SSIs following knee or hip arthroplasty under SA compared to GA. Despite observed heterogeneity, the results underscore the potential benefit of SA over GA in orthopaedic surgeries to reduce the risk of SSIs.

A novel allogeneic acellular matrix scaffold for porcine cartilage regeneration.

BACKGROUND: Cartilage defects are common sports injuries without significant treatment. Articular cartilage with inferior regenerative potential resulted in the poor formation of hyaline cartilage in defects. Acellular matrix scaffolds provide a microenvironment and biochemical properties similar to those of native tissues and are widely used for tissue regeneration. Therefore, we aimed to design a novel acellular cartilage matrix scaffold (ACS) for cartilage regeneration and hyaline-like cartilage formation. METHODS: Four types of cartilage injury models, including full-thickness cartilage defects (6.5 and 8.5 mm in diameter and 2.5 mm in depth) and osteochondral defects (6.5 and 8.5 mm in diameter and 5 mm in depth), were constructed in the trochlear groove of the right femurs of pigs (n = 32, female, 25-40 kg). The pigs were divided into 8 groups (4 in each group) based on post-surgery treatment differences. was assessed by macroscopic appearance, magnetic resonance imaging (MRI), micro-computed tomography (micro-CT), and histologic and immunohistochemistry tests. RESULTS: At 6 months, the ACS-implanted group exhibited better defect filling and a greater number of chondrocyte-like cells in the defect area than the blank groups. MRI and micro-CT imaging evaluations revealed that ACS implantation was an effective treatment for cartilage regeneration. The immunohistochemistry results suggested that more hyaline-like cartilage was generated in the defects of the ACS-implanted group. CONCLUSIONS: ACS implantation promoted cartilage repair in full-thickness cartilage defects and osteochondral defects with increased hyaline-like cartilage formation at the 6-month follow-up.

Long noncoding RNA TUG1 promotes malignant progression of osteosarcoma by enhancing ZBTB7C expression.

BACKGROUND: Dysregulation of long non-coding RNAs (lncRNAs) is an important component of tumorigenesis. Aberrant expression of lncRNA taurine upregulated gene 1 (lncTUG1) has been reported in various tumors; however, its precise role and key targets critically involved in osteosarcoma (OS) progression remains unclear. METHODS: The expression profiles of lncRNAs and its regulated miRNAs related to OS progression were assessed by bioinformatics analysis and confirmed by qRT-PCR of OS cells. The miRNA targets were identified by transcriptome sequencing and verified by luciferase reporter and RNA pull-down assays. Several in vivo and in vitro approaches, including CCK8 assay, western blot, qRT-PCR, lentiviral transduction and OS cell xenograft mouse model were established to validate the effects of lncTUG1 regulation of miRNA and the downstream target genes on OS cell growth, apoptosis and progression. RESULTS: We found that lncTUG1 and miR-26a-5p were inversely up or down-regulated in OS cells, and siRNA-mediated lncTUG1 knockdown reversed the miR-26a-5p down-regulation and suppressed proliferation and enhanced apoptosis of OS cells. Further, we identified that an oncoprotein ZBTB7C was also upregulated in OS cells that were subjected to lncTUG1/miR-26a-5p regulation. More importantly, ZBTB7C knockdown reduced the ZBTB7C upregulation and ZBTB7C overexpression diminished the anti-OS effects of lncTUG1 knockdown in the OS xenograft model. CONCLUSIONS: Our data suggest that lncTUG1 acts as a miR-26a-5p sponge and promotes OS progression via up-regulating ZBTB7C, and targeting lncTUG1 might be an effective strategy to treat OS.

Microtubule stabilization targeting regenerative chondrocyte cluster for cartilage regeneration.

Purpose: Chondrocytes (CHs) in cartilage undergo several detrimental events during the development of osteoarthritis (OA). However, the mechanism underlying CHs regeneration involved in pathogenesis is largely unknown. The aim of this study was to explore the underlying mechanism of regeneration of CHs involved in the pathological condition and the potential therapeutic strategies of cartilage repair. Methods and Materials: CHs were isolated from human cartilage in different OA stages and the high-resolution cellular architecture of human osteoarthritis was examined by applying single-cell RNA sequencing. The analysis of gene differential expression and gene set enrichment was utilized to reveal the relationship of cartilage regeneration and microtubule stabilization. Microtubule destabilizer (nocodazole) and microtubule stabilizer (docetaxel) treated-human primary CHs and rats cartilage defect model were used to investing the effects and downstream signaling pathway of microtubule stabilization on cartilage regeneration. Results: CHs subpopulations were identified on the basis of their gene markers and the data indicated an imbalance caused by an increase in the degeneration and disruption of CHs regeneration in OA samples. Interestingly, the CHs subpopulation namely CHI3L1+ CHs, was characterized by the cell regenerative capacity, stem cell potency and the activated microtubule (MT) process. Furthermore, the data indicated that MT stabilization was effective in promoting cartilage regeneration in rats with cartilage injury model by inhibiting YAP activity. Conclusion: These findings lead to a new understanding of CHs regeneration in the OA pathophysiology context and suggest that MT stabilization is a promising therapeutic target for OA and cartilage injury.

Bone microenvironment regulative hydrogels with ROS scavenging and prolonged oxygen-generating for enhancing bone repair.

Large bone defects resulting from fractures and disease are a major clinical challenge, being often unable to heal spontaneously by the body's repair mechanisms. Lines of evidence have shown that hypoxia-induced overproduction of ROS in bone defect region has a major impact on delaying bone regeneration. However, replenishing excess oxygen in a short time cause high oxygen tension that affect the activity of osteoblast precursor cells. Therefore, reasonably restoring the hypoxic condition of bone microenvironment is essential for facilitating bone repair. Herein, we designed ROS scavenging and responsive prolonged oxygen-generating hydrogels (CPP-L/GelMA) as a "bone microenvironment regulative hydrogel" to reverse the hypoxic microenvironment in bone defects region. CPP-L/GelMA hydrogels comprises an antioxidant enzyme catalase (CAT) and ROS-responsive oxygen-releasing nanoparticles (PFC@PLGA/PPS) co-loaded liposome (CCP-L) and GelMA hydrogels. Under hypoxic condition, CPP-L/GelMA can release CAT for degrading hydrogen peroxide to generate oxygen and be triggered by superfluous ROS to continuously release the oxygen for more than 2 weeks. The prolonged oxygen enriched microenvironment generated by CPP-L/GelMA hydrogel significantly enhanced angiogenesis and osteogenesis while inhibited osteoclastogenesis. Finally, CPP-L/GelMA showed excellent bone regeneration effect in a mice skull defect model through the Nrf2-BMAL1-autophagy pathway. Hence, CPP-L/GelMA, as a bone microenvironment regulative hydrogel for bone tissue respiration, can effectively scavenge ROS and provide prolonged oxygen supply according to the demand in bone defect region, possessing of great clinical therapeutic potential.

Blocking TRPV4 Ameliorates Osteoarthritis by Inhibiting M1 Macrophage Polarization via the ROS/NLRP3 Signaling Pathway.

Osteoarthritis (OA) is a low-level inflammatory disease in which synovial macrophage M1 polarization exacerbates the progression of synovitis and OA. Notedly, the ROS (reactive oxygen species) level in macrophages is intimately implicated in macrophage M1 polarization. TRPV4 (transient receptor potential channel subfamily V member 4), as an ion channel, plays a pivotal role in oxidative stress and inflammation. In this study, we investigated the role of TRPV4 in OA progression and M1 macrophage polarization. Male adult Sprague-Dawley (SD) rats underwent a medial meniscus radial transection operation to create an OA model in vivo and RAW 264.7 cells were intervened with 100 ng/mL LPS (lipopolysaccharide) to induce M1-polarized macrophages in vitro. We demonstrated that the infiltration of M1 synovial macrophages and the expression of TRPV4 were increased significantly in OA synovium. In addition, intra-articular injection of HC067074 (a specific inhibitor of TRPV4) alleviated the progression of rat OA and significantly decreased synovial macrophage M1 polarization. Further mechanisms suggested that ROS production by M1 macrophages was decreased after TRPV4 inhibition. In addition, NLRP3 (pyrin domain containing protein 3) as a downstream effector of ROS in M1-polarized macrophage, was significantly suppressed following TRPV4 inhibition. In conclusion, this study discovered that inhibition of TRPV4 delays OA progression by inhibiting M1 synovial macrophage polarization through the ROS/NLRP3 pathway.

Articular fibrocartilage-targeted therapy by microtubule stabilization.

The fibrocartilage presented on the joint surface was caused by cartilage injury or degeneration. There is still a lack of effective strategies for fibrocartilage. Here, we hypothesized that the fibrocartilage could be viewed as a raw material for the renewal of hyaline cartilage and proposed a previously unidentified strategy of cartilage regeneration, namely, "fibrocartilage hyalinization." Cytoskeleton remodeling plays a vital role in modifying the cellular phenotype. We identified that microtubule stabilization by docetaxel repressed cartilage fibrosis and increased the hyaline cartilage extracellular matrix. We further designed a fibrocartilage-targeted negatively charged thermosensitive hydrogel for the sustained delivery of docetaxel, which promoted fibrocartilage hyalinization in the cartilage defect model. Moreover, the mechanism of fibrocartilage hyalinization by microtubule stabilization was verified as the inhibition of Sparc (secreted protein acidic and rich in cysteine). Together, our study suggested that articular fibrocartilage-targeted therapy in situ was a promising strategy for hyaline cartilage repair.

Heterozygous LRP1 deficiency causes developmental dysplasia of the hip by impairing triradiate chondrocytes differentiation due to inhibition of autophagy.

Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic variants in the LRP1 (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. All patients harboring the LRP1 variants presented a typical DDH phenotype. The heterozygous Lrp1 knockout (KO) mouse (Lrp1+/-) showed phenotypes recapitulating the human DDH phenotypes, indicating Lrp1 loss of function causes DDH. Lrp1 knockin mice with a missense variant corresponding to a human variant identified in DDH (Lrp1R1783W) also presented DDH phenotypes, which were milder in heterozygotes and severer in homozygotes than those of the Lrp1 KO mouse. The timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore, Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mice bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant ß-catenin up-regulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a ß-catenin antagonist) in an shRNA-Lrp1-expressed ATDC5 cell. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment.

Single cell RNA-seq analysis identifies ferroptotic chondrocyte cluster and reveals TRPV1 as an anti-ferroptotic target in osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is the most common degenerative joint disease primarily characterized by cartilage destruction. The aim of this study was to investigate the role, molecular characteristics and potential therapeutic target of chondrocyte ferroptosis in the pathogenesis of OA. METHODS: The expression of ferroptotic hallmarks (iron and lipid peroxidation accumulation, glutathione deletion) were analyzed in paired intact and damaged cartilages from OA patients. Single cell RNA sequencing (scRNA-seq) analysis was performed on 17,638 chondrocytes to verify the presence, investigate the molecular signatures and unveil the potential therapeutic target of ferroptotic chondrocyte cluster in human OA cartilages. Destabilization of medial meniscus (DMM)-induced OA model and tert-butyl hydroperoxide (TBHP)-treated primary mouse chondrocytes and human cartilage explants were used to evaluate the protective effect of pharmacologically activated transient receptor potential vanilloid 1 (TRPV1). The downstream molecular mechanisms of TRPV1 was further investigated in glutathione peroxidase 4 (Gpx4) heterozygous genetic deletion mice (Gpx4+/-). FINDINGS: The concentrations of iron and lipid peroxidation and the expression of ferroptotic drivers in the damaged areas of human OA cartilages were significantly higher than those in the intact cartilage. scRNA-seq analysis revealed a chondrocyte cluster characterized by preferentially expressed ferroptotic hallmarks and genes, namely ferroptotic chondrocyte cluster. Comprehensive gene set variation analysis revealed TRPV1 as an anti-ferroptotic target in human OA cartilage. Pharmacological activation of TRPV1 significantly abrogated cartilage degeneration by protecting chondrocytes from ferroptosis. Mechanistically, TRPV1 promoted the expression of GPX4, and its anti-ferroptotic role was largely mitigated in the OA model of Gpx4+/- mice. INTERPRETATION: TRPV1 activation protects chondrocytes from ferroptosis and ameliorates OA progression by upregulating GPX4. FUNDING: National Key R&D Program of China (2018YFC1105904), Key Program of NSFC (81730067), National Science Foundation of China (81772335, 81941009, 81802196), Natural Science Foundation of Jiangsu Province, China (BK20180127), Jiangsu Provincial Key Medical Talent Foundation, Six Talent Peaks Project of Jiangsu Province (WSW-079).

Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling.

Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-κB) and PI3K-AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

Duo Cadherin-Functionalized Microparticles Synergistically Induce Chondrogenesis and Cartilage Repair of Stem Cell Aggregates.

Mesenchymal stem cell (MSC) aggregates incorporated with microparticles of functional materials have shown promising prospects in the field of cell therapy for cartilage repair. Given the importance of cadherins in modulating the stemness and chondrogenesis of MSCs, the use of transforming growth factor ß1 (TGFß1)-loaded poly (lactic-co-glycolic acid) (PLGA)-based composite microparticles inspired by duo cadherin (human E- and N-cadherin fusion proteins) to construct a bioartificial stem cell niche in engineered human MSC (hMSC) aggregates to promote chondrogenesis and cartilage regeneration is proposed. The hE/N-cadherin-functionalized PLGA/chitosan-heparin-TGFß1 (Duo hE/N-cad@P/C-h-TGFß1) microparticles spatiotemporally upregulates the endogenous E/N-cadherin expression of hMSC aggregates which further amplifies the chondrogenic differentiation and modulate paracrine and anti-inflammatory functions of hMSCs toward constructing a favorable microenvironment for chondrogenesis. The Duo hE/N-cad@P/C-h-TGFß1 microparticles finely regulate the response of hMSCs to biochemical and mechanical signal stimuli in the microenvironment through the cadherin/catenin-Yes-associated protein signal transduction, which inhibits the hypertrophy of hMSC-derived chondrocytes. Furthermore, immunofluorescent and histological examinations show that the Duo hE/N-cad@P/C-h-TGFß1 microparticles significantly improve regeneration of cartilage and subchondral bone in vivo. Together, the application of duo cadherin-functionalized microparticles is considered an innovative material-wise approach to exogenously activate hMSC aggregates for functional applications in regenerative medicine.

Intraarticular injection of SHP2 inhibitor SHP099 promotes the repair of rabbit full-thickness cartilage defect.

BACKGROUND: Cartilage repair has been a challenge in the field of orthopaedics for decades, highlighting the significance of investigating potential therapeutic drugs. In this study, we explored the effect of the SHP2 inhibitor SHP099, a small-molecule drug, on cartilage repair. METHODS: Human synovial mesenchymal stem cells (SMSCs) were isolated, and their three-way differentiation potential was examined. After treatment with chondrogenic medium, the chondrogenic effect of SHP099 on SMSCs was examined by western blot, qPCR, and immunofluorescence (IF). Micro-mass culture was also used to detect the effect of SHP099. To explore the chondrogenic effects of SHP099 in vivo, full-thickness cartilage defects with microfractures were constructed in the right femoral trochlea of New Zealand White rabbits. Intraarticular injection of SHP099 or normal saline was performed twice a week for 6 weeks. Cartilage repair was evaluated by haematoxylin and eosin (HE) staining and safranin O/fast green staining. Immunohistochemistry (IHC) for collagen II (COL2) was also conducted to verify the abundance of cartilage extracellular matrix after SHP099 treatment. The mechanism involving yes-associated protein (YAP) and WNT signalling was investigated in vitro. RESULTS: SMSCs isolated from human synovium have optimal multi-differentiation potential. SHP099 increased chondrogenic marker (SOX9, COL2) expression and decreased hypertrophic marker (COL10, RUNX2) expression in SMSCs. In micro-mass culture, the SHP099-induced cartilage tissues had a better result of Safranin O and Toluidine blue staining and are enriched in cartilage-specific collagen II. Inhibition of YAP and WNT signalling was also observed. Moreover, compared to the normal saline group at 6 weeks, intraarticular injection of SHP099 resulted in better defect filling, forming increased hyaline cartilage-like tissue with higher levels of glycosaminoglycan (GAG) and COL2. CONCLUSION: SHP099 promotes the repair of rabbit full-thickness cartilage defects, representing a potential therapeutic drug for cartilage repair. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study provides evidence that SHP2 inhibition promotes chondrogenesis and the repair of cartilage in defect area, which could be a novel therapeutic approach for cartilage repair.

Methylene blue prevents osteoarthritis progression and relieves pain in rats via upregulation of Nrf2/PRDX1.

Oxidative stress-related cartilage degeneration, synovitis, and joint pain play vital roles in the progress of osteoarthritis (OA). Anti-oxidative stress agents not only prevent structural damage progression but also relieve OA-related pain. In this study, we investigated the therapeutic effect of methylene blue (MB), a classical and important anti-oxidant with strong neural affinity. Experimental OA was established in rats by radial transection of medial collateral ligament and medial meniscus (MCLT + MMT) of the right knee joint. The OA rats received intra-articular injection of MB (1 mg/kg) every week starting one week after surgery. We showed that MB administration exerted significant cartilage protection, synovitis inhibition as well as pain relief in OA rats. In human chondrocytes and fibroblast-like synoviocytes, MB significantly attenuated tert-butyl hydroperoxide (TBHP)-induced inflammatory response and oxidative stress. We demonstrated that these effects of MB resulted from dual targets of important antioxidant enzymes, Nrf2 and PRDX1, which also mutually reinforcing and participated in an interaction. Furthermore, we found that calcitonin gene-related peptide (CGRP), a neural inflammatory mediator, was accumulated around the vessel in synovium and subchondral bone in OA rats and in TBHP-treated primary cortical neurons; MB administration significantly inhibited CGRP expression through upregulation of Nrf2 and PRDX1. Taken together, these results suggest that MB ameliorates oxidative stress via Nrf2/PRDX1 regulation to prevent progression and relieve pain of OA.

Multi-Pathway Microenvironment Regulation for Atherosclerosis Therapy Based on Beta-Cyclodextrin/L-Arginine/Au Nanomotors with Dual-Mode Propulsion.

Most of the current non-pharmacological treatment strategies for atherosclerosis (AS) suffer from poor penetration into the plaque and only aim at a certain factor in its formation process, resulting in limited therapeutic effect. Herein, a kind of nanomotor with dual-mode propulsion is constructed, which is sensitive to higher reactive oxygen species (ROS) at the AS site and near-infrared (NIR) laser by the covalent binding and self-assembly of ß-cyclodextrin (ß-CD) and L-arginine (LA) with immobilization of Au nanoparticles. NIR laser irradiation can be used as a driving force and to ablate inflammatory macrophages through the photothermal effect. The nitric oxide (NO) released by the nanomotors can be used as another driving force and a therapeutic agent to promote endothelial repair in the plaque site. LA can eliminate ROS in the inflammatory site, and ß-CD can promote the removal of cholesterol from foam cells. In particular, the two driving modes of nanomotors synergistically promote their aggregation and penetration in the plaque. This kind of nanomotor can regulate the microenvironment of AS in multiple ways, including combination therapy for endothelial repair, lipid clearance, and reducing ROS, which is expected to become a potential non-pharmacological strategy in the treatment of AS.

Self-Cascade Uricase/Catalase Mimics Alleviate Acute Gout.

Uricase-based therapies are limited for gout partially due to the accumulation of H2O2 in an arthrosis environment with slow metabolism. To tackle this limitation, previous studies adopted a cascade reaction between the degradation of uric acid (UA) and timely elimination of H2O2 using complicated composites of uricase and catalase (CAT)/CAT-like nanozyme. Herein, the self-cascade nanozyme Pt/CeO2 with high efficiency toward simultaneous UA degradation and H2O2 elimination is demonstrated on the basis of both uricase- and CAT-like activities in Pt, Ir, Rh, and Pd platinum-group metals. With an optimized molar ratio of Pt and CeO2, Pt/CeO2 (1/5) not only does better in degrading UA but also has excellent reactive oxygen species (ROS) and reactive nitrogen species (RNS) scavenging activities. In monosodium urate (MSU)-induced acute gout rats, Pt/CeO2 nanozyme markedly alleviates pain along with joint edema, thus improving gait claudication and tissue inflammation. These results provide novel insights into strategies of an efficient enzyme-mimetic treatment for gout.

Is the femoral component flexion affected by the sagittal femoral shaft bowing in conventional intramedullary guided TKA?

BACKGROUND: The aim of the present study was to investigate the influence of sagittal femoral bowing on sagittal femoral component alignment, and whether there was correlation between sagittal femoral component alignment and coronal femoral component alignment. METHODS: We retrospectively reviewed 77 knees in 71 patients who had undergone primary TKA for advanced osteoarthritis. All surgeries were performed by using a standard medial parapatellar approach. The osteotomy was performed with a conventional technique using an intramedullary rod for the femur and a mechanical extramedullary guiding system for the tibia. All patients enrolled in the study were evaluated with full-length lower extremity load-bearing standing scanograms, and the patients had preoperative and postoperative radiographs of the knees. Coronal femoral bowing angle (cFBA), sagittal femoral bowing angle (sFBA), and postoperatively, mechanical tibiofemoral angle of the knee (mTFA), ß angle (femoral component flexion angle) were measured. The radiographic results of both groups were compared using Student's t test. A two-sided Pearson correlation coefficient was obtained to identify the correlations between FBA in the coronal and sagittal planes, as well as FBA and age or BMI, sFBA and ß angle, cFBA and mTFA. Comparison of FSB incidence between different genders was made using Chi-square test. The p value < 0.05 indicates a statistically significant difference. RESULTS: The mean sFBA, cFBA, ß angle, mTFA were 9.34° ± 3.56°(range 1°-16°), 3.25° ± 3.79°(range - 7° to -17°), 3.91° ± 3.15°(range - 1° to -13°), 0.60° ± 1.95°(range - 3° to -6°), respectively. There was no correlation between age and sFBA (CC = 0.192, p = 0.194) or cFBA (CC = 0.192, p = 0.194); similarly, there was no correlation between age and sFBA (CC = 0.067, p = 0.565) or cFBA (CC = 0.069, p = 0.549). The sFBA was correlated with cFBA and ß angle (CC = 0.540, p < 0.01; CC = 0.543, p < 0.01, respectively), and the cFBA was correlated with mTFA (CC = 0.430, p < 0.01). There was no significant difference (p = 0.247) of cFBA between the patients with sFSB and the patients without sFSB. CONCLUSIONS: The current study showed that the sFBA was correlated with cFBA in the patients undergoing TKA and the patients with sFSB usually presented non-cFSB. We also found that sFSB could affect the femoral component alignment in the sagittal plane and cFSB could affect the femoral component alignment in the coronal plane. The sFBA or cFBA was not correlated with age, BMI, or gender.