Ginkgo biloba Extract 50 (GBE50) Exerts Antifibrotic and Antioxidant Effects on Pulmonary Fibrosis in Mice by Regulating Nrf2 and TGF-ß1/Smad Pathways.

BACKGROUND: Pulmonary fibrosis (PF) is a progressive lung disorder with a poor prognosis. GBE50 is a new standardized Ginkgo biloba extract that has been widely used in cardiovascular diseases. However, the protective mechanism of GBE50 against PF remains to be elucidated. METHODS: C57BL/6J mice were treated with bleomycin (Bleo) to induce PF in the presence or absence of GBE50. Protein content in bronchoalveolar lavage fluid (BALF) and wet weight/dry weight ratio were examined for analysis of pulmonary edema. Hematoxylin-eosin staining and Masson trichrome staining were used for histopathological observation of murine lung tissues. Ashcroft score was used for semi-quantitation of lung fibrosis degree. RT-qPCR was utilized for assessing mRNA levels of pro-fibrotic mediators in lung tissues. TUNEL staining was implemented for cell apoptosis assessment. The levels of oxidative stress- and inflammation-related markers were evaluated by corresponding commercial assay kits. Western blotting was used to evaluate levels of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling- and transforming growth factor (TGF)-ß1/SMAD signaling-related proteins. RESULTS: GBE50 alleviated lung injury and severity of fibrosis, reduced collagen deposition and cell apoptosis in lung tissues, and suppressed inflammatory response and oxidative stress injury in Bleo-stimulated PF mice. GBE50 activated Nrf2 signaling pathway and inactivated TGF-ß1/SMAD signaling pathway in the lungs of Bleo-induced PF mice. Inhibition of Nrf2 signaling reversed GBE50-mediated inactivation of TGF-ß1/SMAD signaling and attenuation of inflammation and oxidative stress in Bleo-induced PF mice. CONCLUSION: GBE50 protects against Bleo-induced PF in mice by mitigating fibrosis, inflammation and oxidative stress via Nrf2 and TGF-ß1/SMAD signaling pathways.

Identification of the MMP family as therapeutic targets and prognostic biomarkers in the microenvironment of head and neck squamous cell carcinoma.

BACKGROUND: Head and Neck Squamous Cell Carcinoma is a malignant tumor with high morbidity and mortality. The MMP family plays an important role in tumor invasion and metastasis. However, the mechanistic value of the MMP family as a therapeutic target and prognostic biomarker in HNSC has not been fully elucidated. METHODS: Oncomine, UALCAN, GEPIA, cBioportal, GeneMANIA, STRING, DAVID6.8, TRRUST, TIMER and Linkedomics were used for analysis. RESULTS: The mRNA expression levels of MMP1, MMP3, ILF3, MMP7, MMP9, MMP10, MMP11, MMP12, MMP13 and MMP16 were higher in HNSC than those in normal tissues, while the mRNA expression level of MMP15 was reduced. The relative expression levels of MMP1 and MMP14 were the highest in HNSC tissues. A significant correlation was found between the expression of MMP3, MMP11, MMP25 and the pathological stage of HNSC patients. There was no significant associations between all the MMP family members expression levels and DFS. Increased mRNA levels of MMP1, MMP8 and MMP25 were significantly associated with OS. In addition, we investigated the genetic changes of the MMP family in HNSC and found that all the MMP family members had genetic changes, most of which were amplification and depth loss. In the analysis of neighbor gene network and protein interaction, we found that the MMP family interacted with 25 neighboring genes, except for ILF3, MMP19, MMP20, MMP21, MMP23B, MMP27 and MMP28, other MMP proteins interacted with each other. Functional enrichment analysis showed that the MMP family could be present in the extracellular matrix, regulate peptidase activity, and participate in the catabolism of collagen. Meanwhile, we identified the transcription factor targets and kinase targets of the MMP family and found that ATM and ATR were the two most common kinase targets in the MMP family. We also found a significant correlation between the MMP family expression and immune cell infiltration. Cox proportional risk model analysis showed that macrophages, MMP14, MMP16, and MMP19 were significantly associated with clinical outcomes in HNSC patients. CONCLUSION: The MMP family might serve as therapeutic target and prognostic biomarker in HNSC.

Alternating-Current Microgrid Testbed Built with Low-Cost Modular Hardware.

With the growing popularity of microgrids for alternative energy management, there is demand for tools that allow us to study the effect of microgrids in distributed power systems. Popular methods involve software simulation and prototype validation with physical hardware. Simulations often do not capture the complex interactions, and combinations of software simulations with hardware testbeds promise to give a more accurate picture. These testbeds, however, usually aim at the validation of hardware for industrial-scale use, which makes them expensive and not readily accessible. To fill the gap between full-scale hardware and software simulation, we propose a modular lab-scale grid model at a 1:100 power scale over residential single-phase networks with 12 V AC and 60 Hz grid voltage. We present different modules-power sources, inverters, demanders, grid monitors, and grid-to-grid bridges-that can be assembled into distributed grids of almost arbitrary complexity. The model voltage poses no electrical hazards, and microgrids can readily be assembled with an open power line model. Unlike a prior DC-based grid testbed, the proposed AC model allows us to examine additional aspects, such as frequency, phase, active and apparent power, and reactive loads. Grid metrics, including the discretely sampled voltage and current waveforms, can be collected and sent to higher-tier grid management systems. We integrated the modules with Beagle Bone micro-PCs, which in turn connect any such microgrid with an emulation platform built on CORE (Common Open Research Emulator) and the Gridlab-D power simulator, thereby allowing hybrid software/hardware simulations. Our grid modules were shown to fully operate in this environment. Through the CORE system, multitiered control and even remote grid management is possible. However, we also found that the AC waveform poses design challenges that require us to balance accurate emulation (most notably with respect to harmonic distortion) with per-module costs.

CGF-HLC-I repaired the bone defect repair of the rabbits mandible through tight junction pathway.

Background: The human-like collagen I (HLC-I) combined concentrated growth factors was used to construct CGF-HLC-I composite biomaterials to repair the critical bone defect disease model of rabbit mandible. This study aimed to research the repair mechanism of CGF-HLC-I/Bio-Oss in rabbit mandibular critical bone defect, to provide a new treatment direction for clinical bone defect repair. Methods: The optimal concentration of HLC-I (0.75%) was selected in this study. Nine New Zealand white rabbits were randomly divided into 3 groups, normal control group, Bio-Gide/Bio-Oss and CGF-0.75%HLC-I/Bio-Oss group (n = 3, each group). CGF-0.75%HLC-I/Bio-Oss and Bio-Gide/Bio-Oss were implanted into rabbit mandibles, then X-ray, Micro-CT, HE and Masson staining, immunohistochemical staining and biomechanical testing were performed with the bone continuity or maturity at 4, 8 and 12 weeks after surgery. The repair mechanism was studied by bioinformatics experiments. Results: As the material degraded, the rate of new bone formation in the CGF-0.75% HLC-I/Bio-Oss group was better than that the control group by micro-CT. The biomechanical test showed that the compressive strength and elastic modulus of the CGF-0.75%HLC-I/Bio-Oss group were higher than those of the control group. HE and Masson staining showed that the bone continuity or maturity of the CGF-0.75%HLC-I/Bio-Oss group was better than that of the control group. Immunohistochemical staining showed significantly higher bone morphogenetic protein 2 (BMP2) and Runt-related transcription factor 2 (RUNX2) in the CGF-0.75%HLC-I/Bio-Oss group than the control group at 8 and 12 W and the difference gradually decreased with time. There were 131 differentially expressed proteins (DEPs) in the Bio-Gide/Bio-Oss and CGF-0.75%HLC-I/Bio-Oss groups, containing 95 up-regulated proteins and 36 down-regulated proteins. KEGG database enrichment analysis showed actinin alpha 1 (ACTN1) and myosin heavy-Chain 9 (MYH9) are the main potential differential proteins related to osteogenesis, and they are enriched in the TJs pathway. Conclusion: CGF-0.75%HLC-I/Bio-Oss materials are good biomaterials for bone regeneration which have strong osteoinductive activity. CGF-0.75%HLC-I/Bio-Oss materials can promote new bone formation, providing new ideas for the application of bone tissue engineering scaffold materials in oral clinics.

Aerosol inhalation of ambroxol hydrochloride combined with terbutaline can promote recovery of children with severe pneumonia.

OBJECTIVE: This research aimed to investigate the clinical efficacy of aerosol inhalation of ambroxol hydrochloride combined with terbutaline on children with severe pneumonia, and to evaluate its influence on their immune function and inflammatory level. METHODS: Totally 113 severe pneumonia children were included. Thereinto, 55 children in the control group (CG) were treated with terbutaline aerosol inhalation, while 58 in the research group (RG) were given ambroxol hydrochloride on the basis of the CG. Their symptom alleviating time, blood gas parameters, adverse reactions during treatment, clinical efficacy, immune function and inflammatory factors were compared. RESULTS: The time of fever clearance time, disappearance of cough and pulmonary rates, chest shadow absorption and hospitalization of children in the RG were shorter than those in the CG. The combined treatment did not increase additional adverse reactions; instead, its effective rate was markedly higher than that in the CG. Further research found that after treatment, the arterial partial pressure of oxygen (PaO2), oxygenation index (OI), CD4+ and CD4+/CD8+, and interleukin-10 (IL-10) levels were dramatically increased, while the arterial partial pressure of carbon dioxide (PaCO2), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-17 (IL-17) and CD8+ levels were obviously increased. In addition, these indexes of children in the RG were obviously better than those in the CG. CONCLUSION: Aerosol inhalation of ambroxol hydrochloride combined with terbutaline has a remarkable clinical efficacy on children with severe pneumonia, which can improve their immune function and reduce inflammatory reaction.

Method for extraction of airborne LiDAR point cloud buildings based on segmentation.

The LiDAR technology is a means of urban 3D modeling in recent years, and the extraction of buildings is a key step in urban 3D modeling. In view of the complexity of most airborne LiDAR building point cloud extraction algorithms that need to combine multiple feature parameters, this study proposes a building point cloud extraction method based on the combination of the Point Cloud Library (PCL) region growth segmentation and the histogram. The filtered LiDAR point cloud is segmented by using the PCL region growth method, and then the local normal vector and direction cosine are calculated for each cluster after segmentation. Finally, the histogram is generated to effectively separate the building point cloud from the non-building.Two sets of airborne LiDAR data in the south and west parts of Tokushima, Japan, are used to test the feasibility of the proposed method. The results are compared with those of the commercial software TerraSolid and the K-means algorithm. Results show that the proposed extraction algorithm has lower type I and II errors and better extraction effect than that of the TerraSolid and the K-means algorithm.

Development of ionic liquid assisted-synthesized nano­silver combined with vascular endothelial growth factor as wound healing in the care of femoral fracture in the children after surgery.

This investigation aimed to develop the silver (Ag) nanoparticles incorporated vascular endothelial growth factor (VEGF) for the improvement wound healing and reduce Aseptic necrosis in treatment of femoral fracture healing. The spherical shaped Ag nanoparticles with improved morphology have been effectively synthesized via microwave assisted method using ionic liquids 1-dodecyl-3-methylimidazolium chloride. The morphological structure and crystalline properties of Ag nanoparticles are analyzed by using UV, XRD and TEM-EDX analytical methods. The average grain size of the Ag nanoparticles is 20 nm, which was observed by defining the width of the (111) Bragg reflection with the Debye-Scherer formula and TEM results. The biological analyses confirmed that the Ag nanoparticles with VEGF molecules are promoted the cell adhesion and proliferation of Human mesenchymal stem cells (MSCs) cells. Ag NPs at appropriate concentrations have favorable biocompatibility to encourage cell activation properties like cell proliferation, cytokines release and chemotaxis. In the present study, our experimental results indicated that Ag NPs incorporated VEGF material are highly favorable to fracture healing and mainly as blood vessel repair. The surface morphology improved synthetic Ag NPs using ionic liquids has shown advantageous for cell activity and also improve the materials performances with VEGF for the regeneration of femoral fractures.

Clinical efficacy of recombinant human latrophilin 3 antibody in the treatment of pediatric asthma.

Pediatric asthma is a chronic pulmonary inflammatory disease featuring hypersecretion of mucus and inflammation in the airway, resulting in dysfunction of the airway smooth muscle. Previous evidence demonstrated that latrophilins, a novel family of receptors, present a beneficial effect on airway smooth muscle cells. In the present study, the therapeutic effects of recombinant human latrophilin 3 (rhLPHN3) antibody (Ab) in patients with pediatric asthma were investigated, and the molecular mechanism underlying the function of LPHN3 in the treatment of asthma in clinical practice was examined. A total of 342 pediatric asthma cases were recruited and randomly divided into three groups, receiving treatment with rhLPHN3 Ab (n=134), salbutamol (n=108) or montelukast (n=100) by nasal aerosolization. Each group received the respective clinically tested dose for 16 weeks. Inflammatory factors interleukin (IL)-10, IL-17, IL-4, matrix metallopeptidase-9 (MMP-9), interferon-γ (IFN-γ) and transforming growth factor-ß (TGF-ß) levels in peripheral blood mononuclear cells were analyzed prior to and post treatment. The clinical outcomes revealed that pathological alterations were significantly improved following treatment with rhLPHN3 Ab for patients with pediatric asthma when compared with those receiving salbutamol and montelukast. It was also observed that rhLPHN3 Ab downregulated the plasma concentration levels of IL-10, IL-17, IL-4 and MMP-9, and upregulated IFN-γ and TGF-ß levels in the three groups. In addition, clinical data demonstrated that rhLPHN3 Ab significantly promoted E-selectin and mucin 5AC expression, as well as improved the activation of nuclear factor (NF)-κB p65 DNA binding activity and the phosphorylation levels of protein kinase A. Furthermore, rhLPHN3 Ab markedly improved adhesion and proliferation of airway smooth muscle cells, which led to promotion of the contraction of these cells. In conclusion, these clinical data suggest that rhLPHN3 Ab serves an important role in the inhibition of inflammatory mediators through downregulation of NF-κB signaling pathway, which contributes to airway remodeling and bronchodilation in patients with pediatric asthma.

Promiscuity and selectivity of small-molecule inhibitors across TAM receptor tyrosine kinases in pediatric leukemia.

The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3. The location and conformation of active-site residues of Mer and Axl are highly consistent, suggesting that small-molecule inhibitors generally have a low Mer-over-Axl selectivity and a high Mer-over-Tyro3 selectivity. We demonstrated that the difference in ATP binding potency to the three kinases is also responsible for inhibitor selectivity. We also found that the long-range interactions and allosteric effect arising from rest of the kinase's active site can indirectly influence inhibitor binding and selectivity.

Valproic acid and progestin inhibit lesion growth and reduce hyperalgesia in experimentally induced endometriosis in rats.

Accumulating evidence suggests that endometriosis is an epigenetic disease. This study was designed to evaluate the effect of valproic acid (VPA) and progesterone (P4) in a rat model of endometriosis on serum tumor necrosis factor-α (TNF-α) levels, hot plate and tail-flick latencies, lesion size, and body weight. We used 77 adult female rats, and endometriosis was induced by autotransplanting pieces of uterus (ENDO) or fat (SHAM) to the pelvic cavity. The BLANK group received no surgery. After 2 weeks, the ENDO group was further divided, randomly, into 5 groups, receiving, respectively, treatment with low- and high-dose VPA, P4 alone, VPA + P4, and no treatment. The SHAM rats received no treatment. The BLANK rats were further divided into 2 groups, one received VPA treatment and the other, no treatment. After 4 weeks, all rats were sacrificed. Response latency in hot plate and tail-flick tests, body weight, and serum TNF-α levels were measured before the surgery, before and after the treatment, along with lesion size. We found that induced endometriosis reduced response latency. ENDO rats receiving VPA and/or P4 treatment had significantly reduced lesion size as compared with untreated ones, and had significantly improved response to noxious thermal stimuli. They also had significantly increased weight gain. Serum TNF-α levels increased following surgery but eventually decreased regardless of treatment or not. In conclusion, VPA is well tolerated. Treatment with VPA significantly reduces lesion growth and improves sensitivity to nocifensive stimuli. The improvement is specific to endometriosis-induced hyperalgesia. Thus, histone deacetylase inhibitors may be a promising therapeutics for treating endometriosis.

Use of mifepristone to treat endometriosis: a review of clinical trials and trial-like studies conducted in China.

China was the first country in the world that approved mifepristone (RU-486) for abortion. A total of 6 years after the report published in the Western world indicated that mifepristone may also be effective in treating endometriosis, the first paper on the same topic was published in China in 1997. Since then, over 160 studies on this topic have been published in China. We retrieved 104 papers on clinical trials and trial-like studies conducted in China evaluating the use of mifepristone to treat endometriosis that were published in the last 11 years. We found that the quality of these studies is well below an acceptable level, making it difficult to judge whether mifepristone is truly efficacious. There are intriguing signs that these studies, as a whole, have serious anomalies. The areas that are glaringly deficient are informed consent, choice of outcome measures, the evaluation of outcome measures, data analysis and randomization. The uniformly low quality is disquieting, given the large quantity of studies, the enormous amount of resource and energy put into these studies and, above all, the weighty issue of treatment efficacy that concerns each and every patient with endometriosis. Equally disquieting are the low-quality repetition, the absence of a critical, systematic review on the subject, the lack of suggestions for multicenter clinical trials and the seemingly unnecessary duplication of clinical trials without due informed consent. In view of this, it may be time to institute changes in attitude and practice, and to change education and training programs in the methodology of clinical trials in obstetrics and gynecology research in China.

Sexuality after laparoscopic peritoneal vaginoplasty in women with Mayer-Rokitansky-Kuster-Hauser syndrome.

OBJECTIVE: To evaluate anatomic and sexual outcomes in women with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome after laparoscopic Davydov (laparoscopic peritoneal vaginoplasty). DESIGN: Prospective follow-up study of patients with MRKH syndrome after vaginoplasty (Design classification: II-2). SETTING: Academic hospital. PATIENTS: Patients with MRKH syndrome and frequency-matched age-comparable healthy controls. INTERVENTION: Thirty-one patients with MRKH syndrome underwent surgery with the procedure, and their clinical, surgical, and follow-up data were recorded. A Female Sexual Function Index (FSFI) questionnaire was administrated to evaluate sexual functions of patients who became sexually active and compared them with 50 randomly selected, age-matched healthy women. MEASUREMENTS: FSFI scores in women with MRKH syndrome and in control subjects. Clinical and anatomic measurements of neovagina. MAIN RESULTS: The laparoscopic Davydov was successfully completed in all 31 cases, with 24 patients monitored. The mean length of the neovagina was 6.27+/-1.25 cm. There was no statistical difference in the total FSFI score between the case and control groups. There is indication that shorter neovaginal length, especially of<7 cm, appears to be associated with lower total FSFI scores. CONCLUSION: Laparoscopic Davydov is a safe, effective treatment of Mayer-Rokitansky-Kuster-Hauser syndrome with minimal invasion and a relatively low complication rate.

[Clinicopathological features of 67 cases of endometriosis-associated epithelial ovarian carcinoma.].

OBJECTIVE: To investigate clinicopathological features of endometriosis-associated epithelial ovarian carcinoma. METHODS: Retrospective follow-up study, clinicopathological data from patients with ovarian epithelial carcinoma were retrieved, analyzed and compared. Among the 727 cases, 34 were found to originate from endometriosis (group A), 33 were found to have co-existing ovarian endometriosis (group B), and the remaining 660 had no ovarian endometriosis at all (group C). RESULT: Seven hundred and twenty-seven epithelial ovarian carcinoma patients were identified and their clinicopathological data retrieved. Sixty-seven (9.2%) of these cases were found to have coexisting endometriosis. The frequency of malignant tumors arising from ovarian endometriosis in this case series was estimated to be 0.87% (34/3890). The mean (standard deviation) age in groups A, B, and C were (47.2 +/- 1.3), (47.8 +/- 1.2), (51.2 +/- 0.4) years, respectively, with patients in group C being significantly older (P = 0.013). Patients with coexisting ovarian endometriosis were mostly diagnosed at stage I (P = 0.000) and having subtype of clear-cell (P = 0.000), while other patients were mostly diagnosed at stage III (P = 0.001), and having subtype of serous carcinoma (P = 0.000). The estrogen receptor (ER) positivity was significantly lower in groups A and B than that in group C (22.2%, 31.6% vs 43.9%; P = 0.018), but the difference in positivity of progestogen receptor among the three groups did not reach statistical significance (22.2%, 15.8% vs 35.5%; P = 0.082). While the five-year overall survival rate for all patients was 55.6%, significant difference in overall survival among the three groups was found 78.9%, 92.8%, 51.9%, respectively, for groups A, B and C (P = 0.000). CONCLUSION: Patients of endometriosis-associated epithelial ovarian carcinoma, especially patients with tumors arising from endometriosis, were found to be younger, having a significant lower stage and a better survival, and were mostly diagnosed with the subtype of clear-cell.