Synthesis, biological activity and mechanism of action of novel allosecurinine derivatives as potential antitumor agents.

Cancer with low survival rates is the second main cause of death among all diseases in the world and consequently, effective antineoplastic agents are urgently needed. Allosecurinine is a plant-derived indolicidine securinega alkaloid shown bioactivity. The object of this study is to investigate synthetic allosecurinine derivatives with considerable anticancer capacity against nine human cancer cell lines as well as mechanism of action. We synthesized twenty-three novel allosecurinine derivatives and evaluated their antitumor activity against nine cancer cell lines for 72 h by MTT and CCK8 assays. FCM was applied to analyze the apoptosis, mitochondrial membrane potential, DNA content, ROS production, CD11b expression. Western blot was selected to analyze the protein expression. Structure-activity relationships were established and potential anticancer lead BA-3 which induced differentiation of leukemia cells towards granulocytosis at low concentration and apoptosis at high concentration was identified. Mechanism studies showed that mitochondrial pathway mediated apoptosis within cancer cells with cell cycle blocking was induced by BA-3. In addition, western blot assays revealed that BA-3 induced expression of the proapoptotic factor Bax, p21 and reduced the levels of antiapoptotic protein such as Bcl-2, XIAP, YAP1, PARP, STAT3, p-STAT3, and c-Myc. Collectively, BA-3 was a lead compound for oncotherapy at least in part, through the STAT3 pathway. These results were an important step in further studies on allosecurinine-based antitumor agent development.

Cuff-leak test combined with interventional bronchoscopy benefits early extubation for patients who received tarp surgery.

PURPOSE: This study explored the performance characteristics of a cuff-leak test (CLT) combined with interventional fiberoptic bronchoscopy (FBS) for evaluating whether early nasoendotracheal extubation was possible for patients who had received transoral atlantoaxial reduction plate (TARP) internal fixation surgery. METHODS: 318 patients who underwent surgery were retrospectively analyzed (between January 2006 and December 2012). Extubation was performed by conventional approach (CA group, until December 2008) and improved approach (IA group, from January 2009) including CLT and an interventional FBS procedure. The extubation success within 1-3 days after surgery, incidence of postextubation stridor and tracheal reintubation were examined. RESULTS: More IA-treated patients experienced extubation during the first 2 days than those CA-treated, median extubation time was 3 (2, 3) days in the CA group and 2 (1, 2) days in the IA group (all P < 0.01). The incidence of stridor and reintubation was 5.69 and 0.57 % in IA and 11.98 and 4.93 % in CA, respectively (both P < 0.05). For the CLT-positive patients in the IA group that remained intubated until day 3-4, interventional FBS was applied for safe extubation and achieved 100 % success. CONCLUSION: Early extubation through IA is safe and interventional FBS assists successful extubation for CLT-positive patients who underwent TARP surgery.

[Evaluation on Efficacy and Safety of Jinying Capsule in Treatment of Pelvic Inflammatory Disease Patients with Accumulated Damp-heat Syndrome].

OBJECTIVE: To evaluate the efficacy and safety of Jinying Capsule (JC) in treating pelvic inflammatory disease patients with accumulated damp-heat syndrome (ADHS). METHODS: Totally 328 patients were recruited in a prospective, positive drug parallel controlled, and multi-center clinical trial. Of them 213 patients in the treatment group took JC (0.5 g per capsule), 4 capsules each time, 3 times per day, while 115 patients in the control group took Kangfuyan Capsule (KC, 0.4 g per capsule), 3 capsules each time, twice per day. The course of treatment was 4 weeks for all. Scores of Chinese medical syndromes, visual analogue scale (VAS) of the lower abdominal pain, and European quality of life-five dimension scale (EQ-5D) were observed before treatment and after 4 weeks of treatment. RESULTS: There were 204 patients in the treatment group and 109 in the control group who completed this trial. The total effective rate of Chinese medical syndrome was 89.71% (183/204 cases) in the treatment group and 76.15% (83/109 cases) in the control group (P < 0.01). Compared with before treatment in the same group, EQ-5D scores increased, and VAS scores of the lower abdominal pain decreased in the two groups after treatment. EQ-5D scores was 0.857 ± 0.157 in the treatment group, obviously higher than that in the control group (0.753 ± 0.126, P < 0.05). VAS scores of the lower abdominal pain was 2.14 ± 1.23 in the treatment group, lower than that in the control group (2.33 ± 1.24), but with no statistical difference between the two groups (P > 0.05). No adverse reaction occurred in the two groups. CONCLUSION: JC was superior to KC in improving Chinese medical syndrome and quality of life of pelvic inflammatory disease patients with accumulated damp-heat syndrome.

Association of food intake with a risk of metabolic dysfunction-associated fatty liver disease: a cross-sectional study.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common liver disease, the risk of which can be increased by poor diet. The objective of this study was to evaluate the associations between food items and MAFLD, and to propose reasonable dietary recommendations for the prevention of MAFLD. Methods: Physical examination data were collected from April 2015 through August 2017 at Nanping First Hospital (n = 3,563). Dietary intakes were assessed using a semi-quantitative food frequency questionnaire. The association between food intake and the risk of MAFLD was assessed by using the inverse probability weighted propensity score. Results: Beverages (soft drinks and sugar-sweetened beverages) and instant noodles were positively associated with MAFLD risk, adjusting for smoking, drinking, tea intake, and weekly hours of physical activity [adjusted odds ratio (ORadjusted): 1.568; P = 0.044; ORadjusted: 4.363; P = 0.001]. Milk, tubers, and vegetables were negatively associated with MAFLD risk (ORadjusted: 0.912; P = 0.002; ORadjusted: 0.633; P = 0.007; ORadjusted: 0.962; P = 0.028). In subgroup analysis, the results showed that women [odds ratio (OR): 0.341, 95% confidence interval (CI): 0.172-0.676] had a significantly lower risk of MAFLD through consuming more tubers than men (OR: 0.732, 95% CI: 0.564-0.951). Conclusions: These findings suggest that reducing consumption of beverages (soft drinks and sugar-sweetened beverages) and instant noodles, and consuming more milk, vegetables, and tubers may reduce the risk of MAFLD.

Pharmacological activity and mechanism of pyrazines.

Heterocycles are common in the structure of drugs used clinically to deal with diseases. Such drugs usually contain nitrogen, oxygen and sulfur, which possess electron-accepting capacity and can form hydrogen bonds. These properties often bring enhanced target binding ability to these compounds when compared to alkanes. Pyrazine is a nitrogen-containing six-membered heterocyclic ring and many of its derivatives are identified as bioactive molecules. We review here the most active pyrazine compounds in terms of their structure, activity in vitro and in vivo (mainly antitumor activity) and the reported mechanisms of action. References have been downloaded through Web of Science, PubMed, Science Direct, Google Scholar and SciFinder Scholar. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. We found that compounds in which a pyrazine ring was fused into other heterocycles especially pyrrole or imidazole were the highly studied pyrazine derivatives, whose antineoplastic activity had been widely investigated. To the best of our knowledge, this is the first review of pyrazine derivatives and their bioactivity, especially their antitumor activity. This review should be useful for those engaged in development of medications based on heterocyclic compounds especially those based on pyrazine.

Preliminary application of 3D-printed individualised guiding templates for total hip arthroplasty in Crowe type IV developmental dysplasia of the hip.

OBJECTIVE: To evaluate the feasibility and accuracy of three-dimensional (3D)-printed individualised guiding templates in total hip arthroplasty (THA) for the treatment of developmental dysplasia of the hip (DDH). METHODS: 12 hips in 12 patients with Crowe type IV DDH were treated with THA. A 3D digital model of the pelvis and lower limbs was reconstructed using the computed tomography data of the patients. Preoperative surgical simulations were performed to determine the most suitable surgical planning, including femoral osteotomy and prosthesis placement. Based on the ideal surgical planning, individualised guiding templates were designed by software, manufactured using a 3D printer, and used in acetabulum reconstruction and femoral osteotomy during surgery. RESULTS: 12 patients were followed up for an average of 72.42 months (range 38-135 months). During surgery, the guiding template for each case was matched to the bony markers of the acetabulum and proximal femur. Preoperative and follow-up Harris Hip Scores were 34.2 ± 3.7 and 85.2 ± 4.2; leg-length discrepancy, 51.5 ± 6.5 mm and 10.2 ± 1.5 mm; and visual analogue scale scores, 6.2 ± 0.8 and 1.3 ± 0.3, respectively, with statistical difference. Shortened deformity and claudication of the affected limb were obviously improved after surgery. However, 1 patient had artificial hip dislocation 2 weeks after surgery, and another patient had sciatic nerve traction injury, both of whom recovered after physical treatment. CONCLUSIONS: Preoperative surgical simulation and 3D-printed individualised guiding templates can fulfil surgeon-specific requirements for the treatment of Crowe type IV DDH. Accurate THA can be achieved using 3D-printed individualised templates, which provide a new personalised surgical plan for the precise positioning and orientation of acetabular reconstruction and femoral osteotomy.

Three-Dimensional Printing Technology for Surgical Correction of Congenital Scoliosis Caused by Hemivertebrae.

OBJECTIVE: This study aimed to explore the clinical application of three-dimensional (3D) printing technology in the surgical treatment of congenital scoliosis caused by hemivertebrae. METHODS: Twenty-four patients (11 in the 3D-printing group and 13 in the conventional group) with scoliosis secondary to a single hemivertebra were retrospectively reviewed. All patients underwent hemivertebrectomy and short-segment fixation. Virtual preoperative planning, operation simulation, and intraoperative application of 3D-printed patient-specific templates were performed in the 3D-printing group. Hemorrhage volume, operation time, transfusion, and complications were noted. Radiographic parameters were evaluated preoperatively, postoperatively, and at final follow-up. RESULTS: All patients had different degrees of successfully corrected scoliosis. There was a similar correction of the Cobb angle postoperatively between the 2 groups. The operation time, blood loss, transfusion, time for the insertion of each screw, accuracy of screw placement, and complication rate in the 3D-printing group were significantly superior to those in the control group. No patient experienced major complications. No significant correction loss or instrument dysfunction was observed during follow-up. CONCLUSIONS: As a viable and effective auxiliary technology, 3D printing makes it possible for surgery to meet both surgeon-specific and patient-specific requirements. 3D-printed individualized templates allow surgery for the correction of congenital scoliosis to enter a new stage of personalized precision surgery.

Preparation of Coralline Hydroxyapatite Implant with Recombinant Human Bone Morphogenetic Protein-2-Loaded Chitosan Nanospheres and Its Osteogenic Efficacy.

OBJECTIVE: Spinal fusion is one of the most common surgical interventions for spine reconstruction. Despite the efforts to promote osteogenesis after spinal fusion, osteogenesis after spinal fusion remains a clinical challenge and new methods are still needed. The bone morphogenetic protein-2 (BMP-2) is a widely reported factor that can facilitate the osteogenesis in spinal fusion. In previous research, we found that the delivery of chitosan nanospheres could promote the effects of BMP-2 on osteogenic activity. The coralline hydroxyapatite (CHA) is one of the most frequently used implants in bone fusion. However, up to now no study has focused on the osteogenic efficacy of the CHA composite with recombinant human BMP-2 (rhBMP-2)-loaded chitosan nanospheres. This study aimed to investigate the effects of the CHA implant with rhBMP-2-loaded chitosan nanospheres on osteogenesis in spinal fusion. METHODS: The rhBMP-2-loaded microspheres and CHA composite (rhBMP-2 microspheres/CHA) were prepared and were used for implantation of the rats. All SD rats were divided into four groups: the rhBMP-2 microspheres/CHA composite group (containing 0.5 mg rhBMP-2), the rhBMP-2-loaded CHA (rhBMP-2/CHA) composite group (containing 0.5 mg rhBMP-2), the blank CHA group, and the negative control group. The microsphere morphology was scanned and analyzed using a scanning electron microscope. Micro-computed tomography examination and three-dimensional reconstruction were performed 4 weeks after the surgery. Hematoxylin and eosin staining was conducted for histological analysis. Both alkaline phosphatase (ALP) and calcium content were measured. RESULTS: The rhBMP-2-loaded CHA (rhBMP-2/CHA) composite was successfully prepared. Spherical regularity and a smooth and unwrinkled surface of the spheres were observed in all chitosan (CS)/rhBMP-2 microspheres. No side effects, infections, or abnormal behaviors were found in the animals. After 4 weeks of surgery, obvious new bone formation and bone fusion could be observed around the implant in both the rhBMP-2 microspheres/CHA composite group and the rhBMP-2/CHA composite group. No ectopic osteogenesis was found in the vertebral canal or other muscle tissues. After 4 weeks of implantation, in both the rhBMP-2 microspheres/CHA composite group and the rhBMP-2/CHA composite group, osteoid tissues could be found, and bone cells, bone marrow, and trabecular bone turned into mature sclerotin, obvious bone tissue formation could be also seen. Both ALP activity and calcium content in the rhBMP-2 microspheres/CHA composite group (6.52 ± 0.50 kat/g and 17.54 ± 2.49 µg/mg) were significantly higher than in all other groups. CONCLUSION: The composite with rhBMP-2-loaded CS nanospheres could enhance osteogenic efficacy and increase the ALP activity and calcium content. These results might provide a novel method for osteogenesis in spinal fusion and offer new insight into the role of BMP-2 in osteogenesis.