An injectable hydrogel to disrupt neutrophil extracellular traps for treating rheumatoid arthritis.

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by inflammatory cell infiltration that damages cartilage, disrupts bone, and impairs joint function. The therapeutic efficacy of RA treatments with the severely affected side remains unsatisfactory despite current treatment methods that primarily focus on anti-inflammatory activity, largely because of the complicatedly pathological mechanisms. A recently identified mechanism for RA development involves the interaction of RA autoantibodies with various proinflammatory cytokines to facilitate the formation of neutrophil extracellular traps (NETs), which increased inflammatory responses to express inflammatory cytokines and chemokines. Therefore, NETs architecture digestion may inhibit the positive-feedback inflammatory signal pathway and lessen joint damage in RA. In this work, deoxyribonuclease I (DNase) is connected to oxidized hyaluronic acid (OHA) via Schiff base reaction to extend the half-life of DNase. The modification does not influence the DNase activity for plasmid deoxyribonucleic acid hydrolysis and NETs' architecture disruption. Carboxymethyl chitosan is crosslinked with DNase-functionalised OHA (DHA) to form an injectable, degradable, and biocompatible hydrogel (DHY) to further strengthen the adhesive capability of DHA. Importantly, the collagen-induced arthritis model demonstrates that intra-articular injection of DHY can significantly reduce inflammatory cytokine expression and alleviate RA symptoms, which can be significantly improved by combining methotrexate. Here, a DNase-functionalised hydrogel has been developed for RA treatment by constantly degrading the novel drug target of NETs to decrease inflammatory response in RA.

Macrophage-derived hybrid exosome-mimic nanovesicles loaded with black phosphorus for multimodal rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is chronic inflammation characterized by abundant inflammatory cell infiltration and a major cause of joint function disruption. Despite current therapeutic strategies such as non-steroidal drugs or anti-cytokine biologics having shown promise for RA management, their side effects and clinical response rate remain unsatisfactory, attributed largely to the complicated pathomechanisms and multiplicity of the inflammatory cytokines. In this work, novel hybrid exosome-mimic nanovesicles equipped with broad-spectrum anti-inflammatory activity were developed for RA treatment. The hybrid nanovesicles (HNV) were prepared by fusing an M1 macrophage membrane into exosome-mimic nanovesicles extruded from M2 macrophages. The HNV inherit the anti-inflammatory properties of the M2 macrophages and cytokine receptors derived from the M1 membrane. Accordingly, the HNV possess comprehensive anti-inflammation activity via binding proinflammatory factors and releasing anti-inflammatory mediators. Furthermore, black phosphorus nanosheets (BP) were introduced into the HNV (HNV@BP) to eliminate inflammatory cells upon near-infrared (NIR) irradiation, which intrinsically decreases the inflammatory reaction. In a mouse model of collagen-induced arthritis, the HNV loaded with BP targeted and accumulated at the inflammed knee joints, exhibiting multimodal rheumatoid arthritis therapy combined with NIR irradiation through comprehensive inflammation suppression.

A Hybrid Method Using HAVOK Analysis and Machine Learning for Predicting Chaotic Time Series.

The prediction of chaotic time series systems has remained a challenging problem in recent decades. A hybrid method using Hankel Alternative View Of Koopman (HAVOK) analysis and machine learning (HAVOK-ML) is developed to predict chaotic time series. HAVOK-ML simulates the time series by reconstructing a closed linear model so as to achieve the purpose of prediction. It decomposes chaotic dynamics into intermittently forced linear systems by HAVOK analysis and estimates the external intermittently forcing term using machine learning. The prediction performance evaluations confirm that the proposed method has superior forecasting skills compared with existing prediction methods.

[Bioinformatics-based identification of key genes CDC5L and related pathways in osteosarcoma and Ewing's sarcoma].

OBJECTIVE: Osteosarcoma(OS) and Ewing's sarcoma (EWS) are the two most common primary malignant bone tumors in children. The aim of the study was to identify key genes in OS and EWS and investigate their potential pathways. METHODS: Expression profiling (GSE16088 and GSE45544) were obtained from GEO DataSets. Differentially expressed genes were identified using GEO2R and key genes involved in the occurrence of both OS and EWS were selected using venn diagram. Gene ontology and pathway enrichment analyses were performed for the ensembl. Protein-protein interaction (PPI) networks were established by STRING. Further, UCSC was used to predict the transcription factors of the cell division cycke 5-like(CDC5L) gene, and GEPIA was used to analyze the correlation between the transcription factors and the CDC5L gene. RESULTS: The results showed that CDC5L gene was the key gene involved in the pathogenesis of OS and EWS. The gene is mainly involved in mitosis, and is related to RNA metabolism, processing of capped intron-containing pre-mRNA, mRNA and pre-mRNA splicing. CONCLUSION: CDC5L, as a key gene, plays a role in development of OS and EWS, which may be reliable targets for diagnosis and treatment of these primary malignant tumors.

Resistin induces chemokine and matrix metalloproteinase production via CAP1 receptor and activation of p38-MAPK and NF-κB signalling pathways in human chondrocytes.

OBJECTIVES: Adipokine resistin is highly expressed in the serum and synovial uid (SF) of patients with knee osteoarthritis (KOA) but its pathogenic role in KOA remains unclear. We aimed to explore the mechanism of resistin/CAP1 in human KOA chondrocytes. METHODS: We enrolled 103 patients with radiographic KOA and 86 healthy participants as controls. Resistin levels in serum and SF were determined by enzyme-linked immunosorbent assay (ELISA). CAP1 expression was measured in cartilage tissues using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Effects of resistin on chondrocytes and CAP1 were evaluated via qRT-PCR and co-immunoprecipitation. The roles of CAP1, p38-MAPK, and NF-κB signalling pathways in KOA development were evaluated using adenovirus-mediated CAP1 short hairpin RNA, qRT-PCR, western blot, and ELISA. RESULTS: Resistin expression in serum and SF was elevated in severe radiographic KOA. CAP1 levels were higher in KOA cartilage and were positively correlated with resistin expression. Resistin promoted CCL3, CCL4, MMP13, and ADAMTS-4 expression through the CAP1 receptor. Resistin also directly bound to CAP1, as confirmed by co-immunoprecipitation. CAP1 knockdown in chondrocytes attenuated resistin-induced expression of CCL3, CCL4, MMP13, and ADAMTS-4 and activated p38-MAPK and NF-κB signalling pathways. CONCLUSIONS: Resistin binds CAP1 and upregulates the expression of proinflammatory cytokines and matrix-degrading enzymes via p38-MAPK and NF-κB signalling in human chondrocytes.

An update on the association between metabolic syndrome and osteoarthritis and on the potential role of leptin in osteoarthritis.

Metabolic syndrome (MetS) has been associated with osteoarthritis (OA). Leptin, which is one of the markers of MetS, has been associated with OA pathophysiology. This study aimed to provide an update on the association between MetS and OA and on the potential role of leptin in OA. In this review, we summarized the current knowledge of the association between MetS and OA and updated the evidence on the potential role of leptin in OA. Clinical studies have investigated the epidemiologic association between MetS or its components and OA. Results suggested strong epidemiologic associations between MetS and OA, especially in the Asian population. Animal studies also indicated that metabolic dysregulation may lead to OA pathogenesis. The systemic role of MetS in OA pathophysiology is associated with obesity-related inflammation, the beneficial role of n-3 polyunsaturated fatty acids and deleterious role of cholesterol, physical inactivity, hypertension-induced subchondral ischemia, dyslipidemia-induced ectopic lipid deposition in chondrocytes, hyperglycemia-induced local effects of oxidative stress and advanced glycation end-products, low-grade systemic inflammation, and obesity-related adipokines by inducing the expression of proinflammtory factors. Leptin levels in serum/plasma and synovial fluid were associated with joint pain, radiographic progression, bone formation biomarkers, cartilage volume, knee OA incidence, and total joint arthroplasty in OA patients. Elevated leptin expression and increased effect of leptin on infrapatellar fat pad, synovium, articular cartilage, and bone were also involved in the pathogenesis of OA. Current knowledge indicates a convincing epidemiologic association between MetS and OA, especially in the Asian population. Animal studies have also shown that metabolic dysregulation may lead to OA pathogenesis. Accumulating evidence suggests that leptin may play a potential role in OA pathogenesis. Therefore, leptin and its receptor may be an emerging target for intervention in metabolic-associated OA.

Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells.

Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M double mutations. The IC50 value against EGFRL858R/T790M kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50 values were 0.057 µM, 0.104 µM and 0.916 µM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r2 = 0.965) and CoMSIA (q [2] = 0.875, r2 = 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.

Differential expression of adipokines in the synovium and infrapatellar fat pad of osteoarthritis patients with and without metabolic syndrome.

Objective: To evaluate the expression levels of adipokines in the synovium and infrapatellar fat pad (IPFP) in osteoarthritis (OA) patients with and without metabolic syndrome (MetS). Methods: 120 female patients with OA were enrolled, and 60 healthy women matched body mass index, age, and sex, served as controls. Adipokines levels were measured using a sandwich enzyme-linked immunosorbent assay of the serum of all participants and synovial fluid (SF) of OA patients. Local expression levels of adipokines in the synovium and IPFP were examined by immunohistochemical analysis. The amount of adipokine proteins was analyzed using Western blot, and adipokine mRNA expressions were determined via quantitative real-time polymerase chain reaction (qRT-PCR). Results: Serum leptin levels were significantly higher in the non-MetS-OA group than those in controls (7.97 vs. 4.24 ng/ml, p< 0.001), and even higher leptin levels were found in the MetS-OA group (19.05 ng/ml; p< 0.001 for both). Serum adiponectin levels were significantly lower in the MetS-OA group than those in controls (8.09 vs. 10.07 µg/ml, respectively; p= 0.001). The synovium and IPFP in the MetS-OA group secreted more leptin and less adiponectin than those in the non-MetS-OA group (Leptin: 5.32 vs. 1.28 in synovium, respectively; p= 0.028; 6.44 vs. 0.88 in IPFP, respectively; p= 0.017. Adiponectin: 1.12 vs. 0.12 in synovium, respectively; p= 0.042; 1.07 vs. 0.09 in IPFP, respectively; p= 0.027). Resistin expression levels in the serum, SF, and articular tissues were similar among the groups. Conclusions: Expressions of adipokines were different in the synovium and IPFP of OA patients with and without MetS.

An Update on the Emerging Role of Resistin on the Pathogenesis of Osteoarthritis.

BACKGROUND: Resistin may be involved in the pathogenesis of osteoarthritis (OA), but a systematic understanding of the role of resistin in OA is lacking. METHODS: We reviewed studies that evaluated the role of resistin in OA. The expression levels of resistin in vitro experiments and OA/rheumatoid arthritis (RA) patients were analyzed. We also studied potential resistin receptors and the signaling pathways that these receptors activate, ultimately leading to cartilage degeneration. RESULTS: Resistin levels in both the serum and synovial fluid were higher in OA and RA patients than in healthy subjects. Overall, resistin levels are much higher in serum than in synovial fluid. In human cartilage, resistin induces the expression of proinflammatory factors such as degradative enzymes, leading to the inhibition of cartilage matrix synthesis, perhaps by binding to Toll-like receptor 4 and the adenylyl cyclase-associated protein 1 receptor, which then activates the p38-mitogen-activated phosphate kinase, protein kinase A-cyclic AMP, nuclear factor-κB, and C/enhancer-binding protein ß signaling pathways. CONCLUSION: Resistin levels are higher in OA patients than in healthy controls; however, the precise role of resistin in the pathogenesis of OA needs to be studied further. Resistin may be a novel therapeutic target in OA in the future.

Differential expression of adipokines in knee osteoarthritis patients with and without metabolic syndrome.

PURPOSE: The purpose of this study was to compare adipokines levels in plasma and synovial fluid (SF) between knee osteoarthritis (OA) patients with and without metabolic syndrome (MetS), and to evaluate the associations between adipokines levels and clinical severity of knee osteoarthritis. METHODS: Eighty female patients with knee osteoarthritis were enrolled in the study. These patients were divided into two groups: patients with and without MetS. Clinical severity was evaluated according to visual analogue scale (VAS) pain scores and Western Ontario McMaster University Osteoarthritis Index (WOMAC) scores. Adipokines and soluble leptin receptor levels in plasma and SF were determined by a sandwich enzyme-linked immunosorbent assay. RESULTS: Forty-three (54%) osteoarthritis patients with MetS and 37 (46%) osteoarthritis patients without MetS were enrolled as MetS-OA group and nMetS-OA group, respectively. VAS pain and WOMAC scores were higher in MetS-OA group compared with those in nMets-OA group (p < 0.01). The leptin and free leptin levels in plasma and SF were significantly higher in MetS-OA group than those in nMetS-OA group, while the adiponectin levels were lower (All p < 0.01). Significant differences existed even after adjustment for body mass index (BMI) (p < 0.05). There were no significant associations between adipokines levels and the clinical severity of OA in MetS-OA group and nMetS-OA group respectively (p > 0.05). CONCLUSIONS: Leptin was higher and adiponectin was lower in knee osteoarthritis patients with MetS compared to those without MetS, independent of BMI. The higher SF and plasma levels of leptin in MetS-OA patients may need further studies to delineate their pathophysiological relationships.

Guided-Mode-Leaky-Mode-Guided-Mode Fiber Interferometer and Its High Sensitivity Refractive Index Sensing Technology.

A cascaded symmetrical dual-taper Mach-Zehnder interferometer structure based on guided-mode and leaky-mode interference is proposed in this paper. Firstly, the interference spectrum characteristics of interferometer has been analyzed by the Finite Difference-Beam Propagation Method (FD-BPM). When the diameter of taper waist is 20 µm-30 µm, dual-taper length is 1 mm and taper distance is 4 cm-6 cm, the spectral contrast is higher, which is suitable for sensing. Secondly, experimental research on refractive index sensitivity is carried out. A refractive index sensitivity of 62.78 nm/RIU (refractive index unit) can achieved in the RI range of 1.3333-1.3792 (0%~25% NaCl solution), when the sensor structure parameters meet the following conditions: diameter of taper waist is 24 µm, dual-taper length is 837 µm and taper distance is 5.5 cm. The spectrum contrast is 0.8 and measurement resolution is 1.6 × 10(-5) RIU. The simulation analysis is highly consistent with experimental results. Research shows that the sensor has promising application in low RI fields where high-precision measurement is required due to its high sensitivity and stability.

Collecting duct carcinoma of the kidney: A case report.

Collecting duct carcinoma (CDC) is a rare type of renal tumor, arising from the distal collecting ducts. The prognosis of this disease is extremely poor due to its rapid progression with widespread metastases. The present study reported a case of CDC involving the right renal region of a 62-year-old female patient, presented with right-flank pain that had persisted for one month. A computed tomography scan demonstrated multiple hypoattenuating quasicircular lesions, 0.5-4.3 cm in size, in the upper pole of the right kidney. Following the diagnosis of a right renal tumor, laparoscopic radical resection of the right kidney was performed. Pathological examination demonstrated that the tumor cells were arranged in a glandular or papillary pattern, and marked cytological atypia was observed. Immunohistochemical staining revealed that the tumor cells were positive for epithelial membrane antigen and cytokeratin (CK)7, while they reacted focally with vimentin. However, the tumor cells were negative for CK20, CD10, uroplakin III and p63. Based on these findings, the patient was diagnosed with CDC. In conclusion, immunohistochemical analysis is critical in establishing an accurate diagnosis of CDC and distinguishing this tumor from other subtypes of RCC.