Four-octyl itaconate improves osteoarthritis by enhancing autophagy in chondrocytes via PI3K/AKT/mTOR signalling pathway inhibition.

Osteoarthritis (OA) is a highly prevalent and chronic disorder that is associated with a substantial social and economic burden. Itaconate, as an important regulator of cellular inflammation, is a metabolite synthesised by an enzyme encoded by immune-responsive gene 1. However, there are few studys regarding the effects of itaconate on OA. Here, we show the effect of the cell-permeable itaconate derivative 4-octyl itaconate (OI) on OA. OI attenuates the chondrocyte apoptosis induced by interleukin 1ß (IL-1ß) in vitro, indicating that OI protect chondrocytes against apoptosis. Moreover, OI ameliorates the chondrocyte autophagy inhibition induced by IL-1ß via the inhibition of PI3K/AKT/mTOR signalling pathway. Finally, OI enhances autophagy and reduces cartilage degradation in a rat model of OA established by destabilization of medial meniscus (DMM). In summary, our findings reveal that OI is involved in regulating the progression of OA. The above results shed light on the treatment of OA.

Small molecule natural compound targets the NF-κB signaling and ameliorates the development of osteoarthritis.

Osteoarthritis (OA) is a multifactorial and chronic disease describing the destruction of cartilage that can lead to defects in the elderly. There is currently no practical strategy that can reverse the OA process. Here, we describe nepetin, a small natural compound with extracellular matrix (ECM) and inflammation regulating functions. In this study, we investigated the therapeutic effects of nepetin on interleukin-1ß (IL-1ß)-induced inflammation in mice chondrocyte and OA model. In chondrocytes, treatment with nepetin inhibited the overexpression of pro-inflammatory cytokines and mediators induced by IL-1ß. Moreover, pretreatment or posttreatment with nepetin also reduced the ECM catabolism and enhanced the ECM anabolism. Mechanistically, nepetin suppressed NF-κB signaling pathway in IL-1ß stimulated chondrocyte. Meanwhile, our molecular docking studies indicated nepetin had a powerful binding capacity to p65. Furthermore, nepetin showed a protective and therapeutic effect on the mouse OA model. To sum up, this study indicated nepetin had a new potential therapeutic option in OA.

Inhibition of HDAC6 by Tubastatin A reduces chondrocyte oxidative stress in chondrocytes and ameliorates mouse osteoarthritis by activating autophagy.

The aim of this study was to determine the effect of HDAC6 inhibition using the selective inhibitor Tubastatin A (TubA) on the regulation of tert-butyl hydroperoxide (TBHP)-treated chondrocytes and a mouse OA model. Using conventional molecular biology methods, our results showed that the level of HDAC6 increases both in the cartilage of osteoarthritis (OA) mice and TBHP-treated chondrocytes in vitro. TubA treatment effectively inhibits the expression of HDAC6, attenuates oxidative stress, reduces the level of apoptotic proteins to maintain chondrocyte survival, and suppresses the extracellular matrix (ECM) degradation. In addition, our results also revealed that HDAC6 inhibition by TubA activates autophagy in chondrocytes, whereas the protective effects of TubA were abolished by autophagy inhibitor intervention. Subsequently, the positive effects of HDAC6 inhibition by TubA were also found in a mouse OA model. Therefore, our study provide evidence that HDAC6 inhibition prevents OA development, and HDAC6 could be applied as a potential therapeutic target for OA management.

Maslinic acid prevents IL-1ß-induced inflammatory response in osteoarthritis via PI3K/AKT/NF-κB pathways.

Osteoarthritis (OA) is a degenerative joint disease characterized by destruction of articular cartilage. The inflammatory response is the most important factor affecting the disease process. As interleukin-1ß (IL-1ß) stimulates several key mediators in the inflammatory response, it plays a major role in the pathogenesis of OA. Maslinic acid (MA) is a natural compound distributed in olive fruit. Previous studies have found that maslinic acid has an inhibitory effect on inflammation, but its specific role in the progression of OA disease has not been studied so far. In this study, we aim to assess the protective effect of MA on OA progression by in vitro and in vivo experiments. Our results indicate that, in IL-1ß-induced inflammatory response, MA is effective in attenuating some major inflammatory mediators such as nitric oxide (NO) and prostaglandin E2, and inhibits the expression of IL-6, inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner. Also, MA downregulated the expression levels of thrombospondin motif 5 (ADAMTS5) and matrix metalloproteinase 13 in chondrocytes, resulting in reduced degradation of its extracellular matrix. Mechanistically, MA exhibits an anti-inflammatory effect by inactivating the PI3K/AKT/NF-κB pathway. In vivo, the protective effect of MA on OA development can be detected in a surgically induced mouse OA model. In summary, these findings suggest that MA can be used as a safe and effective potential OA therapeutic strategy.

Activation of AKT signaling via small molecule natural compound prevents against osteoblast apoptosis and osteonecrosis of the femoral head.

Vinpocetine (Vinp), a natural compound extracted from the leaves of Phyllostachys pubescens with apoptosis modulatory properties in variety of disorders. In the present study, we investigated the possible mechanism of Vinp in alleviating of the progress of osteonecrosis of the femoral head (ONFH) both in vitro and in vivo experiments. The results showed that treatment with Vinp suppressed the dexamethasone (Dex) induced over-regulation of ROS level and apoptotic factors. Mechanistically, the Vinp activated Akt signaling pathway in osteoblast. Moreover, Vinp exerted a protective role in animal ONFH model. To summarize, this work illustrated Vinp possessed a new potential therapeutic drug in ONFH.

Hederacoside-C protects against AGEs-induced ECM degradation in mice chondrocytes.

Hederacoside-C (HDC), a natural compound extracted from the leaves of Hedera helix with inflammation modulatory properties in variety of disorders. In this study, we investigated the latent mechanism of HDC in alleviating of the progress of OA in vitro experiment. The results showed that HDC pretreatment suppressed the advanced glycation end-products (AGEs) induced over-regulation of ROS level and inflammatory factors. Moreover, HDC also downregulate the degradation of ECM induced by AGEs. Mechanistically, the HDC suppressed NF-κB signaling pathway in chondrocyte. To sum up, this study indicated HDC possessed a new potential therapeutic option in osteoarthritis.

Comparing Augmentative Plating and Exchange Nailing for the Treatment of Nonunion of Femoral Shaft Fracture after Intramedullary Nailing: A Meta-analysis.

OBJECTIVE: The aim of this meta-analysis was to systematically evaluate the efficacy of augmentative plating (AP) and exchange nailing (EN) in the treatment of nonunion of femoral shaft fracture. METHODS: For the present meta-analysis, PubMed, EMBASE, and the Cochrane Library were searched to identify relevant articles up to April 2019. Two investigators independently evaluated the quality of original publications following the guidelines proposed by the Cochrane Handbook. Data were extracted from the studies and analyzed using Review Manager 5.3. RESULTS: Five studies were included in this meta-analysis, with a total of 506 patients. There were 232 patients in the AP group and 276 patients in the EN group. The AP group was associated with higher union rate (OR, 11.66; 95% CI, 4.31-31.50; P < 0.01), shorter union time (SMD, -1.10; 95% CI, -2.09 to -0.11; P = 0.03), shorter operation time (SMD, -0.55; 95% CI, -0.88 to -0.21; P < 0.01), less blood loss (SMD, -1.72; 95% CI, -3.33 to -0.11; P < 0.01), and fewer complications (OR, -0.11; 95% CI, -0.16 to -0.07; P < 0.01) than the EN group. CONCLUSION: The results of the meta-analysis showed that AP is found to be superior for nonunion of femoral shaft fractures in both intraoperatively (ie, shorter operation time and less blood loss) and postoperatively (ie, higher union rate, shorter union time, and lower complication rate). Overall, AP was superior to EN in the treatment of nonunion of femoral shaft fractures after intramedullary nailing (IMN).

Stepwise resection of the posterior ligamentous complex for stability of a thoracolumbar compression fracture: An in vitro biomechanical investigation.

To quantify the mechanical contribution of posterior ligamentous structures to the stability of thoracolumbar compression fractures.Twelve fresh human T11-L3 spinal specimens were harvested in this study. The 1/3 L1 vertebral body was resected in a wedged shape. After the preinjury had been created, the specimens were subjected to flexion-compression to create a fracture model. Resection of the ligaments was performed in a sequential manner from the bilateral facet capsule ligament (FCL), interspinous ligament, and supraspinous ligament (SSL) to the ligamentum flavum at the T12-L1 level. Then, for the intact specimen, fracture model, and ligament disruption steps, the range of motion (ROM) and neutral zone (NZ) of T12-L1 and L1-L2 were collected for each simulated movement.Sequential transection of the posterior ligamentous complex (PLC), ROM, and NZ were increased in all movements at the T12-L1 segment. In the flexion-extension (FE), the ROM and NZ demonstrated significant increases after the fracture model and resection of SSL and LF. In lateral bending (LB), the ROM increased after the fracture and removal of the LF, while the NZ showed a slight increase. In axial rotation, the fracture model and removal of the LF resulted in a significant increase in the ROM, and the NZ showed a slight change after step reduction. For the L1-L2 segment, resection of the FCL led to an increased ROM in LB.With rupture of SSL or LF, the stability of the segment decreased significantly compared with the intact and fracture model, particularly in FE motion, the function of the PLC was considered to be incompetent.

Computed tomography morphometric analysis of anterior instrumentation in the pediatric thoracic spine.

OBJECT The authors' goal in this paper was to quantify reference data on the dimensions and relationships of the maximum posterior screw angle and the thoracic spinal canal in different pediatric age groups. METHODS One hundred twelve pediatric patients were divided into 4 age groups, and their thoracic vertebrae were studied on CT scans. The width, depth, and maximum posterior screw angles with different screw entrance points were measured on a Philips Brilliance 16 CT. The statistical analysis was performed using the Student t-test and Pearson's correlation analysis. RESULTS The width and depth of the thoracic vertebrae increased from T-5 to T-12. The width ranged from 18.5 to 37.1 mm, while the depth ranged from 16.1 to 28.2 mm. The maximum posterior screw angle decreased from T-5 to T-12 in all groups. The ranges and mean angles at the entrance points were as follows: initial entrance point, 6.9° to 12.3° with a mean angle of 9.1°; second entrance point, 20.6° to 27.0° with a mean angle of 24.2°; and third entrance point, 29.2° to 37.5° with a mean angle of 33.7°. There were no significant age-related differences noted for the maximum posterior screw angles. CONCLUSIONS The angle decreased from T-5 to T-12. No significant age-related differences were noted in the maximum posterior screw angles. Screws should be placed between the initial and second points and parallel to the coronal section or at a slight anterior orientation.

Bone marrow-derived mesenchymal stem cells attenuate acute liver injury and regulate the expression of fibrinogen-like-protein 1 and signal transducer and activator of transcription 3.

In recent years, bone marrow-derived mesenchymal stem cells (BMSCs) have been demonstrated to exert extensive therapeutic effects on acute liver injury; however, the underlying mechanisms of these effects have remained to be elucidated. The present study focused on the potential anti-apoptotic and pro-regenerative effects of BMSCs in D-galactosamine (D-Gal) and lipopolysaccharide (LPS)-induced acute liver injury in rats. An experimental rat acute liver injury model was established by intraperitoneal injection of D-Gal (400 mg/kg) and LPS (80 µg/kg). BMSCs and an identical volume of saline were administered via the caudal vein 2 h after the D-Gal and LPS challenge. Subsequently, the serum samples were collected to detect the levels of alanine aminotransferase and aspartate aminotransferase. Hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay and immunohistochemical staining were performed to determine apoptosis, regeneration and histological changes of liver sections. Western blotting and reverse transcription-quantitative polymerase chain reaction were performed to detect the protein and mRNA expression levels of fibrinogen-like-protein 1 (FGL1), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), STAT3 and B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) in liver tissue samples. The results indicated that intravenous transplantation of BMSCs significantly decreased the levels of alanine aminotransferase and aspartate aminotransferase, and reduced hepatocellular necrosis and inflammatory cell infiltration. Additionally, a terminal deoxynucleotidyl transferase-mediated nick-end labeling assay and immunohistochemical staining revealed that BMSC treatment reduced hepatocyte apoptosis and enhanced liver regeneration. Furthermore, Bcl-2 expression was increased, whilst the protein expression of Bax was reduced. The expression of FGL1 and p-STAT3 were elevated concurrently with the improvement of liver function. These results demonstrated that BMSCs may provide a promising potential agent for the prevention of acute liver injury via inhibition of hepatocyte apoptosis and acceleration of liver regeneration. The mechanism may be, a least in part, a consequence of the upregulation of FGL1 expression and the induction of STAT3 phosphorylation.

A Computed Tomographic Morphometric Study of the Pediatric Occipital Bone Thickness: Implications for Pediatric Occipitocervical Fusion.

STUDY DESIGN: This study is a computed tomographic-based morphometric analysis of the pediatric occipital bones as related to pediatric occipitocervical fusion. OBJECTIVE: To quantify reference data concerning the thicknesses of the immature occipital bones to guide the pediatric occipitocervical fusion. SUMMARY OF BACKGROUND DATA: To the best of our knowledge, no published study has provided insight into the thicknesses of pediatric occiputs with different age groups. METHODS: 80 pediatric patients were divided into 4 age groups, and their occiputs were studied on Philips Brilliance 256 iCT scan. RESULTS: The mean thickness ± standard deviations of the pediatric occipital bones with different age groups is shown. The median and the paramedian regions are always thicker than the more lateral regions at each age group and the thickest point in the occiputs is mostly at the external occipital protuberance. The mean thickness of occiputs showed an obvious significant difference between each 2 age groups and no significant difference between male and female in different age groups except the group 4. CONCLUSION: Our investigation provides insight into the anatomy of occiputs in pediatric population and preoperative CT evaluation must be required to further decrease the risk of occipitocervical fusion.

Effect of low-level prenatal mercury exposure on neonate neurobehavioral development in China.

BACKGROUND: This study aimed to assess the effects of low-level prenatal mercury exposure on neonate neurobehavioral development in China. METHODS: In total, 418 mother-neonate pairs were included in the study. Maternal urine, hair, and blood samples and cord blood samples were used to document prenatal exposure to mercury. The Neonatal Behavioral Neurological Assessment was used to estimate neurobehavioral development in the neonates at 3 days of age. RESULTS: Total mercury level was significantly higher in cord blood than that in maternal blood. A strong correlation was found between total mercury levels in maternal blood and those in cord blood (r = 0.7431; P < 0.0001). Trend analysis revealed that mothers who consumed more fish had higher blood and cord blood mercury levels (all P < 0.0001). Significant differences were also found between male and female cord blood mercury levels among groups with different fish consumption frequencies (all P < 0.0001). Cord blood mercury level was significantly associated with total Neonatal Behavioral Neurological Assessment scores (ß = 0.03; standard error = 0.01; P = 0.0409), passive muscle tone (odds ratio = 1.07; 95% confidence interval = 1.12-1.13; P = 0.0071), and active muscle tone (odds ratio = 1.06; 95% confidence interval = 1.01-1.11; P = 0.0170) scores after adjustment, respectively. CONCLUSIONS: Neonatal neurodevelopment was associated with prenatal exposure to mercury. Women with high mercury levels should avoid intake seafood excessively during pregnancy. Long-term effects of exposure to mercury on childhood development need to be further explored.

Computed tomography morphometric analysis of C2 translaminar screw fixation of Wright's technique and a modified technique in the pediatric cervical spine.

PURPOSE: To establish reference data on the dimensions of C2 lamina to guide the use of translaminar screws with Wright's technique and a modified technique for pediatric patients in different age groups. METHODS: 113 pediatric patients were divided into six age groups, and their cervical vertebrae were studied on CT scans. Laminar height, width, length and screw angle were measured. Statistical analysis was performed using Student t tests, Pearson's correlation and linear regression analysis. RESULTS: Mean laminar height was 10.95 ± 2.81 mm, and mean width was 6.01 ± 0.90 mm. For Wright's technique, mean laminar length was 30.65 ± 3 mm, and the screw angle was 56.02° ± 3.62°. For the modified technique, mean laminar length was 22.07 ± 2.38 mm, and the screw angle was 67.40° ± 3.39°. 95.6% (108/113) of the children could insert a screw into the lamina (laminar width ≥ 4.5 mm), 72.6% (82/113) could accept bilateral translaminar screws (laminar width ≥ 4.5 mm and laminar height ≥ 9 mm). CONCLUSION: Our investigation provides insight into the anatomy of C2 lamina in six pediatric age groups. Compared to adults, the benefits of C2 translaminar screws fixation are more obvious in the pediatric spine which has a large C2 lamina. Compared to Wright's technique, the modified technique should insert a screw with bigger insert angle and shorter screw length.

Computed tomographic morphometric analysis of the pediatric occipital condyle for occipital condyle screw placement.

STUDY DESIGN: This study is a computed tomographic (CT)-based morphometric analysis of the pediatric occipital condyles as related to occipital condyle screw placement. OBJECTIVE: To quantify reference data concerning the dimensions of the immature occipital condyles to guide the placement of occipital condyle screw. SUMMARY OF BACKGROUND DATA: To the best of our knowledge, no published study has provided insight into the anatomy of occipital condyle of the pediatric population with different age groups. METHODS: Sixty-nine pediatric patients were divided into 4 age groups, and their occipital condyles were studied on CT scans. Condylar length, width, height, sagittal angle, and sagittal angle lengths were measured on Philips Brilliance 16 CT. RESULTS: The mean pediatric coronal height, sagittal length, and axial width noted statistically significant age-related differences were 9.0 mm, 21.3 mm, and 9.8 mm, respectively. The mean sagittal angle for all patients was 27.2 ± 5.1° (range, 15.1-41.0°). In 82.6% (114/138) of the occipital condyles, the anatomy could accept the occipital condyle screw (width ≥8 mm and height ≥6.5 mm). CONCLUSION: Our investigation provides insight into the anatomy of occipital condyle of the pediatric population with different age groups. As the pediatric occipital condyles have sufficient occipital bone for appropriate fixation or fusion, the occipital condyle screws fixation is a feasible technique for children. Even so, given the evolution of this technique being still in its infancy and the complexity inherent to the craniovertebral junction, a careful radiological analysis of occipital condyle must be required in preoperative planning and feasibility determination. LEVEL OF EVIDENCE: N/A.