Spermidine ameliorates osteoarthritis via altering macrophage polarization.

OBJECTIVE: Spermidine (SPD) is an anti-aging natural substance, and it exerts effects through anti-apoptosis and anti-inflammation. However, the specific protective mechanism of SPD in osteoarthritis (OA) remains unclear. Here, we explored the role of SPD on the articular cartilage and the synovial tissue, and tested whether the drug would regulate the polarization of synovial macrophages by in vivo and in vitro experiments. METHODS: By constructing an OA model in mice, we preliminarily explored the protective effect of SPD on the articular cartilage and the synovial tissue. Meanwhile, we isolated and cultured human primary chondrocytes and bone marrow-derived macrophages (BMDMs), and prepared a conditioned medium (CM) to explore the specific protective effect of SPD in vitro. RESULTS: We found that SPD alleviated cartilage degeneration and synovitis, increased M2 polarization and decreased M1 polarization in synovial macrophages. In vitro experiments, SPD inhibited ERK MAPK and p65/NF-κB signaling in macrophages, and transformed macrophages from M1 to M2 subtypes. Interestingly, SPD had no direct protective effect on chondrocytes in vitro; however, the conditioned medium (CM) from M1 macrophages treated with SPD promoted the anabolism and inhibited the catabolism of chondrocytes. Moreover, this CM markedly suppressed IL-1ß-induced p38/JNK MAPK signaling pathway activation in chondrocytes. CONCLUSIONS: This work provides new perspectives on the role of SPD in OA. SPD does not directly target chondrocytes, but can ameliorate the degradation of articular cartilage through regulating M1/M2 polarization of synovial macrophages. Hence, SPD is expected to be the potential therapy for OA.

Geographic differences in pharmacotherapy patterns and outcomes of acute ischemic stroke in China.

BACKGROUND: Vast economic and healthcare status discrepancies exist among regions in China, contributing to different treatment patterns. This study was aimed to investigate the current status of pharmacotherapy for acute ischemic stroke (AIS) and outcomes in China and explore the geographic variation in stroke care. METHODS: This study was a multicenter prospective registry study, which collected the data of patients with AIS from 80 hospitals in 46 cities in 2015-2017 across China. Poor functional outcome defined as a modified Rankin Scale score of 3-6 was assessed at 3 and 12 months. Multivariate logistic regression was used. RESULTS: Among 9973 eligible patients, the number of receiving intravenous thrombolysis (IVT), antiplatelet agents, anticoagulants, statin and human urinary kallidinogenase was 429 (4.3%), 9363 (93.9%), 1063 (10.7%), 6828 (74.7%) and 5112 (51.2%), respectively. Multivariable analysis showed IVT use in northeastern was significantly more frequent than in eastern region (OR = 3.17, 95% CI, 2.53-3.99), while the antiplatelets agents use were less frequent (OR = 0.46, 95%CI: 0.38-0.57). The proportions of poor outcomes at 3 and 12 months were 20.7% and 15.8%, respectively. Multivariate analysis showed AIS patients from northeastern and central region had significantly lower risk of poor outcome at month 3 and 12 than those from eastern region (all P < 0.05). CONCLUSIONS: There was a low IVT use and a high antiplatelet agent and statin use for AIS in China. The pharmacotherapy and prognosis of AIS had variation by geographic region. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (NCT02470624).

Shedding light on experimental intra-articular drugs for treating knee osteoarthritis.

INTRODUCTION: Knee osteoarthritis (KOA) is a leading cause of disability among older adults without a curative therapy available. The development of disease-modifying OA drugs based on intra-articular injection (IA) is drawing extensive attention for its advantages in bioavailability and reduced systemic exposure. Based on the newly revealed pathogenesis of OA, several experimental IA drugs are successful in preclinical studies; moreover, some of them are in different phases of randomized clinical trials, bringing new opportunities for disease modification of OA. AREAS COVERED: This is a targeted literature review to summarize experimental IA drugs targeting cartilage repair, cellular homeostasis, cellular senescence, and pain control. We also introduced targeted gene/oligonucleotide products. EXPERT OPINION: Currently available therapeutics for KOA remain symptomatic relief and surgical replacement of damaged joints. Recently emerging experimental IA drugs are in different stages of development and are likely to enter practice in the near future and address many of the unmet needs. The major challenges for development of the new drugs are limited knowledge about the responsive subjects, heterogenicity of subjects and the complexity of the disease. Despite this, IA-based experimental drugs still hold great potential to be future disease-modifying treatments for their intrinsic advantages.

DNA Supramolecular Hydrogel-Enabled Sustained Delivery of Metformin for Relieving Osteoarthritis.

Osteoarthritis (OA) is a musculoskeletal disorder affecting ∼500 million people worldwide. Metformin (MET), as an oral hypoglycemic drug approved by the Food and Drug Administration, has displayed promising potential for treating OA. Nonetheless, in the articular cavity, MET suffers from rapid clearance and cannot circumvent the severe inflammatory environment, greatly confining the therapeutic efficacy. Herein, DNA supramolecular hydrogel (DSH) has been utilized as a sustained drug delivery vehicle for MET to treat OA, which dramatically prolonged the retention time of MET in the articular cavity from 3 to 14 days and simultaneously exerted a greater anti-inflammatory effect. Our delivery platform, termed MET@DSH, better protects cartilage than single-agent MET. Additionally, the corresponding molecular mechanisms underlying the therapeutic effects were also analyzed. We anticipate this DNA supramolecular hydrogel-enabled sustained drug delivery and anti-inflammatory strategy will reshape the current landscape of OA treatment.

Metformin attenuates osteoarthritis by targeting chondrocytes, synovial macrophages and adipocytes.

OBJECTIVE: To investigate the therapeutic effect and mechanism of metformin on knee OA in normal diet (ND) mice or high-fat diet (HFD)-induced obese mice. METHODS: Destabilization of the medial meniscus surgery was performed in ND mice or HFD mice, and metformin was administrated in drinking water or not. The changes of OA joint structure, infiltration and polarization of synovial macrophages and circulating and local levels of leptin and adiponectin were evaluated. In vitro, the effects of metformin on chondrocytes and macrophages, and of conditioned mediums derived from mouse abdominal fat on murine chondrogenic cell line ATDC5 and murine macrophage cell line RAW264.7, were detected. RESULTS: Metformin showed protective effects on OA, characterized by reductions on OARSI score [2.00, 95% CI (1.15, 2.86) for ND mice and 3.17, 95% CI (2.37, 3.96) for HFD mice] and synovitis score [1.17, 95% CI (0.27, 2.06) for ND mice and 2.50, 95% CI (1.49, 3.51) for HFD mice] after 10 weeks of treatment, and the effects were more significant in HFD mice than in ND mice. Mechanistically, in addition to decreasing apoptosis and matrix-degrading enzymes expression in chondrocytes as well as infiltration and pro-inflammatory differentiation of synovial macrophages, metformin reduced leptin secretion by adipose tissue in HFD mice. CONCLUSIONS: Metformin protects against knee OA which could be through reducing apoptosis and catabolism of chondrocytes, and suppressing infiltration and pro-inflammatory polarization of synovial macrophages. For obese mice, metformin has a greater protective effect in knee OA additionally through reducing leptin secretion from adipose tissue.

Enhanced osteoarthritis therapy by nanoengineered mesenchymal stem cells using biomimetic CuS nanoparticles loaded with plasmid DNA encoding TGF-ß1.

Mesenchymal stem cells (MSCs) therapy shows the potential benefits to relieve clinical symptoms of osteoarthritis (OA), but it is uncertain if it can repair articular cartilage lesions - the main pathology of OA. Here, we prepared biomimetic cupper sulfide@phosphatidylcholine (CuS@PC) nanoparticles (NPs) loaded with plasmid DNA (pDNA) encoding transforming growth factor-beta 1 (TGF-ß1) to engineer MSCs for enhanced OA therapy via cartilage regeneration. We found that the NPs not only promoted cell proliferation and migration, but also presented a higher pDNA transfection efficiency relative to commercial transfection reagent lipofectamine 3000. The resultant CuS/TGF-ß1@PC NP-engineered MSCs (termed CTP-MSCs) were better than pure MSCs in terms of chondrogenic gene expression, glycosaminoglycan deposition and type II collagen formation, favoring cartilage repair. Further, CTP-MSCs inhibited extracellular matrix degradation in interleukin-1ß-induced chondrocytes. Consequently, intraarticular administration of CTP-MSCs significantly enhanced the repair of damaged cartilage, whereas pure MSCs exhibited very limited effects on cartilage regeneration in destabilization of the medial meniscus (DMM) surgical instability mice. Hence, this work provides a new strategy to overcome the limitation of current stem cell therapy in OA treatment through developing more effective nanoengineered MSCs.

Osteophytes mediate the associations between cartilage morphology and changes in knee symptoms in patients with knee osteoarthritis.

AIMS: To investigate whether the associations between cartilage defects and cartilage volumes with changes in knee symptoms were mediated by osteophytes. METHODS: Data from the Vitamin D Effects on Osteoarthritis (VIDEO) study were analyzed as a cohort. The Western Ontario and McMaster Universities Osteoarthritis Index was used to assess knee symptoms at baseline and follow-up. Osteophytes, cartilage defects, and cartilage volumes were measured using magnetic resonance imaging at baseline. Associations between cartilage morphology and changes in knee symptoms were assessed using linear regression models, and mediation analysis was used to test whether these associations were mediated by osteophytes. RESULTS: A total of 334 participants (aged 50 to 79 years) with symptomatic knee osteoarthritis were included in the analysis. Cartilage defects were significantly associated with change in total knee pain, change in weight-bearing pain, and change in non-weight-bearing pain after adjustment for age, sex, body mass index, and intervention. Cartilage volume was significantly associated with change in weight-bearing pain and change in physical dysfunction after adjustment. Lateral tibiofemoral and patellar osteophyte mediated the associations of cartilage defects with change in total knee pain (49-55%) and change in weight-bearing pain (61-62%) and the association of cartilage volume with change in weight-bearing pain (27-30%) and dysfunction (24-25%). Both cartilage defects and cartilage volume had no direct effects on change in knee symptoms. CONCLUSIONS: The significant associations between cartilage morphology and changes in knee symptoms were indirect and were partly mediated by osteophytes.

Deep Learning Reveals Key Immunosuppression Genes and Distinct Immunotypes in Periodontitis.

BACKGROUND: Periodontitis is a chronic immuno-inflammatory disease characterized by inflammatory destruction of tooth-supporting tissues. Its pathogenesis involves a dysregulated local host immune response that is ineffective in combating microbial challenges. An integrated investigation of genes involved in mediating immune response suppression in periodontitis, based on multiple studies, can reveal genes pivotal to periodontitis pathogenesis. Here, we aimed to apply a deep learning (DL)-based autoencoder (AE) for predicting immunosuppression genes involved in periodontitis by integrating multiples omics datasets. METHODS: Two periodontitis-related GEO transcriptomic datasets (GSE16134 and GSE10334) and immunosuppression genes identified from DisGeNET and HisgAtlas were included. Immunosuppression genes related to periodontitis in GSE16134 were used as input to build an AE, to identify the top disease-representative immunosuppression gene features. Using K-means clustering and ANOVA, immune subtype labels were assigned to disease samples and a support vector machine (SVM) classifier was constructed. This classifier was applied to a validation set (Immunosuppression genes related to periodontitis in GSE10334) for predicting sample labels, evaluating the accuracy of the AE. In addition, differentially expressed genes (DEGs), signaling pathways, and transcription factors (TFs) involved in immunosuppression and periodontitis were determined with an array of bioinformatics analysis. Shared DEGs common to DEGs differentiating periodontitis from controls and those differentiating the immune subtypes were considered as the key immunosuppression genes in periodontitis. RESULTS: We produced representative molecular features and identified two immune subtypes in periodontitis using an AE. Two subtypes were also predicted in the validation set with the SVM classifier. Three "master" immunosuppression genes, PECAM1, FCGR3A, and FOS were identified as candidates pivotal to immunosuppressive mechanisms in periodontitis. Six transcription factors, NFKB1, FOS, JUN, HIF1A, STAT5B, and STAT4, were identified as central to the TFs-DEGs interaction network. The two immune subtypes were distinct in terms of their regulating pathways. CONCLUSION: This study applied a DL-based AE for the first time to identify immune subtypes of periodontitis and pivotal immunosuppression genes that discriminated periodontitis from the healthy. Key signaling pathways and TF-target DEGs that putatively mediate immune suppression in periodontitis were identified. PECAM1, FCGR3A, and FOS emerged as high-value biomarkers and candidate therapeutic targets for periodontitis.

Chinese acute ischemic stroke treatment outcome registry (CASTOR): protocol for a prospective registry study on patterns of real-world treatment of acute ischemic stroke in China.

RATIONALE: Stroke presents a serious health problem in China. Despite progresses made in recent years, there is still a lack of effective treatments for acute ischemic stroke (AIS) in clinical practices. AIMS: The Chinese Acute Ischemic Stroke Treatment Outcome Registry (CASTOR) is designed to evaluate the patterns and cost-effectiveness of current treatments for AIS in real-world settings in China. DESIGN: CASTOR is a prospective, multi-center study registered with ClinicalTrials.gov (NCT02470624) with a target sample size of 10,000 patients who are experiencing AIS. The patients are treated for AIS following the Chinese stroke guideline and local practice. Real-world data on treatment regimens, outcomes and costs are collected at baseline (Visit 1) and during subsequent visits (Visit 2 to Visit 5) after medication treatments. OUTCOME: The primary objective of the present study is to analyze the current treatment status of AIS in real world settings. The secondary objectives include: 1) to compare the effectiveness of common treatment regimens, 2) to analyze the cost-effectiveness of different treatment regimens for AIS, 3) to analyze the incidence of adverse events and complications in enrolled patients with AIS, 4) to analyze the effect of Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification on the specific therapies during acute phase treatment period. DISCUSSION: In face of changing treatment patterns and increasing demand from medical insurers for cost-effectiveness data in China, a large-scale registry study examining the real-world patterns of AIS in hospitals is needed. The CASTOR study will help to find favorable cost-utility treatment regimens for AIS and improve the overall treatment outcome of Chinese patients with AIS.