Discovery and Characterization of Moracin C as an Anti-Gouty Arthritis/Hyperuricemia Candidate by Docking-Based Virtual Screening and Pharmacological Evaluation.

In the present study, a natural product database of compounds associated with herbs traditionally verified to treat gout/hyperuricemia/arthritis was constructed. 3D-shape and docking-based virtual screening was conducted. To identify potential xanthine oxidase (XOD) inhibitors in the database, eight compounds with commercial availability were identified as high 3D-shape similarity with febuxostat (1), a known XOD inhibitor. Docking was used to further predict the possible interactions between XOD and these compounds. Moracin C (2), moracin D (3), and isoformononetin (8) exhibited higher docking scores and binding energies than other compounds. In vitro, 2 inhibited XOD with an IC50 value of 0.25 ± 0.14 µM, which is similar to that of 1 (0.16 ± 0.08 µM). In a hyperuricemic mouse model, 5-20 mg/kg 2 exhibited satisfying urate-lowering and XOD inhibitory effects. Compound 2 also exhibited antiarthritis activities. In RAW264.7 cells, 2 at 1-10 µM inhibited the expression of IL-1ß and TNF-α induced by MSU. In an acute gouty arthritis model in SD rats, 5-20 mg/kg 2 significantly alleviated the toe swelling, inflammatory response, and dysfunction disorder caused by monosodium urate (MSU). Compound 2 inhibited serum IL-1ß and TNF-α cytokines as well as reduced the expression of the NLRP3/ASC/caspase-1 inflammasome in joints. In summary, 2 was an effective compound for the treatment of hyperuricemia/gouty arthritis.

The origin of genetic and metabolic systems: Evolutionary structuralinsights.

DNA is derived from reverse transcription and its origin is related to reverse transcriptase, DNA polymerase and integrase. The gene structure originated from the evolution of the first RNA polymerase. Thus, an explanation of the origin of the genetic system must also explain the evolution of these enzymes. This paper proposes a polymer structure model, termed the stable complex evolution model, which explains the evolution of enzymes and functional molecules. Enzymes evolved their functions by forming locally tightly packed complexes with specific substrates. A metabolic reaction can therefore be considered to be the result of adaptive evolution in this way when a certain essential molecule is lacking in a cell. The evolution of the primitive genetic and metabolic systems was thus coordinated and synchronized. According to the stable complex model, almost all functional molecules establish binding affinity and specific recognition through complementary interactions, and functional molecules therefore have the nature of being auto-reactive. This is thermodynamically favorable and leads to functional duplication and self-organization. Therefore, it can be speculated that biological systems have a certain tendency to maintain functional stability or are influenced by an inherent selective power. The evolution of dormant bacteria may support this hypothesis, and inherent selectivity can be unified with natural selection at the molecular level.

IL-23 Inhibits Trophoblast Proliferation, Migration, and EMT via Activating p38 MAPK Signaling Pathway to Promote Recurrent Spontaneous Abortion.

As a vital problem in reproductive health, recurrent spontaneous abortion (RSA) affects about 1% of women. We performed this study with an aim to explore the molecular mechanism of interleukin-23 (IL-23) and find optimal or effective methods to improve RSA. First, ELISA was applied to evaluate the expressions of IL-23 and its receptor in HTR-8/SVneo cells after IL-23 treatment. CCK-8, TUNEL, wound healing and transwell assays were employed to assess the proliferation, apoptosis, migration and invasion of HTR-8/SVneo cells, respectively. Additionally, the expressions of apoptosis-, migration-, epithelial-mesenchymal transition- (EMT-) and p38 MAPK signaling pathway-related proteins were measured by western blotting. To further investigate the relationship between IL-23 and p38 MAPK signaling pathway, HTR-8/SVneo cells were treated for 1 h with p38 MAPK inhibitor SB239063, followed by a series of cellular experiments on proliferation, apoptosis, migration and invasion, as aforementioned. The results showed that IL-23 and its receptors were greatly elevated in IL-23-treated HTR-8/SVneo cells. Additionally, IL-23 demonstrated suppressive effects on the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells. More importantly, the molecular mechanism of IL-23 was revealed in this study; that is to say, IL-23 inhibited the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells via activating p38 MAPK signaling pathway. In conclusion, IL-23 inhibits trophoblast proliferation, migration, and EMT via activating p38 MAPK signaling pathway, suggesting that IL-23 might be a novel target for the improvement of RSA.

Tranexamic acid usage in hip fracture surgery: a meta-analysis and meta-regression analysis of current practice.

INTRODUCTION: The use of tranexamic acid (TXA) in hip fracture surgery remains inconclusive. The aim of the present meta-analysis was to assess the role of TXA use in hip fracture surgery, and attempt to disclose possible factors which might influence TXA efficacy and safety. MATERIALS AND METHODS: A systematic computerized literature search was conducted to retrieve all randomized controlled trials (RCTs) and cohort studies regarding TXA use in hip fracture surgery. Overall efficacy and safety were evaluated. Then, subgroup and meta-regression analyses were conducted to disclose the influence of geographic area, fracture type, administration route, frequency and dosage of TXA, blood transfusion threshold, and follow-up duration on the overall effect. RESULTS: Thirty-four RCTs and 11 cohort studies were included. Patients receiving TXA had a significant decrease in the need for blood transfusion, reduced total, intra-operative and post-operative blood loss, a decrease in pre- and postoperative hemoglobin difference, without increasing thromboembolic events risk. Subgroup analysis showed that topical TXA had a lower transfusion rate compared with controls, yet the result did not reach statistical significance. Also, TXA had similar efficacy and safety profiles in patients with different frequency and dosage of TXA. CONCLUSION: Current evidence indicated that intravenous administration of TXA could significantly reduce blood transfusion and blood loss without increasing risk of thromboembolic events. The frequency and dosage of TXA might not alter the beneficial effect. The application of topical TXA should be cautious.

IRAK-4 in macrophages contributes to inflammatory osteolysis of wear particles around loosened hip implants.

TLRs recognizing PAMPS play a role in local immunity and participate in implant-associated loosening. TLR-mediated signaling is primarily regulated by IL-1 receptor associated kinase-M (IRAK-M) negatively and IRAK-4 positively. Our previous studies have proved that wear particles promote endotoxin tolerance in macrophages by inducing IRAK-M. However, whether IRAK-4 is involved in inflammatory osteolysis of wear particles basically, and the specific mechanism of IRAK-4 around loosened hip implants, is still unclear. IRAK-4 was studied in the interface membranes from patients in vivo and in particle-stimulated macrophages to clarify its role. Also, IL-1ß and TNF-α levels were measured after particle and LPS stimulation in macrophages with or without IRAK-4 silenced by siRNA. Our results showed that the interface membranes around aseptic and septic loosened prosthesis expressed more IRAK-4 compared with membranes from osteoarthritic patients. IRAK-4 in macrophages increased upon particle and LPS stimulation. In the former, IL-1ß and TNF-α levels were lower compared with those of LPS stimulation, and IRAK-4 siRNA could suppress production of pro-inflammatory cytokines. These findings suggest that besides IRAK-M, IRAK-4 also plays an important role in the local inflammatory reaction and contributes to prosthesis loosening.

Icariin enhances the chemosensitivity of cisplatin­resistant ovarian cancer cells by suppressing autophagy via activation of the AKT/mTOR/ATG5 pathway.

Icariin is a flavonoid derived from Epimedium sagittatum, and has a wide range of biological and pharmacological effects; however, little is known regarding its effect on drug­resistant ovarian cancer and the signal transduction pathways underlying the regulation of apoptosis and autophagy. The present study aimed to investigate the re­sensitization effects of icariin exerted on an ovarian cancer cell line. Autophagy was analyzed in a SKVCR cell line that had been treated with icariin. We investigated the sensitivity of SKVCR cells to cisplatin, as well as the effects of an autophagy agonist (rapamycin) on autophagy, apoptosis, and the protein kinase B (AKT) signaling pathway. Finally, the mechanism underlying the effects of autophagy­related (ATG) protein ATG5 overexpression on autophagy, apoptosis and AKT signaling in SKVCR cells were determined. The results revealed that treatment with icariin inhibited cell viability and autophagy, but promoted G0/G1 phase cell cycle arrest and apoptosis as determined by Cell Counting Kit­8, immunofluorescence and flow cytometry assays, respectively. Icariin reduced the resistance of SKVCR cells to cisplatin in vitro by inducing G1/S cell cycle transition, apoptosis and inhibiting autophagy. Furthermore, enhanced autophagy induced by rapamycin treatment or overexpression of ATG5 partially reversed the effect of icariin on cisplatin resistance and autophagy in SKVCR cells. At the molecular level, rapamycin treatment or overexpression of ATG5 reversed the effects of icariin on the expression of autophagy­associated proteins, including microtubule­associated protein 1 light chain 3ß, Beclin­1, ATG5 and p62, and the AKT/mammalian target of rapamycin (mTOR) pathway. Collectively, our results suggested that icariin enhances the chemosensitivity of SKVCR cells by suppressing autophagy via activation of the AKT/mTOR signaling pathway.

[The Roles of Icariin on the Proliferation and Apoptosis Abilities of Human Oophoroma Cells and Multi-drug Resistant Cell Line].

OBJECTIVE: To explore the effects of icariin on the proliferation and apoptosis abilities of human ovarian cancer cells SKOV3 and multi-drug resistant SKVCR cells. METHODS: Human ovarian cancer cells SKOV3 and multi-drug resistant SKVCR cells were treated with various concentrations of icariin. The inhibitory concentration and the half maximal inhibitory concentration were detected by CCK8 kit. The proliferation and apoptosis abilities of SKOV3 and SKVCR cells were measured by flow cytometry. The migration and invasion abilities of SKOV3 and SKVCR cells were evaluated by Transwell assays. The protein expression level of Caspase-3 was detected by Western blot analysis. RESULTS: Icariin significantly suppressed the proliferation abilities of SKOV3 and SKVCR cells in a dose-dependent manner at variant levels from 5-100 µg/mL. SKOV3 and SKVCR cells were treated with 19.5 µg/mL icariin and 48.4 µg/mL icariin (0.8×IC50) for 48 h, respectively. The results showed that the cell proliferation, migration and invasion abilities were markedly decreased comparing with control group, and the apoptosis rate was significantly increased as compared with control group (P<0.05). Western blot results indicated that icariin significantly increased the protein expression level of caspase-3 in SKOV3 and SKVCR cells (P<0.05). CONCLUSION: Icariin suppressed the proliferation, migration and invasion abilities of human ovarian cancer cells. Increasing expression of Caspase-3 might be the mechanism of its enhancement of apoptosis.

Icariin inhibits autophagy and promotes apoptosis in SKVCR cells through mTOR signal pathway.

Autophagy is a conserved biological process, which is regulated by mTOR pathway and is reported to be a self-protective process of cancer cells to counteract apoptosis. Icariin is an active flavonoid that is reported to inhibit autophagy. In this study, we investigated whether Icariin could induce a reduction of cell proliferation by inhibiting autophagy. SKVCR cells, which are resistant to vincristine, were used for the investigation. We used CCK8 test and flow cytometry assay to study the effects of Icariin on cell proliferation, cell apoptosis and cell circle. We performed transmission electron microscope (TEM), immunohistochemical assay and western blotting assay to study the level of autophagy after Icariin treatment. Finally, we investigated whether the mTOR pathway is a target of Icariin by using mTOR inhibitor rapamycin and detected autophagy and apoptosis via flow cytometry assay, TEM, immunohistochemical assay and western blotting assay. Decreased proliferation and increased apoptosis was observed after Icariin treatment in SKVCR cells, together with decreased level of autophagy. Application of rapamycin could reverse the anti-autophagic and pro- apoptotic effect of Icariin. Icariin can inhibit autophagy and promote apoptosis in SKVCR cells by activating mTOR signal pathway. Icariin attenuates tumorigenesis by inhibiting autophagy and inducing apoptosis.

Evaluation of the effects of standard rescue procedure on severe trauma treatment in china.

BACKGROUND: This study aimed to evaluate the effects of standard rescue procedure (SRP) in improving severe trauma treatments in China. METHODS: This study was conducted in 12 hospitals located in geographically and industrially different cities in China. A standard procedure on severe trauma rescue was established as a general rule for staff training and patient treatment. A regional network (system) efficiently integrating prehospital rescue, emergency room treatments, and hospital specialist treatments was built under the rule for information sharing and improving severe trauma treatments. Treatment outcomes were compared between before and 1 year after the implementation of the SRP. RESULTS: The outcomes of a total of 74,615 and 12,051 trauma cases were collected from 12 hospitals before and after the implementation of the SRP. Implementation of the SRP led to efficient cooperation and information sharing of different treatment services. The emergency response time, prehospital transit time, emergency rescue time, consultation call time, and mortality rate of patients were 24.24 ± 4.32 min, 45.69 ± 3.89 min, 6.38 ± 1.05 min, 17.53 ± 0.72 min, and 33.82% ± 3.87% (n = 441), respectively, before the implementation of the standardization and significantly reduced to 10.11 ± 3.21 min, 22.39 ± 4.32 min, 3.26 ± 0.89 min, 3.45 ± 0.45 min, and 20.49% ± 3.11%, separately (n = 495, P < 0.05) after that. CONCLUSIONS: Staff training and SRP can significantly improve the efficiency of severe trauma treatments in China.

[Analysis of characteristics of road traffic injuries in Bao'an District, Shenzhen from 2004 to 2011].

OBJECTIVE: To analyze the characteristics of road traffic accidents in Bao'an District, Shenzhen from 2004 to 2011, and to provide scientific basis for the prevention and treatment of traffic accidents. METHODS: The traffic injury cases recorded by Shenzhen traffic police from 2004 to 2011 were analyzed, including the time (year, month, date); the space (crossings and road segments, road type); the injury of patients (injuries, death). RESULTS: A total of 422 730 accidents from road traffic occurred in Bao'an District, Shenzhen from 2004 to 2011, with 63 809 people injured and 2 790 people died, and the mortality ratio was 22.87:1. Traffic accidents occurred in Bao'an District showed an increasing trend, especially in 2010, and the highest number up to 90 358, while the most deaths occurred in 2007, up to 473 people. As to the single month, the highest traffic accident rate was in August, accounting for 9.77% of the total, while the lowest was in February, accounting for 5.39% of the total; mortality rate in December reached 9.02%. As to one single day, the peaks of accidents occurred in two periods: 9:00-11:00 and 15:00-18:00, and 3:00-6:00 had the smallest number. Traffic injuries often occurred in the intersection, straight line, main road and the section only marked marking. CONCLUSION: According to the characteristics of regional traffic injury, we should enhance the populace traffic safe awareness, efficiently arrange the human resources, such as emergency personnel, traffic management personnel, set scientific preventive measures, and modify the emergency system and service mode. All of these are essential measures for the prevention and control of traffic injuries.

Anterior corpectomy and reconstruction with titanium mesh cage and dynamic cervical plate for cervical spondylotic myelopathy in elderly osteoporosis patients.

OBJECTIVE: This retrospective study was to evaluate the relationship between osteoporosis and dynamic cervical plates in screw-plate or screw-bone interface of elderly cervical spondylotic myelopathy (CSM) patients. METHODS: Retrospective study was conducted on elderly CSM patients, treated by anterior corpectomy and reconstruction with titanium mesh cages (TMC) and dynamic cervical plate between July 2004 and June 2007. All patients underwent bone mineral density (BMD) assessment in preoperation, and according to the osteoporosis degree they have been divided into two groups: moderate osteoporosis degree group and severe osteoporosis degree group. The clinical outcome [Japanese Orthopaedic Association score (JOA) and Visual Analogue Scale (VAS)], bone fusion assessment (CT mielogram), the change of titanium mesh cages and plate of cephalic screw-plate-angle (SPA) and cephalic endplate-plate-angle (EPA) of plain X-ray films were measured. RESULTS: The mean JOA score and recovery rate were not different between the two groups (P > 0.05). There was no loss of sagittal alignment after surgery in any patient, and no significant difference between both groups on lordosis measurements (P > 0.05). Although there was a significant difference of the cage subsidence rate between the two groups (P < 0.001), all patients had favorable bone union and none required additional treatment. The average changes of SPA were greater in A group patients than in B group patients, while the variation of EPA was higher in B group patients than in A group patients (P < 0.001). CONCLUSIONS: Despite the fact that there is a significant difference of the cage subsidence rate between the two groups no clinical outcome, nor sagittal alignment or fusion rate differences among groups was observed in elderly CSM patients.