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Extracellular vesicles (EVs) are increasingly used as delivery vehicles for drugs and bioactive molecules, which usually require intravascular administration. The endothelial cells covering the inner surface of blood vessels are susceptible to the shear stress of blood flow. Few studies demonstrate the interplay of red blood cell-derived EVs (RBCEVs) and endothelial cells. Thus, the phagocytosis of EVs by vascular endothelial cells during blood flow needs to be elucidated. In this study, red blood cell-derived extracellular vesicles (RBCEVs) were constructed to investigate endothelial cell phagocytosis in vitro and animal models. Results showed that low magnitude shear stress including low shear stress (LSS) and oscillatory shear stress (OSS) could promote the uptake of RBCEVs by endothelial cells in vitro. In addition, in zebrafish and mouse models, RBCEVs tend to be internalized by endothelial cells under LSS or OSS. Moreover, RBCEVs are easily engulfed by endothelial cells in atherosclerotic plaques exposed to LSS or OSS. In terms of mechanism, oxidative stress induced by LSS is part of the reason for the increased uptake of endothelial cells. Overall, this study shows that vascular endothelial cells can easily engulf EVs in areas of low magnitude shear stress, which will provide a theoretical basis for the development and utilization of EVs-based nano-drug delivery systems in vivo., Graphical abstract Image 1, Highlights • We recently reported that endothelial cells were amateur phagocytic cells for RBCEVs engulfment. • Low magnitude shear stress (LSS and OSS) can increase the uptake of RBCEVs by endothelial cells in vitro and in vivo. • ROS induced by low magnitude shear stress acts as an accelerator to enhance endothelial cells uptake of RBCEVs.

Infected wound healing remains a critical threat, which frequently delays the healing process and even leads to severe life-threatening complications. Herein, we reported an effective anti-infection approach, which was based on copper ions-releasing hydroxyapatite/polydopamine (HA-Cu/PDA) nanocomposites with photothermal effect. The HA-Cu/PDA nanocomposites was fabricated through a co-precipitation reaction between polydopamine (PDA)-coated hydroxyapatite nanoparticles (HA)-loaded Cu2+ (HA-Cu). Through a synergistic effect of released Cu2+ and photothermal efficiency of PDA coating, and the HA-Cu/PDA nanocomposites exhibited extraordinary antibacterial capacities against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The nanocomposites presented good biocompatibility for mouse embryonic fibroblast (NIH-3T3) cells and promoted NIH3T3 cells to migrate toward wound sites. Additionally, this nanocomposite could stimulate the tissue remodeling-related gene expression to induce the blood vessels formation, granulation tissues and collagen deposition, and eventually enhance wound healing. In vivo study further verified that HA-Cu/PDA nanocomposites with NIR irradiation could significantly improve bacterial infected wound healing through the prominent antibacterial property, reduced inflammatory response, the formation of granulation tissue, collagen deposition, and angiogenesis ability. Thus, this study develops a versatile strategy for a broad range of wound healing and skin reconstruction caused by bacterial infection.

Background Intimal hyperplasia caused by vascular injury is an important pathological process of many vascular diseases, especially occlusive vascular disease. In recent years, Nano-drug delivery system has attracted a wide attention as a novel treatment strategy, but there are still some challenges such as high clearance rate and insufficient targeting. Results In this study, we report a biomimetic ROS-responsive MM@PCM/RAP nanoparticle coated with macrophage membrane. The macrophage membrane with the innate “homing” capacity can superiorly regulate the recruitment of MM@PCM/RAP to inflammatory lesion to enhance target efficacy, and can also disguise MM@PCM/RAP nanoparticle as the autologous cell to avoid clearance by the immune system. In addition, MM@PCM/RAP can effectively improve the solubility of rapamycin and respond to the high concentration level of ROS accumulated in pathological lesion for controlling local cargo release, thereby increasing drug availability and reducing toxic side effects. Conclusions Our findings validate that the rational design, biomimetic nanoparticles MM@PCM/RAP, can effectively inhibit the pathological process of intimal injury with excellent biocompatibility. Graphical Abstract

This study investigated the immediate biomechanical effects of a biter-width partial medial meniscectomy. Small tears on the free edge of the meniscus are occasionally discovered during arthroscopic knee procedures. Removal of these tears often requires no more width than that of a biter from the edge. While past cadaveric partial meniscectomy studies have reported on the effects of meniscectomies from resection of one-third to three-quarters of meniscal width, the biomechanical sequelae of substantially smaller meniscectomies remain unknown. This study was performed to determine how single-biter-width meniscectomies affect the pressure distribution and peak pressure on the tibial plateau, as these parameters are correlated with increased likelihood of development of osteoarthritis. Eight cadaveric knees were instrumented with a thin-film pressure sensor underneath the menisci while retaining the major ligaments and most of the capsule. Knees were loaded to 1000 N at angles of flexion of 0, 15, 30, and 45 in normal tibio-femoral angles and in 7° of varus. Pressure, peak pressure, force and contact area were recorded. Afterwards, biter-width meniscectomies were performed, and measures repeated. There were significant changes in contact area at most flexion and tibio-femoral angles. There were no changes in the amount of force that was transmitted through the medial compartment. The overall pressure on the tibial plateau did not change in most knee conditions and peak pressure did not change significantly in any condition. The changes in contact area were consistent with our expectations. Similarly, the lack of change in force was also expected. However, the lack of significant changes in pressure and peak pressure represent findings indicating that a biter sized meniscectomy may have clinically insignificant effects on biomechanics.

In order to quantify the poroelastic mechanical signals conduction and evaluate the biomechanical effectiveness of functional units (osteocyte processes, canaliculi and lacuna) in lacunar-canalicular system (LCS), a multiscale poroelastic finite element model was established by using the Comsol Multiphysics software. The poroelastic mechanical signals (pore pressure, fluid velocity, von-Mises stress, strain) were analyzed inside the osteon-osteocyte system. The effects of osteocyte (OCY)’s shape (ellipse and circle), long axis directions (horizontal and vertical) and mechanical properties (Elastic modulus and permeability) on its poroelastic responses were examined. It is found that the OCY processes is the best mechanosensor compared with the OCY body, lacunae and canaliculi. The mechanotransduction ability of the elliptic shaped OCY is stronger than that of circular shaped. The pore pressure and flow velocity around OCYs increase as the elastic modulus and permeability of OCY increase. The established model can be used for studying the mechanism of bone mechanotransduction at the multiscale level.

Purpose: To study the effect of different doses of dexmedetomidine on lung function and lung tissue cell apoptosis in a rat model of hyperoxic acute lung injury. Methods: Five groups of healthy male Sprague-Dawley rats were used: normal rats, untreated hyperoxic rats, and hyperoxic rats given 3 different doses of dexmedetomidine, with 20 rats in each group. The levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined usingenzyme-linked immunosorbent assay (ELISA). Parietal paraffin cuts were taken from the right upper lobe for measurement of apoptosis using in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and the apoptosis index was calculated. Results: At 24 and 48 h, the levels of IL-6 and TNF-α in the hyperoxia model group were significantly higher than those in the normal control group, and their levels in the middle- and high-dose groups were markedly lowered, relative to untreated hyperoxia rats (p < 0.05). Apoptosis index in the hyperoxia model rats significantly increased, relative to normal rats (p < 0.05). The apoptosis index in the mediumand high-dose groups decreased significantly (p < 0.05). Conclusion: Dexmedetomidine inhibits inflammatory responses caused by high concentration of oxygen inhalation, minimizes lung injury, improves lung function and inhibits lung apoptosis. Keywords: Dexmedetomidine, Hyperoxia, Acute lung injury, Lung function, Apoptosis

It is increasingly aware that gut microbiota is closely associated with atherosclerosis. However, which and how specific gut bacteria regulate the progression of atherosclerosis is still poorly understood. In this study, modified linear discriminant analysis was performed in comparing the gut microbiota structures of atherosclerotic and non-atherosclerotic mice, and Desulfovibrio desulfuricans (D. desulfuricans) was found to be associated with atherosclerosis. D. desulfuricans-treated Apoe−/− mice showed significantly aggravated atherosclerosis. The proatherogenic effect of D. desulfuricans was attributed to its ability to increase intestinal permeability and subsequent raise in the transit of lipopolysaccharide (LPS) from the intestine to the bloodstream. Excessive LPS in the blood can elicit local and systemic inflammation and activate Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling of endothelial cells. TAK-242, a specific inhibitor of TLR4, can ameliorate the development of D. desulfuricans-induced atherosclerosis by blocking the LPS-induced activation of TLR4/NF-κB signaling.

This study investigated the effects of low-intensity pulsed ultrasound (LIPUS) of different spatial-average-temporal-average intensity (ISATA) ranging from 15–150 mW/cm2 on the treatment of osteoporosis in ovariectomized rats. Healthy 3-mo-old female Sprague–Dawley rats were randomly divided into nine groups (n = 12 per group): sham-ovariectomy (OVX) control group, OVX control group and OVX groups treated with LIPUS at seven different intensities (ISATA: 15, 30, 50, 75, 100, 125 and 150 mW/cm2, respectively). LIPUS was applied to bilateral femurs 12 wk post-OVX for 20 min/d for 6 wk. Micro-computed tomography, biomechanical tests, serum biochemical analysis and grip strength tests were performed to evaluate the therapeutic effects of LIPUS at different intensities. Results revealed that LIPUS intensity yielded strong correlations with bone mineral density and bone microstructure (R2 = 0.57–0.83) and bone mechanical strength (R2 = 0.80–0.97), and that the intensity of 150 mW/cm2, instead of the 30 mW/cm2 widely used in bone fracture healing, was most effective in maintaining bone mass among all the LIPUS signals between 15 and 150 mW/cm2. This suggests that higher ultrasound intensity (i.e., 150 mW/cm2) may be more effective than lower intensity in mitigation of osteopenia and osteoporosis.

Hydrogen sulfide (H2S) is involved in regulating cell apoptosis and proliferation. However, The effects and mechanism of H2S on the apoptosis of mammary epithelial cells that suffer from an inflammatory response remain unknown. An inflammatory cell model was used to explore whether exogenous H2S regulates lipopolysaccharides (LPS)-induced cell proliferation and apoptosis. We found that H2S affected cell viability, the inflammatory response and apoptosis in LPS-treated cells in a concentration-dependent manner. Moreover, exogenous H2S rescued LPS-induced cystathionine γ-lyase (CSE) inhibition and cystathionine β-synthase (CBS) synthesis. Interestingly, in cells undergoing inflammation-induced apoptosis, H2S activated the PI3K/Akt and NFκB signal pathways both tested concentrations. Akt appeared to be a key crosstalk molecule that played a “bridge” role. H2S regulates LPS-induced inflammation and apoptosis by activating the PI3K/Akt/NFκB signaling pathway. Hence, NaHS may be clinically useful for preventing or treating mastitis.

A 60‐day feeding trial was conducted to estimate the effects of dietary iron (Fe) levels on growth, Fe concentration in the liver, spleen, and blood, and transferrin and hepcidin concentrations in the blood of bighead carp (Aristichthys nobilis). The six experimental diets were formulated to contain different Fe levels (0, 43.1, 84.2, 123.3, 162.2 and 203.1 mg/kg of dry diet) using ferrous sulphate (FeSO₄) as the source. The weight gain (WG) and the specific growth ratio (SGR) of A. nobilis fed with a dietary Fe level of 123.3 mg/kg were significantly higher than that of the 0 mg/kg Fe group (p liver > whole body. When the Fe dietary content increases to 162.2 mg/kg, the blood concentrations of Fe significantly decreased and thereafter increased, hepcidin significantly decreased and thereafter decreased, and transferrin significantly increased and thereafter decreased. The results indicate that the transferrin blood content significantly increased with decreasing hepcidin of up to 264.63 μg/ml content and thereafter decreased. It could be concluded that after transferrin saturation, hepcidin functions to maintain iron balance in the blood of A. nobilis by decreasing transferrin content.

Background Bone is a hierarchically structured composite material, and different hierarchical levels exhibit diverse material properties and functions. The stress and strain distribution and fluid flow in bone play an important role in the realization of mechanotransduction and bone remodeling. Methods To investigate the mechanotransduction and fluid behaviors in loaded bone, a multiscale method was developed. Based on poroelastic theory, we established the theoretical and FE model of a segment bone to provide basis for researching more complex bone model. The COMSOL Multiphysics software was used to establish different scales of bone models, and the properties of mechanical and fluid behaviors in each scale were investigated. Results FE results correlated very well with analytical in macroscopic scale, and the results for the mesoscopic models were about less than 2% different compared to that in the macro–mesoscale models, verifying the correctness of the modeling. In macro–mesoscale, results demonstrated that variations in fluid pressure (FP), fluid velocity (FV), von Mises stress (VMS), and maximum principal strain (MPS) in the position of endosteum, periosteum, osteon, and interstitial bone and these variations can be considerable (up to 10, 8, 4 and 3.5 times difference in maximum FP, FV, VMS, and MPS between the highest and the lowest regions, respectively). With the changing of Young’s modulus (E) in each osteon lamella, the strain and stress concentration occurred in different positions and given rise to microscale spatial variations in the fluid pressure field. The heterogeneous distribution of lacunar–canalicular permeability (klcp) in each osteon lamella had various influence on the FP and FV, but had little effect on VMS and MPS. Conclusion Based on the idealized model presented in this article, the presence of endosteum and periosteum has an important influence on the fluid flow in bone. With the hypothetical parameter values in osteon lamellae, the bone material parameters have effect on the propagation of stress and fluid flow in bone. The model can also incorporate alternative material parameters obtained from different individuals. The suggested method is expected to provide dependable biological information for better understanding the bone mechanotransduction and signal transduction.

The biological effect of ultrasound on bone regeneration has been well documented, yet the underlying mechanotransduction mechanism is largely unknown. In relation to the mechanobiological modulation of the cytoskeleton and Ca2+ influx by short-term focused acoustic radiation force (FARF), the current study aimed to visualize and quantify Ca2+ oscillations in real-time of in situ and in vivo osteocytes in response to focused low-intensity pulsed ultrasound (FLIPUS). For in situ studies, fresh mice calvaria were subjected to FLIPUS stimulation at 0.05, 0.2, 0.3, and 0.7 W. For the in vivo study, 3-month-old C57BL/6J Ai38/Dmp1-Cre mice were subjected to FLIPUS at 0.15, 1, and 1.5 W. As observed via real-time confocal imaging, in situ FLIPUS led to more than 80% of cells exhibiting Ca2+ oscillations at 0.3-0.7 W and led to a higher number of Ca2+ spikes with larger values at >0.3 W. In vivo FLIPUS at 1-1.5 W led to more than 90% of cells exhibiting Ca2+ oscillations. Higher FLIPUS energies led to larger Ca2+ spike magnitudes. In conclusion, this study provided a pilot study of both in situ and in vivo osteocytic Ca2+ oscillations under noninvasive FARF, which aids further exploration of the mechanosensing mechanism of the controlled bone cell motility response to the stimulus.

In this study, we evaluated the effect of functional disuse-induced bone remodeling on its mechanical properties, individually at periosteum and medullary endosteum regions of the cortical bone. Left middle tibiae were obtained from 5-month-old female Sprague-Dawley rats for the baseline control as well as hindlimb suspended (disuse) groups. Micro-nano-mechanical elastic moduli (at lateral region) was evaluated along axial (Z), circumferential (C) and radial (R) orientations using nanoindentation. Results indicated an anisotropic microstructure with axial orientation having the highest and radial orientation with the lowest moduli at periosteum and medullary endosteum for both baseline control as well as disuse groups. Between the groups: at periosteum, an insignificant difference was evaluated for each of the orientations (p 0.05) and at endosteum, a significant decrease of elastic moduli in the radial (p 0.0001), circumferential (p 0.001) and statistically insignificant difference in axial (p 0.05) orientation. For the moduli ratios between groups: at periosteum, only significant difference in the Z/R (p 0.05) anisotropy ratio, whereas at endosteum, a statistically significant difference in Z/C (p 0.001), and Z/R (p 0.001), as well as C/R (p 0.05) anisotropy ratios, was evaluated. The results suggested initial bone remodeling impaired bone micro-architecture predominantly at the medullary endosteum with possible alterations in the geometric orientations of collagen and mineral phases inside the bone. The findings could be significant for studying the mechanotransduction pathways involved in maintaining the bone micro-architecture and possibly have high clinical significance for drug use against impairment from functional disuse.

Background: Neuroendocrine tumors are heterogeneous malignancies that originate from the neuroendocrine system. Previous studies show that this cancer type mainly localizes in the gastrointestinal tract and often metastasizes to the liver. Primary liver neuroendocrine tumors are very rare and primary hepatic neuroendocrine tumors (PHNET) with concurrent hepatocellular carcinoma (HCC) are extremely rare. To the best of our knowledge, only few PHNET cases have been identified, making their diagnosis difficult. Here, we report the biggest ever reported and “deceiving” lesion of a mixed neuroendocrine-non-neuroendocrine neoplasm in the liver, aiming to raise awareness and improve treatment of the disease.Case Presentation: Here, we report a preoperative misdiagnosed case that presented with hepatocellular carcinoma clinical features and no extrahepatic tumors. Postoperative pathology confirmed that it was a mixed neuroendocrine-non-neuroendocrine neoplasm. The patient was then referred for etoposide and cisplatin-based chemotherapy. No disease recurrence was observed at the 6-month follow-up.Conclusion: We report a very rare and easily misdiagnosed case and we speculate that there were “undifferentiated cells” undergoing neuroendocrine and hepatocellular carcinoma differentiation, during which some hepatocellular carcinoma cells express neuroendocrine features. We recommend proper surgery and postoperative platinum-based chemotherapy in the management of this disease.

ObjectivesPanzhihua has implemented the Diagnosis Related Groups (DRGs) since 2018, and the quality of medical under the DRG-Based Payment System is concerned. This study aimed to examine the characteristics of patients under the DRG payment system based on the related factors, length of stay, readmission of inpatients.MethodsWe conducted a retrospective cohort study using data from Hospital Information System (HIS) from 2019 . The study used logistic regression analysis to investigate the factors related to hospitalization time and readmission rate of patients under the DRG payment system.ResultsIn this study ,68210 inpatients were included in the study. Among these inpatients ,5.84% were readmitted within 30 days.The factors associated with the increased risk of readmission included age, DRG payment, admission, critical condition, and discharge (p

Background The objective of this study was to establish a risk assessment model for lower extremity deep venous thrombosis in critically ill patients and compared with Caprini, Padua and Wells risk assessment model to evaluate its efficacy. Methods We conducted a pooled analysis of prospective cohort studies. The outcomes of interest were lower extremity deep vein thrombosis group and Non-lower extremity deep vein thrombosis group were determined by univariate analysis, and SPSS was used to establish the back propagation artificial neural network prediction model. ROC curve was used to evaluate the predictive effectiveness of the model. Medcalc15.2 was used to compare the predictive capabilities of different models. Results 600 cases of intensive care unit patients were selected in this study. The prevalence of lower extremity venous thromboembolism after ICU admission was 12.5%. The results of univariate analysis that showed 16 statistically significant difference influencing factors. The ROC curve area of BP-ANN risk assessment model was 0.828, showing good predictive efficacy. In addition to the ROC curve area of BP-ANN risk assessment model was higher than Caprini, Padua and Wells model. Conclusion BP-ANN risk assessment model can play an auxiliary role in predicting the occurrence of lower extremity venous thromboembolism in critically ill patients. This model can provide a reference for medical staff to take preventive management measures.

Coronavirus disease 2019 (COVID-19) is highly contagious. It may rapidly progress to acute respiratory distress syndrome (ARDS) and result in multiorgan dysfunction or death in some cases.(1,2) Here, we report the case of a patient with hepatocellular carcinoma (HCC) who underwent liver transplantation and experienced COVID-19 infection during the perioperative period. This case may help clinicians by alerting them to potential COVID-19 infection in transplant recipients during the outbreak.

Background Myocardial infarction (MI) is the leading cause of death from cardiovascular disease (CVD). Currently, the efficacy for MI treatment remains unsatisfactory. Therefore, it is urgent to develop a novel therapeutic strategy. Methods Left anterior descending arteries (LAD) of mice were ligated to induce MI. Another set of mice were intravenously injected with PTEN inhibitor BPV (1 mg/kg) 1 h after LAD ligation and continued to receive BPV injection daily for the following 6 days. Mice were performed echocardiography 14 days after surgery. Results Mice in MI group displayed an increased expression of PTEN with impaired cardiac function, enhanced cardiomyocyte apoptosis and decreased angiogenesis. BPV treatment significantly improved cardiac function, with reduced cardiomyocyte apoptosis, promoted angiogenesis, and activated PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway. Conclusion PTEN inhibitor BPV could effectively prevent myocardial infarction in mice, highlighting its potential as a candidate therapeutic drug.

Overloaded iron can deposit in the reproductive system and impair ovarian function. But few studies have identified the exact effect of overloaded iron on the endocrine function and fertility capacity in female mice. Here, we established iron-overloaded mouse models by intraperitoneal injection of iron dextran to adult female C57BL/6J mice at 0.1 g/kg (LF group), 0.5 g/kg (MF group), and 1.0 g/kg (HF group) concentrations once a week for eight consecutive weeks. We found that overloaded iron resulted in smaller ovaries, as well as accumulated oxidative damages. The endocrine function and follicle development were also impeded in the MF and HF groups. The 10-month breeding trial indicated that (1) Low concentration of iron (0.1 g/kg) wasn’t detrimental to the ovary; (2) Middle concentration of iron (0.5 g/kg) impeded the childbearing process, though it could be recovered following the iron excretion; and (3) High concentration of iron (1.0 g/kg) damaged the fertility, even gave rise to sterility. Yet for those fertile mice, litter number and litter size were smaller and the ovarian reserve of their offspring was impaired. Transcriptome profiling results indicated that overloaded iron could compromise ovarian function by disrupting ovarian steroidogenesis, interfering with ovarian microenvironment, and inhibiting Wnt signaling. Taken together, we have demonstrated the effect that chronic concentration-dependent iron overload exerted on mouse ovarian function, which may act as a preliminary basis for further mechanism and intervention investigations.

Background Chronic intestinal schistosomiasis has been reported to be associated with colonic polyps, colorectal cancer and ulcerative colitis. We aim to investigate the clinical characteristics of intestinal-related lesions caused by chronic intestinal schistosomiasis japonicum. Methods Patients with and without chronic intestinal schistosomiasis were retrospectively enrolled from the endoscopy center of Wuhan Union Hospital from September 1, 2014, to June 30, 2019 with a ratio of 4:1. The characteristics of infected intestinal segments were analyzed in patients with chronic intestinal schistosomiasis. We also compared the characteristics of intestinal-related lesions, including colorectal polyps, colorectal cancer (CRC), ulceration or erosion of the intestinal mucosa and hemorrhoids, between the two groups. Results A total of 248 patients with chronic intestinal schistosomiasis and 992 patients without chronic intestinal schistosomiasis were analyzed. The most common sites of chronic intestinal schistosomiasis were the sigmoid colon (79.0%) and rectum (84.7%). The frequency of intestinal polyps (64.5% vs. 42.8%, p p = 0.002), in the intestinal schistosomiasis group was significantly higher than that in the control group. Morphologically, type IIa polyps were more common in the schistosomiasis enteropathy group (68.5% vs. 60.7%, p = 0.001). Female patients with intestinal schistosomiasis had a higher detection rate of CRC than women in the control group (13.8% vs. 5.4%, p = 0.017). There was no significant difference in the incidence of ulcerative colitis between the two groups (0.8% vs. 0.6%, p = 0.664). In addition, the schistosomiasis enteropathy patients had a higher detection rate of internal hemorrhoids (58.9% vs. 51.0%, p = 0.027). Conclusions Chronic intestinal schistosomiasis mainly involved the rectum and sigmoid colon and was more likely to induce intestinal polyps, especially rectal polyps and internal hemorrhoids. Women with chronic schistosomiasis have a higher risk of colorectal cancer.

This study is focussed on evaluating and comparing two mediators of osteoclast, osteoprotegerin (OPG) and nuclear factor-κB ligand (RANKL), in plasma and tissue levels in patients with steroid-induced osteonecrosis of femoral head (SIONFH). Subjects were included in this cross-sectional case-control study in 2016. Bone histomorphology, immunohistochemistry, Western blotting, OPG and RANKL plasma levels, post-hoc statistical power and receiver-operating characteristic (ROC) curves were evaluated. Eighty-six patients diagnosed with SIONFH and 51 healthy subjects were included. OPG expression levels in bone samples increased with ARCO stage, and RANKL expression levels decreased with ARCO stages. Plasma OPG and RANKL levels were significantly higher in the SIONFH group compared with the healthy control group. The plasma OPG level and ratio of OPG and RANKL were positively associated with ARCO stages and significantly higher in stages III and IV. Plasma RANKL levels were negatively associated with ARCO stage and were significantly higher in ARCO stages II and III. Plasma OPG and RANKL may represent potential biomarkers during SIONFH at different stages. Higher plasma OPG levels indicated late-stage SIONFH, and higher plasma RANKL levels indicated early stage. Our findings may provide a clue for the development of diagnostic tools and therapies for SIONFH.

Hepatocellular carcinoma (HCC) is one of the most common malignancies today. Patients suffer from HCC since its high malignancy and limited treatment means. With the development of genetic research, new therapeutic strategy comes up in the way of gene editing. Clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) was discovered as an immune sequence in bacteria and archaea. After artificial transformation and follow-up research, it is widely used as a gene editing tool. In this review, the development of CRISPR/Cas9 is summarized in retrospect. Through the evaluation of novel research in HCC, it is concluded that CRISPR/Cas9 would promote cancer research and provide a new tool for genetic treatment in prospect.

Atherosclerosis (AS), the underlying cause of most cardiovascular events, is one of the most common causes of human morbidity and mortality worldwide due to the lack of an efficient strategy for targeted therapy. In this work, we aimed to develop an ideal biomimetic nanoparticle for targeted AS therapy.\ud \ud Methods: Based on macrophage “homing” into atherosclerotic lesions and cell membrane coating nanotechnology, biomimetic nanoparticles (MM/RAPNPs) were fabricated with a macrophage membrane (MM) coating on the surface of rapamycin-loaded poly (lactic-co-glycolic acid) copolymer (PLGA) nanoparticles (RAPNPs). Subsequently, the physical properties of the MM/RAPNPs were characterized. The biocompatibility and biological functions of MM/RAPNPs were determined in vitro. Finally, in AS mouse models, the targeting characteristics, therapeutic efficacy and safety of the MM/RAPNPs were examined.\ud \ud Results: The advanced MM/RAPNPs demonstrated good biocompatibility. Due to the MM coating, the nanoparticles effectively inhibited the phagocytosis by macrophages and targeted activated endothelial cells in vitro. In addition, MM-coated nanoparticles effectively targeted and accumulated in atherosclerotic lesions in vivo. After a 4-week treatment program, MM/RAPNPs were shown to significantly delay the progression of AS. Furthermore, MM/RAPNPs displayed favorable safety performance after long-term administration.\ud \ud Conclusion: These results demonstrate that MM/RAPNPs could efficiently and safely inhibit the progression of AS. These biomimetic nanoparticles may be potential drug delivery systems for safe and effective anti-AS applications.

It has been demonstrated that articular facet degeneration can cause local strain alterations and induce neck pain. This study aims to quantify the biomechanical effects of normal and degenerated C5-C6 articular facets, and evaluate the correlation of mechanical strain between healthy and degenerated spine. A 3-dimensional finite element (FE) model of the C5-C6 cervical spine was developed [Model 0 (M0)]. The asymmetric models of C5-C6 bilateral articular facet joint were established separately to mimic articular facet joint degeneration. The capsule ligament stiffness of C5-C6 unilateral facet joint was altered with minimum and maximum threshold to simulate capsule ligaments' lesion and calcification [Model 1 (M1) and Model 2 (M2), respectively]. Besides, the cervical C5-C6 unilateral articular facet joint direction was changed by 5° and 10° forward to imitate the moderate joint hyperplasia and severe osteophyte (Model 3 and Model 4 respectively). M1 increased the rotation range of ipsilateral side (left), while M2 reduced, and both had limited effect on the contralateral side (right). The angle increased in Model 3 (M3) (61°) and Model 4 (M4) (55°) comparing to M0 during the axial rotation, and the angle of M4 was larger. M3 and M4 increased the nucleus pulposus pressure with and without controlled angular displacement during axial rotation. The pressure of nucleus pulpous increased during M1 rotating to the abnormal side but decreased when rotating to the other side, but the results of M2 were opposite. The capsule ligament stiffness made an impact on segmental mobility and vertebral spatial position, and the sagittal angle of articular facet joint exerted an influence on disc pressure distribution.

The purpose of this study was to evaluate the effect of low-intensity ultrasound on articular cartilage and subchondral bone alterations in joints under normal and functional disuse conditions during osteoarthritis (OA) progression. Total of thirty 5-mo-old female Sprague–Dawley rats were randomly assigned to six groups (n = 5/group): age-matched group, OA group, OA + ultrasound (US) group, hindlimb suspension (HLS) group, HLS + OA group and HLS + OA + US group. The surgical anterior cruciate ligament was used to induce OA in the right knee joints. After 2 wk of OA induction, low-intensity ultrasound generated with a 3-MHz transducer with 20% pulse duty cycle and 30 mW/cm2 acoustic intensity was delivered to the right knee joints for 20 min a day, 5 d a week for a total of 6 wk. Then, the right tibias were harvested for micro-computed tomography, histologic and mechanical analysis. Micro-computed tomography results indicated that the thickness and sulfated glycosaminoglycan content of cartilage decreased, but the thickness of the subchondral cortical bone plate and the formation of subchondral trabecular bone increased in the OA group under the normal joint use condition. Furthermore, histologic results revealed that chondrocyte density and arrangement in cartilage corrupted and the underlying subchondral bone increased during OA progression. These changes were accompanied by reductions in mechanical parameters in OA cartilage. However, fewer OA symptoms were observed in the HLS + OA group under the joint disuse condition. The cartilage degeneration and subchondral bone sclerosis were alleviated in the US treatment group, especially under normal joint use condition. In conclusion, low-intensity ultrasound could improve cartilage degeneration and subchondral sclerosis during OA progression. Also, it could provide a promising strategy for future clinical treatment for OA patients.

Chemotherapy-induced ovarian aging not only increases the risk for early menopause-related complications but also results in infertility in young female cancer survivors. Oogonial stem cells have the ability to generate new oocytes and thus provide new opportunities for treating ovarian aging and female infertility. Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural phenol derived from plants, that has been shown to have positive effects on longevity and redox flow in lipid metabolism and a preventive function against certain tumors. To evaluate whether resveratrol could promote the repair of oogonial stem cells damage in a busulfan/cyclophosphamide (Bu/Cy)-induced accelerated ovarian aging model, female mice were administered 30 and 100 mg/kg/d resveratrol through a gavage for 2 weeks. We demonstrated that resveratrol (30 mg/kg/d) relieved oogonial stem cells loss and showed an attenuating effect on Bu/Cy-induced oxidative apoptosis in mouse ovaries, which may be attributed to the attenuation of oxidative levels in ovaries. Additionally, we also showed that Res exerted a dose-dependent effect on oogonial stem cells and attenuated H2O2-induced cytotoxicity and oxidative stress injury by activating Nrf2 in vitro. Therefore, resveratrol could be of a potential therapeutic drug used to prevent chemotherapy-induced ovarian aging.

Diagnosis of subclinical mastitis is very important in management of the dairy industry and improvement of dairy cow productivity. S100A12, that is found in related tissues of mammals, is considered as an index for diagnosing inflammatory reaction. To evaluate whether S100A12 is involved in subclinical mastitis, milk somatic cell mRNA from 276 dairy cows was used to detect the transcriptional level of S100A12 by real-time quantitative polymerase chain reaction. A predictive analysis for mastitis was performed, and the correlation between S100A12 and other subclinical mastitis indicators was also assessed. The transcriptional levels of S100A12 in the milk of cows with mastitis were significantly higher than those in the milk of healthy cows (p < 0.05). The correlation analysis showed that S100A12 was positively associated with the somatic cell count and the sodium and chloride concentrations of milk. In contrast, a negative correlation was found between S100A12 and the potassium concentration and pH of milk. However, no significant correlation was detected between S100A12 and the other parameters, such as protein, lactose, ash, fat, density, Ca2+ and SNF. These results suggested that the S100A12 level in milk may serve as a diagnostic tool for subclinical mastitis in cows without obvious clinical signs.

Subacute ruminal acidosis (SARA) can cause rapid lipopolysaccharide (LPS) elevation and milk yield decline in lactating ruminants. LPS has been shown to promote apoptosis and reduce the proliferation of mammary epithelial cells. Previous studies have shown that γ- amino butyric acid (GABA) can enhance production performance, regulating β-cell apoptosis and proliferation. Whether GABA can regulate apoptosis and proliferation induced by LPS in mammary epithelial cells is unknown. In this paper, we detected the role of GABA on proliferation and apoptosis as well as inflammation induced by LPS in bovine mammary epithelial cells (MAC-T cell line). In addition, we explored the role mechanism of GABA in LPS-induced MAC-T cells response through detecting the NFκB signaling pathway key molecules. The results suggested that GABA reduced the effects of cell apoptosis induced by LPS. Furthermore, GABA inhibited the expression of inflammatory cytokines activated by LPS. More importantly, blocking GABA receptors with its antagonist, GABA could not reduce the expression of inflammatory and pro-apoptotic factors activated by LPS. Notably, GABA significantly decreased the TLR4, NFκB p65, and MyD88 mRNA expression levels that were elevated by LPS. Our data indicated that GABA can improve cell viability and decrease apoptosis induced by LPS, while exerting an anti-inflammatory effect through the NFκB signaling pathway.

Sclerostin is an osteocyte-derived protein that has a potent inhibitory effect on osteoblast activity. The osteocyte apoptosis induced by various causes of osteonecrosis of the femoral head (ONFH) plays a key role in the promotion of femoral head collapse. But the effect of altering sclerostin level on the collapse of ONFH has not been studied. Our aim was to assess the role of sclerostin level in the collapse of ONFH. Between May 2016 and November 2016, 236 subjects were enrolled in the present study. The patients were classified according to the Association Research Circulation Osseous (ARCO) classification. The clinical bone histomorphology, the expression position, and level of sclerostin as well as the plasma sclerostin level were evaluated. The sclerostin level was significantly lower in the non-traumatic ONFH group than those in the healthy control group (P = 0.002). The sclerostin level was negatively associated with ARCO stages (r = − 0.239, P = 0.009) and significantly lower in the postcollapse group (P = 0.025). The reduced expression of sclerostin may play a key role in the collapse process of ONFH and be predictive of the disease progression of ONFH.

Zn2+ is an essential element for cell survival/growth, and its deficiency is linked to many disorders. Extracellular Zn2+ concentration changes participate in modulating fundamental cellular processes such as proliferation, secretion, ion transport, and cell signal transduction in a mechanism that is not well understood. Here, we hypothesize that the Zn2+-sensing receptor ZnR/G protein-coupled receptor 39 (GPR39), found in tissues where dynamic Zn2+ homeostasis takes place, enables extracellular Zn2+ to trigger intracellular signaling pathways regulating key cell functions in vascular cells. Thus, we investigated how extracellular Zn2+ regulates cell viability, proliferation, motility, angiogenesis, vascular tone, and inflammation through ZnR/GPR39 in endothelial cells. Knockdown of GPR39 through siRNA largely abolished Zn2+-triggered cellular activity changes, Ca2+ responses, as well as the downstream activation of Gαq-PLC pathways. Extracellular Zn2+ promoted vascular cell survival/growth through activation of cAMP and Akt as well as overexpressing of platelet-derived growth factor-α receptor and vascular endothelial growth factor A. It also enhanced cell adhesion and mobility, endothelial tubule formation, and cytoskeletal reorganization. Such effects from extracellular Zn2+ were not observed in GPR39−/− endothelial cells. Zn2+ also regulated inflammation-related key molecules such as heme oxygenase-1, selectin L, IL-10, and platelet endothelial cell adhesion molecule 1, as well as vascular tone-related prostaglandin I2 synthase and nitric oxide synthase-3. In sum, extracellular Zn2+ regulates endothelial cell activity in a ZnR/GPR39-dependent manner and through the downstream Gαq-PLC pathways. Thus, ZnR/GPR39 may be a therapeutic target for regulating endothelial activity.

Background Cerebral hypoperfusion is a pivotal risk factor for vascular dementia (VD), for which effective therapy remains inadequate. Persistent inflammatory responses and excessive chemotaxis of microglia/macrophages in the brain may accelerate the progression of VD. Endocannabinoids are involved in neuronal protection against inflammation-induced neuronal injury. Cannabinoids acting at cannabinoid receptor 2 (CB2R) can decrease inflammation. Based on the identification of paeoniflorin (PF) as a CB2R agonist, we investigated the neuroprotective and microglia/macrophages M1 to M2 polarization promoting effects of PF in a permanent four-vessel occlusion rat model. Methods One week after surgery, PF was intraperitoneally administered at a dose of 40 mg/kg once a day for 28 successive days. The effects of PF on memory deficit were investigated by a Morris water maze test, and the effects of PF on hippocampal neuronal damage were evaluated by light microscope and electron microscope. The mRNA and protein expression levels of key molecules related to the M1/M2 polarization of microglia/macrophages were assessed by RT-qPCR and Western blotting, respectively. Results Administration of PF could significantly attenuate cerebral hypoperfusion-induced impairment of learning and memory and reduce the morphological and ultrastructural changes in the hippocampal CA1 region of rats. Moreover, PF promoted an M1 to M2 phenotype transition in microglia/macrophages in the hippocampus of rats. In addition to its inhibitory property against proinflammatory M1 mediator expression, such as IL-1β, IL-6, TNF-α and NO, PF dramatically up-regulated expression of anti-inflammatory cytokines IL-10 and TGF-β1. Importantly, CB2R antagonist AM630 abolished these beneficial effects produced by PF on learning, memory and hippocampus structure in rats, as well as the polarization of microglia/macrophages to the M2 phenotype. Additionally, PF treatment significantly inhibited cerebral hypoperfusion-induced mTOR/NF-κB proinflammatory pathway and enhanced PI3K/Akt anti-inflammatory pathway. Effects of PF on these signaling pathways were effectively attenuated when rats were co-treated with PF and AM630, indicating that the mTOR/NF-κB and PI3K/Akt signaling pathways were involved in the PF effects through CB2R activation. Conclusion These findings demonstrated PF exerts its neuroprotective effect and shifts the inflammatory milieu toward resolution by modulation of microglia/macrophage polarization via CB2R activation. Electronic supplementary material The online version of this article (10.1186/s13020-018-0173-1) contains supplementary material, which is available to authorized users.

Background Infection with the hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC). The osmoregulatory transcription factor nuclear factor of activated T-cells 5 (NFAT5) has been shown to play an important role in the development of many types of human cancers. The role of NFAT5 in HBV-associated HCC has never previously been investigated. Methods We compared expression profiles of NFAT5, DARS2 and miR-30e-5p in HCC samples, adjacent nontumor tissues and different hepatoma cell lines by quantitative real-time polymerase chain reaction and /or Western blot. Clinical data of HCC patients for up to 80 months were analyzed. The regulatory mechanisms upstream and convergent downstream pathways of NFAT5 in HBV-associated HCC were investigated by ChIP-seq, MSP, luciferase report assay and bioinformation anaylsis. Results We first found that higher levels of NFAT5 expression predict a good prognosis, suggesting that NFAT5 is a potential tumor-suppressing gene, and verified that NFAT5 promotes hepatoma cell apoptosis and inhibits cell growth in vitro. Second, our results showed that HBV could suppress NFAT5 expression by inducing hypermethylation of the AP1-binding site in the NFAT5 promoter in hepatoma cells. In addition, HBV also inhibited NFAT5 through miR-30e-5p targeted MAP4K4, and miR-30e-5p in turn inhibited HBV replication. Finally, we demonstrated that NFAT5 suppressed DARS2 by directly binding to its promoter. DARS2 was identified as an HCC oncogene that promotes HCC cell cycle progression and inhibits HCC cell apoptosis. Conclusion HBV suppresses NFAT5 through the miR-30e-5p/mitogen-activated protein kinase (MAPK) signaling pathway upstream of NFAT5 and inhibits the NFAT5 to enhance HCC tumorigenesis via the downstream target genes of DARS2. Electronic supplementary material The online version of this article (10.1186/s13046-017-0618-x) contains supplementary material, which is available to authorized users.

IFITM3 is involved in cell adhesion, apoptosis, immune, and antivirus activity. Furthermore, IFITM3 gene has been considered as a preferential marker for inflammatory diseases, and positive correlation to pathological grades. Therefore, we assumed that IFITM3 was regulated by different signal pathways. To better understand IFITM3 function in inflammatory response, we cloned swine IFITM3 gene, and detected IFITM3 distribution in tissues, as well as characterized this gene. Results indicated that the length of swine IFITM3 gene was 438 bp, encoding 145 amino acids. IFITM3 gene expression abundance was higher in spleen and lungs. Moreover, we next constructed the eukaryotic expression vector PBIFM3 and transfected into PK15 cells, finally obtained swine IFITM3 gene stable expression cell line. Meanwhile, we explored the effects of LPS on swine IFITM3 expression. Results showed that LPS increased IFITM3 mRNA abundance and exhibited time-dependent effect for LPS treatment. To further demonstrate the mechanism that IFITM3 regulated type I IFNs production, we also detected the important molecules expression of TLR4 signaling pathway. In transfected and non-transfected IFITM3 PK15 cells, LPS exacerbated the relative expression of TLR4-NFκB signaling molecules. However, the IFITM3 overexpression suppressed the inflammatory development of PK15 cells. In conclusion, these data indicated that the overexpression of swine IFITM3 could decrease the inflammatory response through TLR4 signaling pathway, and participate in type I interferon production. These findings may lead to an improved understanding of the biological function of IFITM3 in inflammation.

Injuries to the posterolateral corner of the knee can lead to chronic degenerative changes, external rotation instability, and varus instability if not repaired adequately. A proximal fibula avulsion fracture, referred to as an arcuate fracture, has been described in the literature, but a definitive repair technique has yet to be described. The objective of this study was to present a novel arcuate fracture repair technique, using a spiked-washer with an intramedullary screw, and to compare its biomechanical integrity to a previously described suture and bone tunnel method.Ten fresh-frozen cadaveric knees underwent a proximal fibula osteotomy to simulate a proximal fibula avulsion fracture. The lateral knee capsule and posterior cruciate ligament were also sectioned to create maximal varus instability. Five fibulas were repaired using a novel spiked-washer technique and the other 5 were repaired using the suture and bone tunnel method. The repaired knees were subjected to a monotonic varus load using a mechanical testing system instrument until failure of the repair or associated posterolateral corner structures.Compared with the suture repair group, the spiked-washer repair group demonstrated a 100% increase in stiffness, 100% increase in yield, 110% increase in failure force, and 108% increase in energy to failure.The spiked-washer technique offers superior quasi-static biomechanical performance compared with suture repair with bone tunnels for arcuate fractures of the proximal fibula. Further clinical investigation of this technique is warranted and the results of this testing may lead to improved outcomes and patient satisfaction for proximal fibula avulsion fractures.

Human metapneumovirus (hMPV) is an important pathogen that causes upper and lower respiratory tract infections in children worldwide. hMPV has two major genotypes, hMPV-A and hMPV-B. Epidemiological studies have shown that the two hMPV genotypes alternate in predominance worldwide in recent years. Co-circulation of the two genotypes of hMPV was usually observed and there is no study about the interaction between them, such as competitive replication, which maybe the possible mechanisms for alternating prevalence of subtypes. Our present study have used two different genotypes of hMPV (genotype A: NL/1/00; B: NL/1/99) in different proportions in animal model (BALB/c mice) and cell model (Vero-E6) separately. The result showed that the competitive growth does exist in BALB/c mice, genotype B had a strong competitive advantage. However, genotype B did not cause more severe disease than non-predominant (genotype A) or mixed strains in the study, which were evaluated by the body weight, airway hyperresponsiveness and lung pathology of mouse. In cell model, competitive growth and the two genotypes alternately prevalence were observed. In summary, we confirmed that there was a competitive replication between hMPV genotype A and B, and no difference in disease severity caused by the two subtypes. This study shows a new insight to understand the alternation of hMPV genotype prevalence through genotype competition and provide experimental evidence for disease control and vaccine design.

The use of mechanical biology and biomechanical signal transduction is a novel approach to attenuate musculoskeletal degeneration, whereas the understanding of specific cellular responses is critical to delineate the underlying mechanism. Dynamic mechanical signals with optimized loading signals, i.e., intensity and frequency, have been shown to have the potential to regulate bone and cartilage adaptation. Mechanotransduction pathways are of great interests in elucidating how mechanical signals produce such observed effects, including reduced bone loss, increased bone formation, and osteogenic cell differentiation. The objective of this review is to develop a molecular understanding of the mechanotransduction processes in tissue regeneration, which may provide new insights into bone physiology. In this chapter, we discuss the potential for mechanical loading to induce dynamic bone fluid flow, i.e., generated by the intramedullary pressure (ImP) and strains in bone, regulation of bone adaptation, and optimization of stimulation parameters in the loading regimen. The potential for mechanical loading to regulate bone fluid flow and microcirculation is also discussed. Particular attention is allotted to the responses of mechanical loading, including potential cellular and molecular pathways, osteocytes associated with Wnt signaling, the elevation of marrow stem cells and suppression of adipose cells, as well as the roles of LRP5 and microRNA. Altogether, these discussed data highlight the complex yet highly coordinated process of mechanotransduction in bone tissue regeneration.

Mechanical biology and biomechanical signal transduction is a novel approach to attenuate musculoskeletal degeneration, and the understanding of specific cellular responses is critical to delineate the underlying mechanism. Dynamic mechanical signals with optimized loading signals, i.e., intensity and frequency, have been shown to have the potential to regulate bone and cartilage adaptation. Mechanotransduction pathways are of great interest in elucidating how mechanical signals produce such observed effects, including reduced bone loss, increased bone formation, and osteogenic cell differentiation. The objective of this chapter is to develop a molecular understanding of the mechanotransduction processes in tissue regeneration, which may provide new insights into bone physiology. In this chapter, we discuss the potential for mechanical loading to induce dynamic bone fluid flow, i.e., generated by the intramedullary pressure and strains in bone; regulation of bone adaptation; and optimization of stimulation parameters in the loading regimen. The potential for mechanical loading to regulate bone fluid flow and microcirculation is also discussed. Particular attention is allotted to the responses of mechanical loading, including potential cellular and molecular pathways, osteocytes associated with Wnt signaling, the elevation of marrow stem cells and suppression of adiposis cells, and the roles of LRP5 and microRNA. Altogether, these discussed data highlight the complex yet highly coordinated process of mechanotransduction in bone tissue regeneration.

The nucleus pulposus (NP) in the intervertebral disk (IVD) depends on diffusive fluid transport for nutrients through the cartilage endplate (CEP). Disruption in fluid exchange of the NP is considered a cause of IVD degeneration. Furthermore, CEP calcification and sclerosis are hypothesized to restrict fluid flow between the NP and CEP by decreasing permeability and porosity of the CEP matrix. We performed a finite element analysis of an L3–L4 lumbar functional spine unit with poro-elastic constitutive equations. The aim of the study was to predict changes in the solid and fluid parameters of the IVD and CEP under structural changes in CEP. A compressive load of 500 N was applied followed by a 10 Nm moment in extension, flexion, lateral bending, and axial rotation to the L3–L4 model with fully saturated IVD, CEP, and cancellous bone. A healthy case of L3–L4 physiology was then compared to two cases of CEP sclerosis: a calcified cartilage endplate and a fluid constricted sclerotic cartilage endplate. Predicted NP fluid velocity increased for the calcified CEP and decreased for the calcified + less permeable CEP. Decreased NP fluid velocity was prominent in the axial direction through the CEP due to a less permeable path available for fluid flux. Fluid pressure and maximum principal stress in the NP were predicted to increase in both cases of CEP sclerosis compared to the healthy case. The porous medium predictions of this analysis agree with the hypothesis that CEP sclerosis decreases fluid flow out of the NP, builds up fluid pressure in the NP, and increases the stress concentrations in the NP solid matrix.

Transforming growth factor β1(TGF-β1)/Smad3 pathway promotes the pathological progression of subchondral bone in osteoarthritis. The aim of this study is to determine the effect of low-intensity pulsed ultrasound (LIPUS) on the pathological progression and TGF-β1/Smad3 pathway of subchondral bone in temporomandibular joint osteoarthritis (TMJOA). Rabbit TMJOA model was established by type II collagenase induction. The left joint in this model was continuously stimulated with LIPUS for 3 and 6 weeks (1 MHz; 30 mW/cm2 ) for 20 min/day. The morphological and histological features of subchondral bone were respectively examined by microcomputed tomography and Safranin-O staining. The number of osteoclasts was quantitatively assessed by tartrate-resistant acid phosphatase staining. Immunohistochemistry and Western blot analysis were conducted to evaluate the protein expression of Cathepsin K and TGF-β1/Smad3 pathway. The results indicated that LIPUS could improve the trabecular microstructure and histological characteristics of subchondral bone in rabbit TMJOA. It also suppressed abnormal subchondral bone resorption and activation of TGF-β1/Smad3 pathway, characterized by the number of osteoclasts, protein expression levels of Cathepsin K, TGF-β1, type II TGFβ receptor, and phosphorylated Smad3 (pSmad3) were decreased. In conclusion, LIPUS promoted the quality of subchondral bone by suppressing osteoclast activity and TGF-β1/Smad3 pathway in rabbit TMJOA.

Background Our study aimed to investigate the clinical outcomes and survival rates following porous tantalum rod surgery (PTRS) and conversion total hip arthroplasty (THA) subsequent to failed PTRS. Methods A total of 38 subjects (40 hips) with osteonecrosis of the femoral head (ONFH) were included in this retrospective study between January 2008 and December 2011. All subjects were evaluated before surgery by using the Association Research Circulation Osseous (ARCO) classification system, the Japan Investigation Committee (JIC) classification and the Harris hip score (HHS). The endpoint of this study was set as final follow-up (including the survival time of PTRS and conversion THA). The rates of radiological progression were also evaluated. Patients who received conversion THA were further followed and compared to a control group of 58 patients with ONFH who underwent primary THA. Results The mean follow-up time was 120.7 ± 9.2 (range, 104–143) months, and the overall survival rate was 75% at 96 months (ARCO stage II: 81.5%; stage III: 38.5%; JIC type C1: 83.3%; C2: 30%). The HHS before surgery was 59 (55–61), in contrast to 94 (91–96) at 96 months follow-up (P P = 0.91, P = 0.30). Twelve hips requiring secondary THA were followed for 66.9 ± 31.7 months, and control hips that underwent primary THA was followed for 75.4 ± 14.9 months. The HHS in the conversion group was 89 (86–93) and that in the primary THA group was 92 (79–95, P = 0.09) at the 5-year follow-up. Conclusion In the mid-term follow-up, porous tantalum implants showed an encouraging survival rate in symptomatic patients in early stages (ARCO stage II) or with limited necrotic lesions (JIC type C1). In addition, our results did not demonstrated any difference between primary THA and conversion THA.

A number of studies have shown that metformin can delay aging process and extend healthy lifespan in animals. However, its role in female reproductive lifespan is unclear. This study was aimed to explore the potential anti-aging effect of metformin on the ovary and its possible mechanisms. Female C57BL/6 mice of 27-week old were divided into two groups, the control group (CON) and metformin-treated group (MET). CON mice were fed ad libitum, while MET mice were fed on chows supplied with 100mg/kg metformin for half a year. Ovarian reserve and function were assessed by ovarian follicle counts, estrous cycle and sex hormones levels. The expressions of oxidized metabolites, such as 8-hydroxy-2´-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), and ovarian aging associated proteins P16, SIRT1, p-rpS6 and Bcl2 were examined. The MET mice exhibited increased level of serum E2 hormone and higher percentage of regular estrous cycles after 6 months' feeding, compared to the CON mice. The amount of primordial and primary follicles and the expression of SIRT1 were significantly increased, but the levels of P16, 8-OHdG, 4-HNE and p-rpS6 were decreased in the MET mice. These results indicate that metformin can delay ovarian aging process, probably by inducing the expression of SIRT1 and reducing the oxidative damage.

Background Hepatocellular carcinoma (HCC) remains difficult to cure due to lack of effective treatment and the molecular mechanisms are complex and not completely understood. In this study, We investigated the role of CDK16 in tumor progression of HCC. Methods We interrogated the expression level of CDK16 by polymerase chain reaction and immunohistochemistry(IHC) and studied its clinical significance. The functional role of CDK16 on HCC was studied via gain and loss of function in vitro and in vivo. Luciferase reporter assay and Chromatin immunoprecipitation(ChIP) assay were performed to investigate the transcriptional and post-transcriptional mechanisms involved in the regulation of CDK16. Results CDK16 expression was significantly up-regulated in HCC and higher expression of CDK16 was positively correlated with aggressive clinicopathological phenotype and poorer survival rates. Functionally, knockdown of CDK16 suppressed proliferation in vitro and in vivo. Inactivation of CDK16 also induced apoptosis and cell cycle arrest. Most importantly, CDK16 promoted epithelial mesenchymal transition and tumor invasion by activating β-catenin signaling. In addition, We identified E2F1 as a positive transcriptional regulator of CDK16. Moreover, down regulation of miR-125b-5p enhanced CDK16 expression at post-transcriptional level. Conclusion We provided the first evidence that CDK16 is an bona fide oncogene in HCC, and multiple activating mechanisms at transcriptional and posttranscriptional levels together contributes to CDK16 up-regulation in HCC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0569-2) contains supplementary material, which is available to authorized users.

PURPOSE: To biomechanically compare alternative graft constructs for all-inside anterior cruciate ligament (ACL) reconstruction in the event that the semitendinosus harvested is too narrow or too short to make a graft larger than 8 mm. METHODS: Bovine extensor tendons were used to make 6 different 9-mm-diameter grafts: traditional 4-strand, anastomosis 4-strand, 6-strand, 3-strand, button-fixation 4-strand, and loop-and-tack 4-strand grafts. The grafts were then subjected to cyclic biomechanical testing followed by failure loading. Force at 3 and 5 mm of displacement and ultimate force were recorded for all grafts. RESULTS: Compared with the traditional 4-strand graft, the only graft that showed significant biomechanical differences during the cyclic phase of testing was the button-fixation 4-strand graft, which was characterized by lower force at 3 mm of displacement (74 ± 34 N vs 122 ± 13 N, P = .004) and 5 mm of displacement (122 ± 35 N vs 172 ± 3 N, P = .006). During failure loading, ultimate force was significantly lower for both the 6-strand graft (491 ± 186 N, P = .041) and button-fixation 4-strand graft (326 ± 27 N, P < .001) than for the traditional 4-strand graft (778 ± 176 N). All other grafts were equivalent for the parameters tested. CONCLUSIONS: The anastomosis 4-strand, 3-strand, and loop-and-tack 4-strand grafts do not biomechanically differ in cyclic loading and ultimate force from traditional 4-strand grafts. This study supports the use of anastomosis 4-strand, 3-strand, or loop-and-tack 4-strand grafts in the event that a traditional all-inside 4-strand graft cannot be prepared from a harvested semitendinosus tendon in ACL reconstruction. CLINICAL RELEVANCE: This study tests and describes alternatives to the traditional 4-strand semitendinosus autograft for all-inside ACL reconstruction in the event that the harvested tendon is not adequate.

This paper reports nerve growth factor functionalized superparamagnetic iron oxide–gold core-shell nanoparticles (NGF-SPIO-Au NPs), an engineered nanomedicine for non-invasive neuron regeneration when irradiated by a low-intensity light-emitting diode (LED). NGF-SPIO-Au NPs of 20 μg/ml, were tested on PC-12 neuron-like cells, irradiated by LEDs (525 nm, 1.09, 1.44, and 1.90 mW/cm(2)). A remarkable Ca(2+) influx was detected in differentiated PC-12 cells treated with NPs, irradiated by LED of 1.90 and 1.44 mW/cm(2) with great cell viability (>84%) and proliferations. The strong heat generated through their plasmonic surface upon LED irradiation on NGF-SPIO-Au NPs was observed. For cells treated with LED (1.90 mW/cm(2)) and NGF-SPIO-Au NPs, a dramatic enhancement of neuronal differentiation (83%) and neurite outgrowth (51%) was found, and the upregulation of both the neural differentiation specific marker (β3-tubulin) and the cell adhesive molecule (integrin β1) was observed by the reverse transcription-polymerase chain reaction and western blot analysis.