Lung Ultrasound for the Diagnosis and Management of Neonatal Respiratory Distress Syndrome: A Minireview.

Lung ultrasound (LUS) is useful for diagnosis of respiratory distress syndrome in neonates. Recently, it has been proved to play an important role in the management of neonatal respiratory distress syndrome (RDS). It is feasible to grade RDS and select therapeutic modalities accordingly by LUS. The treatment also should be adjusted with the change in ultrasound images. In conclusion, LUS is valuable for the diagnosis and management of neonatal respiratory distress syndrome.

A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism.

Diacylglycerol acyltransferase 1 (DGAT1) plays a pivotal role in lipid metabolism by catalyzing the committed step in triglyceride (TG) synthesis and has been considered as a potential therapeutic target of multiple metabolic diseases, including dyslipidemia, obesity and type 2 diabetes. Here we report a novel DGAT1 inhibitor, Yhhu2407, which showed a stronger DGAT1 inhibitory activity (IC50 = 18.24 ± 4.72 nM) than LCQ908 (IC50 = 78.24 ± 8.16 nM) in an enzymatic assay and led to a significant reduction in plasma TG after an acute lipid challenge in mice. Pharmacokinetic studies illustrated that Yhhu2407 displayed a low systemic, liver- and intestine-targeted distribution pattern, which is consistent with the preferential tissue expression pattern of DGAT1 and therefore might help to maximize the beneficial pharmacological effects and prevent the occurrence of side effects. Cell-based investigations demonstrated that Yhhu2407 inhibited free fatty acid (FFA)-induced TG accumulation and apolipoprotein B (ApoB)-100 secretion in HepG2 cells. In vivo study also disclosed that Yhhu2407 exerted a beneficial effect on regulating plasma TG and lipoprotein levels in rats, and effectively ameliorated high-fat diet (HFD)-induced dyslipidemia in hamsters. In conclusion, we identified Yhhu2407 as a novel DGAT1 inhibitor with potent efficacy on improving lipid metabolism in rats and HFD-fed hamsters without causing obvious adverse effects.

DGAT1 inhibitors protect pancreatic ß-cells from palmitic acid-induced apoptosis.

Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids (FFA), especially saturated fatty acids, could lead to pancreatic ß-cell apoptosis, which plays an important role in the progression of type 2 diabetes (T2D). Diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) synthesis, has been reported as a novel target for the treatment of multiple metabolic diseases. In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic ß-cells, and further verified their antidiabetic effects in db/db mice. We showed that DGAT1 inhibitors (4a and LCQ908) at the concentration of 1 µM significantly ameliorated palmitic acid (PA)-induced apoptosis in MIN6 pancreatic ß-cells and primary cultured mouse islets; oral administration of a DGAT1 inhibitor (4a) (100 mg/kg) for 4 weeks significantly reduced the apoptosis of pancreatic islets in db/db mice. Meanwhile, 4a administration significantly decreased fasting blood glucose and TG levels, and improved glucose tolerance and insulin tolerance in db/db mice. Furthermore, we revealed that pretreatment with 4a (1 µM) significantly alleviated PA-induced intracellular lipid accumulation, endoplasmic reticulum (ER) stress, and proinflammatory responses in MIN6 cells, which might contribute to the protective effects of DGAT1 inhibitors on pancreatic ß-cells. These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.

Comprehensive Quantitative Assessment of Lung Liquid Clearance by Lung Ultrasound Score in Neonates with No Lung Disease during the First 24 Hours.

OBJECTIVES: To comprehensively and quantitatively assess the process of lung liquid clearance using the lung ultrasound score. This study is to evaluate the whole healthy lungs of neonates during the first 24 h. METHODS: Lung ultrasound was performed in neonates with no respiratory symptoms within 3 h after birth, and scans were then repeated at 6 hours and 24 hours, respectively. The entire chest wall was divided into 12 regions. The lung ultrasound scores of the anterior, posterior, upper, and lower regions and sum of all regions were calculated according to the ultrasound pattern of each region examined. RESULTS: The total lung ultrasound score decreased gradually during the first 24 h, with the total lung ultrasound score at 6 h being significantly lower than that at <3 h (P < 0.05). At <3 h, B-lines were more abundant in the posterior chest than in the anterior chest (P < 0.05). At <3 h, B-lines were more abundant in the posterior chest than in the anterior chest (P < 0.05). At <3 h, B-lines were more abundant in the posterior chest than in the anterior chest (. CONCLUSION: Changes in the lung ultrasound score may quantitatively reflect the characteristics of different regions and processes of lung liquid clearance during the first 24 h.

Root and nitrate-N distribution and optimization of N input in winter wheat.

Scientific management of nitrogen (N) fertilizer has a significant effect on yield while also reducing the environmental risks. In this study, we conducted field experiments over three years at two different sites (Zhengzhou and Shangshui) in Henan Province, China, using different N application rates (0, 90,180, 270, and 360 kg ha-1) to determine the relationships between soil N supply and N demand in winter wheat (Triticum aestivum L.). Optimal N input was then determined. Both sites showed the same trend. Namely, aboveground N uptake and soil nitrate N (NO3--N) increased with increasing N, while NO3--N decreased with increasing soil depth, gradually moving downwards with growth. A significant correlation (p < 0.001) between increasing aboveground N uptake and increasing NO3--N was also observed under N application, with the best relationships occurring in the 20-60 cm layer during jointing-anthesis (R2 = 0.402-0.431) and the 20-80 cm layer at maturity (R2 = 0.474). Root weight density showed the same spatial-temporal characteristics as NO3--N, following a unimodal trend with increasing N, and peaking at 90 kg ha-1. The root weight density was mainly distributed in the 0-60 cm layer (above 80%), with the 20-60 cm layer accounting for 30% of the total root system. In this layer, the root weight density was also significantly positively correlated with aboveground N uptake. Wheat yield reached saturation under high N (>270 kg ha-1), with a sharp decrease in N use efficiency (NUE) and linear increase in residual NO3--N. To balance yield and the risk of environmental pollution in the experimental area, an N application rate of 180-270 kg ha-1 is recommended under sufficient irrigation, thereby supporting a well-developed root system while ensuring balance between N supply and demand.

Remotely Estimating Aerial N Uptake in Winter Wheat Using Red-Edge Area Index From Multi-Angular Hyperspectral Data.

Remote sensing techniques can be efficient for non-destructive, rapid detection of wheat nitrogen (N) nutrient status. In the paper, we examined the relationships of canopy multi-angular data with aerial N uptake of winter wheat (Triticum aestivum L.) across different growing seasons, locations, years, wheat varieties, and N application rates. Seventeen vegetation indices (VIs) selected from the literature were measured for the stability in estimating aerial N uptake of wheat under 13 view zenith angles (VZAs) in the solar principal plane (SPP). In total, the back-scatter angles showed better VI behavior than the forward-scatter angles. The correlation coefficient of VIs with aerial N uptake increased with decreasing VZAs. The best linear relationship was integrated with the optimized common indices DIDA and DDn to examine dynamic changes in aerial N uptake; this led to coefficients of determination (R2) of 0.769 and 0.760 at the -10° viewing angle. Our novel area index, designed the modified right-side peak area index (mRPA), was developed in accordance with exploration of the spectral area calculation and red-edge feature using the equation: mRPA = (R760/R600)1/2 × (R760-R718). Investigating the predictive accuracy of mRPA for aerial N uptake across VZAs demonstrated that the best performance was at -10° [R2 = 0.804, p < 0.001, root mean square error (RMSE) = 3.615] and that the effect was relatively similar between -20° to +10° (R2 = 0.782, p < 0.001, RMSE = 3.805). This leads us to construct a simple model under wide-angle combinations so as to improve the field operation simplicity and applicability. Fitting independent datasets to the models resulted in relative error (RE, %) values of 12.6, 14.1, and 14.9% between estimated and measured aerial N uptake for mRPA, DIDA, and DDn across the range of -20° to +10°, respectively, further confirming the superior test performance of the mRPA index. These results illustrate that the novel index mRPA represents a more accurate assessment of plant N status, which is beneficial for guiding N management in winter wheat.

The Pharmacokinetics of Morphine and Codeine in Human Plasma and Urine after Oral Administration of Qiangli Pipa Syrup.

Papaveris pericarpium, a natural source of morphine and codeine, is the principal active component in many antitussive traditional Chinese medicines. We herein report the first PK study of papaveris pericarpium in human plasma and urine following oral administration of single (15, 30, 60 mL) and multiple dose (15 mL) of Qiangli Pipa Syrup (MOR 0.1 mg/mL, COD 0.028 mg/mL) by monitoring morphine and codeine using a HPLC-MS/MS method. Their Tmax and t1/2 values are independent of dosages, while the AUC0-t linearly increased with higher dosages, indicating linear PK characteristics. AUC0-t increased obviously after multiple doses, indicating possible risk of accumulative toxicity. Urine studies suggested risks of positive opiate drug tests with a cutoff of 300 ng/mL, which lasted 6-14 h at different doses. These results provide important information for clinical safety, efficacy and rational drug use of Qiangli Pipa Syrup and also guide the related judicial expertise of its administration.

Low dosage of arsenic trioxide inhibits vasculogenic mimicry in hepatoblastoma without cell apoptosis.

Hepatoblastoma (HB) is the most common type of pediatric liver malignancy, which predominantly occurs in young children (aged <5 years), and continues to be a therapeutic challenge in terms of metastasis and drug resistance. As a new pattern of tumor blood supply, vasculogenic mimicry (VM) is a channel structure lined by tumor cells rather than endothelial cells, which contribute to angiogenesis. VM occurs in a variety of solid tumor types, including liver cancer, such as hepatocellular carcinoma. The aim of the present study was to elucidate the effect of arsenic trioxide (As2O3) on VM. In vitro experiments identified that HB cell line HepG2 cells form typical VM structures on Matrigel, and the structures were markedly damaged by As2O3 at a low concentration before the cell viability significantly decreased. The western blot results indicated that As2O3 downregulated the expression level of VM­associated proteins prior to the appearance of apoptotic proteins. In vivo, VM has been observed in xenografts of HB mouse models and identified by periodic acid­Schiff+/CD105­ channels lined by HepG2 cells without necrotic cells. As2O3 (2 mg/kg) markedly depresses tumor growth without causing serious adverse reactions by decreasing the number of VM channels via inhibiting the expression level of VM­associated proteins. Thus, the present data strongly indicate that low dosage As2O3 reduces the formation of VM in HB cell line HepG2 cells, independent of cell apoptosis in vivo and in vitro, and may represent as a candidate drug for HB targeting VM.

Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-RafV600E inhibitors.

The mutation of B-RafV600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-RafV600E is an ideal drug target. This study focused on developing novel B-RafV600E inhibitors as drug leads against various cancers with B-RafV600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-RafV600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-RafV600E inhibitors. A highly potent fragment binding to the hinge area of B-RafV600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-RafV600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-RafV600E inhibitor with an IC50 value of 0.05 µmol/L, which was lower than that of vemurafenib (0.13 µmol/L). Moreover, the selectivity of 1m against B-RafWT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-RafV600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.

Chlorogenic acid analogues from Gynura nepalensis protect H9c2 cardiomyoblasts against H2O2-induced apoptosis.

AIM: Chlorogenic acid has shown protective effect on cardiomyocytes against oxidative stress-induced damage. Herein, we evaluated nine caffeoylquinic acid analogues (1-9) isolated from the leaves of Gynura nepalensis for their protective effect against H2O2-induced H9c2 cardiomyoblast damage and explored the underlying mechanisms. METHODS: H9c2 cardiomyoblasts were exposed to H2O2 (0.3 mmol/L) for 3 h, and cell viability was detected with MTT assay. Hoechst 33342 staining was performed to evaluate cell apoptosis. MMPs (mitochondrial membrane potentials) were measured using a JC-1 assay kit, and ROS (reactive oxygen species) generation was measured using CM-H2 DCFDA. The expression levels of relevant proteins were detected using Western blot analysis. RESULTS: Exposure to H2O2 markedly decreased the viability of H9c2 cells and catalase activity, and increased LDH release and intracellular ROS production; accompanied by a loss of MMP and increased apoptotic rate. Among the 9 chlorogenic acid analogues as well as the positive control drug epigallocatechin gallate (EGCG) tested, compound 6 (3,5-dicaffeoylquinic acid ethyl ester) was the most effective in protecting H9c2 cells from H2O2-induced cell death. Pretreatment with compound 6 (1.56-100 µmol/L) dose-dependently alleviated all the H2O2-induced detrimental effects. Moreover, exposure to H2O2 significantly increased the levels of Bax, p53, cleaved caspase-8, and cleaved caspase-9, and decreased the level of Bcl-2, resulting in cell apoptosis. Exposure to H2O2 also significantly increased the phosphorylation of p38, JNK and ERK in the H9c2 cells. Pretreatment with compound 6 (12.5 and 25 µmol/L) dose-dependently inhibited the H2O2-induced increase in the level of cleaved caspase-9 but not of cleaved caspase-8. It also dose-dependently suppressed the H2O2-induced phosphorylation of JNK and ERK but not that of p38. CONCLUSION: Compound 6 isolated from the leaves of Gynura nepalensis potently protects H9c2 cardiomyoblasts against H2O2-induced apoptosis, possibly by inhibiting intrinsic apoptosis and the ERK/JNK pathway.