circIFNGR2 regulating ankylosing spondylitis-associated inflammation through macrophage polarization.

Macrophages activation is crucial in pathogenesis of rheumatic diseases like ankylosing spondylitis (AS). Circular RNAs (circRNAs)-induced macrophage-associated inflammation participates in many autoimmune diseases but remains elusive in AS. Here, we verified increased expression of circIFNGR2 in peripheral blood mononuclear cells from patients with AS and its expression levels were correlated with the AS severity. In vitro assays revealed that circIFNGR2 enhances macrophage proliferation, and regulates M1/M2 macrophage polarization and NF-κB/Akt pathways. We identified that circIFNGR2 promoted the expression of iNOS/TNFα and M1 polarization, and restrained M2 polarization by sponging miR-939. Additionally, the RNA-binding protein, eIF4A3, was found to enhance the production of circIFNGR2. Interestingly, miR-939 attenuated joint damage in collagen-induced arthritis mice, whereas circIFNGR2 reversed this effect. Our findings highlight the pro-inflammatory roles of eIF4A3-induced circIFNGR2 in AS by modulating macrophage-associated inflammation through miR-939.

An all-silk-derived bilayer hydrogel for osteochondral tissue engineering.

Osteochondral repair remains a challenge in clinical practice nowadays despite extensive advances in tissue engineering. The insufficient recruitment of endogenous cells in the early stage and incomplete cell differentiation in the later stage constitute the major difficulty of osteochondral repair. Here, a novel all-silk-derived multifunctional biomaterial platform for osteochondral engineering is reported. The bilayer methacrylated silk fibroin (SilMA) hydrogel was fabricated through stratified photocuring as the basic provisional matrix for tissue regeneration. Platelet-rich plasma (PRP) incorporation promoted the migration and pre-differentiation of the bone marrow mesenchymal stem cells (BMSCs) in the early stage of implantation. The long-term regulation of BMSCs chondrogenesis and osteogenesis was realized by the stratified anchoring of the silk fibroin (SF) microspheres respectively loaded with Kartogenin (KGN) and berberine (BBR) in the hydrogel. The composite hydrogels were further demonstrated to promote BMSCs chondrogenic and osteogenic differentiation under an inflammatory microenvironment and to achieve satisfying cartilage and subchondral bone regeneration with great biocompatibility after 8 weeks of implantation. Since all the components used are readily available and biocompatible and can be efficiently integrated via a simple process, this composite hydrogel scaffold has tremendous potential for clinical use in osteochondral regeneration.

Puerarin inhibits FUNDC1-mediated mitochondrial autophagy and CSE-induced apoptosis of human bronchial epithelial cells by activating the PI3K/AKT/mTOR signaling pathway.

Increasing evidence suggests that the pathogenesis of chronic obstructive pulmonary disease (COPD) is associated with FUN14 domain protein 1 (FUNDC1)-mediated mitophagy. Recently, studies have reported that puerarin has protective effects against excessive oxidative damage in cells. Therefore, we hypothesized that puerarin may be involved in COPD progression via regulating FUNDC1 mediated mitophagy. We found that the viability of cigarette smoke extract (CSE)-stimulated human bronchial epithelial cells (HBECs) was enhanced and apoptosis was reduced after treatment with different concentrations of puerarin. Puerarin reversed mitochondrial membrane potential (MMP) levels and ATP content, and decreased reactive oxygen species (ROS) content in CSE stimulated HBECs. Moreover, puerarin significantly inhibited apoptosis related proteins, as well as the expression of mitophagy related proteins. After inhibition of FUNDC1 phosphorylation by protein phosphatase inhibitor (PH0321), puerarin restored MMP level, decreased ROS content, promoted ATP synthesis, and downregulated autophagy related protein expression in HBECs. In addition, mitochondrial division inhibitor (Mdivi) inhibited the expression of autophagy related proteins and reduced apoptosis after blocking cell autophagy, which was the same as the inhibition of puerarin. Finally, puerarin activated the PI3K/Akt/mTOR signaling pathway to participate in COPD progression by up regulating the phosphorylation levels of PI3K, Akt and mTOR.

Mechanisms linking mitochondrial mechanotransduction and chondrocyte biology in the pathogenesis of osteoarthritis.

Mechanical loading is essential for chondrocyte health. Chondrocytes can sense and respond to various extracellular mechanical signals through an integrated set of mechanisms. Recently, it has been found that mitochondria, acting as critical mechanotransducers, are at the intersection between extracellular mechanical signals and chondrocyte biology. Much attention has been focused on identifying how mechanical loading-induced mitochondrial dysfunction contributes to the pathogenesis of osteoarthritis. In contrast, little is known regarding the mechanisms underlying functional alterations in mitochondria induced by mechanical stimulation. In this review, we describe how chondrocytes perceive environmental mechanical signals. We discuss how mechanical load induces mitochondrial functional alterations and highlight the major unanswered questions in this field. We speculate that AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis, may play an important role in coupling force transmission to mitochondrial health and intracellular biological responses.

Injection route affects intra-articular hyaluronic acid distribution and clinical outcome in viscosupplementation treatment for knee osteoarthritis: a combined cadaver study and randomized clinical trial.

The coverage of hyaluronic acid (HA) on the impaired cartilage should be the precondition to exert its beneficial effect on knee osteoarthritis (KOA) according to the pharmacological mechanism. However, the intra-articular distribution of HA might be correlated with the route of drug delivery. Forty-two cadaver knees with radiographic evidence of osteoarthritis were given anteromedial (AM) or medial midpatellar (MMP) injection of HA (molecular weight 600-1500 kD) followed by gait stimulation. Although 2.5 ml HA delivered through both routes failed to cover the entire cartilage, HA covered 96.12% cartilage of patellofemoral joint (PFJ) and 71.44% of medial femorotibial joint (FTJ) through MMP route, whereas mainly distributed into FTJ and posterior condyles through AM route. HA in the MMP group distributed more in PFJ than that in the AM group (P < 0.001), but no significant difference presented in medial FTJ (P = 0.084). The clinical efficacy was also associated with the route of drug delivery. One hundred patients with unilateral mild-to-moderate KOA were recruited and randomly assigned to receive five weekly HA injections with AM route (n = 50) or MMP route (n = 50). Patients in the MMP group obtained better improvement in WOMAC index total score, pain score, stiffness score, and Lequesne index total score over the entire follow-up period, as compared to patients in the AM group (all P < 0.01). More patients in the MMP group claimed pain relief (71.7%, P = 0.024) and felt satisfying (63.1%, P = 0.007) than in the AM group at the end of follow-up. Therefore, intra-articular HA injection through MMP route is recommended in treating mild-to-moderate KOA. Graphical Abstract .

Hsa_circ_0000652 Aggravates Inflammation by Activation of Macrophages and Enhancement of OX40/OX40L Interaction in Ankylosing Spondylitis.

Circular RNAs (circRNAs) have emerged as important roles in various inflammatory processes of rheumatic diseases. However, their expression profiles and influences in the pathogenesis of ankylosing spondylitis (AS) remain unclear. In this study, we revealed the differential expression profiles of circRNAs in peripheral blood mononuclear cells (PBMCs) in AS by circRNA sequencing. We screened the differentially expressed circRNAs in AS and verified that hsa_circ_0000652 was upregulated and had potential to be a biomarker of progression. Functionally, hsa_circ_0000652 promoted proliferation and cytokine production in macrophages and inhibited apoptosis. Through dual-luciferase assays and RNA pull-down assays, we demonstrated that hsa_circ_0000652 acted as a competing endogenous RNA (ceRNA) by binding with hsa-miR-1179 and regulated OX40L, which is characterized as a co-stimulatory molecule and found to be upregulated in AS patients. As a result, hsa_circ_0000652 aggravated the inflammation in the coculture system containing CD4+ T cells and macrophages via OX40/OX40L interaction. Our findings suggest that hsa_circ_0000652 was upregulated in AS patients and may serve as a pro-inflammatory factor in macrophages and a positive regulator of OX40/OX40L by sponging hsa-miR-1179.

Joint motion of bipolar hemiarthroplasty in routine hip functional movements: a dynamic motion study.

BACKGROUND: Many motion studies have shown that the inner bearing of bipolar prostheses moves less than expected under non-weight-bearing and static weight-bearing positions, which are not routine functional movements performed postoperatively. The aim of this study was to investigate the behaviours of bipolar prostheses during normal gait and simulative squatting. METHODS: Thirty-one femoral neck fracture patients were enrolled, and fluoroscopy examinations of walking on a treadmill, simulative squatting, and non-weight-bearing abduction-adduction and flexion-extension motions were performed at an average of 40 months postoperatively. The rate of acetabular cartilage degeneration was calculated. The ranges of motion of the outer bearing and inner bearing were determined, and the O/I ratios were calculated. Clinical efficacy was assessed by HHS and EQ-5D score. RESULTS: The inner bearing moved more than the outer bearing did, with an O/I ratio of 0.81, during the normal gait examination, while the motion of the outer bearing was obviously dominant during the simulative squatting and non-weight-bearing abduction-adduction and flexion-extension examinations. The mean acetabular cartilage degeneration rate was 0.82 ± 0.54 mm/year at the follow-up. In subgroup analyses, the motion of the outer bearing decreased to some extent with the increase in acetabular wear, and the corresponding O/I ratios among the groups showed a trend of decreasing first and then increasing. The HHS and EQ-5D scores of the patients with osteolysis and femoral stem loosening were much worse than those with fixed implants. CONCLUSION: Bipolar prostheses do function as originally intended during gait, but movement primarily occurs at the outer bearing during other examinations. The motion patterns of bipolar prostheses change with the increase in acetabular wear.

Active ankylosing spondylitis increases blood loss during total hip arthroplasty for a stiff hip joint.

BACKGROUND: Total hip arthroplasty (THA) has been highlighted as the best treatment option for ankylosing spondylitis (AS) patients with advanced hip involvement. The huge blood loss associated with THA is a common concern of postoperative complications. Disease activity is a specific reflection of systematic inflammation of AS. The purpose of this study was to determine the effect of disease activity on blood loss during THA in patients with AS. METHODS: Forty-nine patients with AS who underwent unilateral THAs were retrospectively studied. Ankylosing Spondylitis Disease Activity Score (ASDAS) was employed to evaluate the disease activity. Orthopedic Surgery Transfusion Hemoglobin European Overview (OSTHEO) formula was used to assess the surgical blood loss. The patients were divided into active group (ASDAS≥1.3; n = 32) and stable groups (ASDAS< 1.3; n = 17) based on the ASDAS. Peri-operative laboratory values, plain radiographs, intra-operative data, transfusion volume, and use of hemostatic agents were recorded and statistically analyzed. RESULTS: The ASDAS, pre-operative C-reactive protein level, erythrocyte sedimentation rate, and fibrinogen concentration in the active group were higher than the stable group (all P < 0.05); however, the pre-operative hemoglobin concentration and albumin level were higher in the stable group (both P < 0.05). The total blood loss during THA in stable patients was 1415.31 mL and 2035.04 mL in active patients (P = 0.006). The difference between the two groups was shown to be consistent after excluding the gender difference (P = 0.030). A high transfusion rate existed in both groups (stable group, 76.47% with an average of 1.53 units; active group, 84.37% with an average of 2.31 units), but there was no significant difference between the two groups (both P > 0.05). Compensated blood loss, corresponding to transfusion, was noted significantly more in the active group compared to the stable group (P = 0.027). There was no significant difference with regard to functional recovery (P > 0.05). CONCLUSION: Active AS patients are at high risk for increased blood loss during THA compared to stable patients. The underlying mechanism includes disorders of the coagulation and fibrinolytic systems, poor nutrition status, osteoporosis, imbalance of oxidative-antioxidative status and local inflammatory reaction. It is strongly recommended to perform THA in AS patients with stable disease.

Novel halos in light kaonic nuclei as an indicator of nuclear equation of state at supra-normal densities.

The sensitive correlations between the low-density halo structure and the high-density properties of the nuclear equation of state (EOS) are constructed in light kaonic nuclei with the relativistic mean-field theory. More specifically, the 1p 1/2 halo spreads out linearly with increasing the pressure and sound velocity square at supra-normal densities and decreasing the incompressibility at saturation density. These results suggest that the novel halo in light kaonic nuclei can serve as a sensitive indicator of the nuclear EOS of symmetric matter at supra-normal densities. The experimental production and detection of the light kaonic nuclei, yet to be available, is discussed in some details at last.

Perioperative Blood Loss During Total Hip Arthroplasty Among Patients With Ankylosing Spondylitis.

Intraoperative blood loss is frequently an overarching concern during total hip arthroplasty (THA) for patients who have ankylosing spondylitis with hip involvement. However, the factors that affect blood loss have not been identified. The goal of this study was to investigate these factors among patients with ankylosing spondylitis. Patients in the authors' department who had ankylosing spondylitis and underwent unilateral THA from 2011 to 2016 were studied retrospectively. Demographic characteristics, perioperative laboratory values, intraoperative data, transfusion rate, transfusion volume, and data on hemostatic use were collected and analyzed statistically. Multiple and univariate linear regression analyses were performed. As a result, 44 patients were eligible for inclusion in the study. Mean age was 31.7±10.6 years, and mean disease duration was 9.7±5.8 years. Mean body mass index was 21.30±3.01 kg/m2. Mean volume of blood loss during THA was 1735.19±756.04 mL. Multiple linear regression analysis showed that perioperative blood loss was positively associated with Ankylosing Spondylitis Disease Activity Score (ASDAS), fibrinogen concentration, and surgical time. Further evaluation with univariate linear regression analysis suggested that ASDAS, red blood cell transfusion, and change of hematocrit concentration from preoperatively to postoperatively were correlated with blood loss. Disease activity, allogeneic blood transfusion volume, and change of hematocrit concentration from preoperatively to postoperatively appeared to be positively associated with perioperative blood loss during THA for patients with ankylosing spondylitis. For these patients, disease activity and the potential for allogeneic transfusion should be considered carefully before surgery. [Orthopedics. 2017; 40(5):e904-e910.].

Fast water channeling across carbon nanotubes in far infrared terahertz electric fields.

Using molecular dynamics simulations, we investigate systematically the water permeation properties across single-walled carbon nanotubes (SWCNT) in the presence of the terahertz electric field (TEF). With the TEF normal to the nanotube, the fracture of the hydrogen bonds results in the giant peak of net fluxes across the SWCNT with a three-fold enhancement centered around 14 THz. The phenomenon is attributed to the resonant mechanisms, characterized by librational, rotational, and rotation-induced responses of in-tube polar water molecules to the TEF. For the TEF along the symmetry axis of the nanotube, the vortical modes for resonances and consequently the enhancement of net fluxes are greatly suppressed by the alignment of polar water along the symmetry axis, which characterizes the quasi one-dimensional feature of the SWCNT nicely. The resonances of water molecules in the TEF can have potential applications in the high-flux device designs used for various purposes.

Water transport through carbon nanotubes with the radial breathing mode.

Molecular dynamics simulations are performed to investigate the water permeation across the single-walled carbon nanotube with the radial breathing mode (RBM) vibration. It is found that the RBM can play a significant role in breaking the hydrogen bonds of the water chain, accordingly increasing the net flux dramatically, and reducing drastically the average number of water molecules inside the tube with the frequency ranging from 5000 to 11 000 GHz, while far away from this frequency region the transport properties of water molecules are almost unaffected by the RBM. This phenomenon can be understood as the resonant response of the water molecule chain to the RBM. Our findings are expected to be helpful for the design of high-flux nanochannels and the understanding of biological activities, especially the water channelling.