[Early risk factors for death in neonates with persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide]. / ç»ä¸€æ°§åŒ–æ°®å¸å ¥æ²»ç–—çš„æ–°ç”Ÿå„¿æŒç»­è‚ºåŠ¨è„‰é«˜åŽ‹æ‚£å„¿æ­»äº¡çš„æ—©æœŸå½±å“å› ç´ åˆ†æž.

OBJECTIVES: To evaluate the early risk factors for death in neonates with persistent pulmonary hypertension of the newborn (PPHN) treated with inhaled nitric oxide (iNO). METHODS: A retrospective analysis was performed on 105 infants with PPHN (gestational age ≥34 weeks and age <7 days on admission) who received iNO treatment in the Department of Neonatology, Children's Hospital of Nanjing Medical University, from July 2017 to March 2021. Related general information and clinical data were collected. According to the clinical outcome at discharge, the infants were divided into a survival group with 79 infants and a death group with 26 infants. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for death in infants with PPHN treated with iNO. The receiver operating characteristic (ROC) curve was used to calculate the cut-off values of the factors in predicting the death risk. RESULTS: A total of 105 infants with PPHN treated with iNO were included, among whom 26 died (26/105, 24.8%). The multivariate Cox regression analysis showed that no early response to iNO (HR=8.500, 95%CI: 3.024-23.887, P<0.001), 1-minute Apgar score ≤3 points (HR=10.094, 95%CI: 2.577-39.534, P=0.001), a low value of minimum PaO2/FiO2 within 12 hours after admission (HR=0.067, 95%CI: 0.009-0.481, P=0.007), and a low value of minimum pH within 12 hours after admission (HR=0.049, 95%CI: 0.004-0.545, P=0.014) were independent risk factors for death. The ROC curve analysis showed that the lowest PaO2/FiO2 value within 12 hours after admission had an area under the ROC curve of 0.783 in predicting death risk, with a sensitivity of 84.6% and a specificity of 73.4% at the cut-off value of 50, and the lowest pH value within 12 hours after admission had an area under the ROC curve of 0.746, with a sensitivity of 76.9% and a specificity of 65.8% at the cut-off value of 7.2. CONCLUSIONS: Infants with PPHN requiring iNO treatment tend to have a high mortality rate. No early response to iNO, 1-minute Apgar score ≤3 points, the lowest PaO2/FiO2 value <50 within 12 hours after admission, and the lowest pH value <7.2 within 12 hours after admission are the early risk factors for death in such infants. Monitoring and evaluation of the above indicators will help to identify high-risk infants in the early stage.

Dihydropyrazothiazole derivatives as potential MMP-2/MMP-8 inhibitors for cancer therapy.

MMP-2/MMP-8 is established as one of the most important metalloenzymes for targeting cancer. A series of dihydropyrazothiazole derivatives (E1-E18) bearing a salicylaldehyde group linked to Pyrazole ring were designed, synthesized, and evaluated for their pharmacological activity as MMP-2/MMP-8 inhibitors. Among them, compound E17 exhibited most potent inhibitory activity (IC50 = 2.80 µM for MMP-2 and IC50 = 5.6 µM for MMP-8), compared to the positive drug CMT-1 (IC50 = 1.29 µM). Compounds (E1-E18) were scrutinized by CoMFA and CoMSIA techniques of Three-dimensional quant. structure-activity relationship (3D-QSAR), as well as a docking simulation. Moreover, treatment with compound E4 could induce MCF-7 cell apoptosis. Overall, the biological profile of E1-E18 may provide a research basis for the development of new agents against cancer.

A three-channel fluorescent probe for selective detection of ONOO- and its application to cell imaging.

The fluorescent probe, GXY-ADP-2, with xanthene structure as the fluorescent core was designed and prepared for the selective detection of peroxynitrite (ONOO-). ONOO- can be produced endogenously and exogenously and is a strong oxidant with a short half-life. Oxidative modifications of biomolecules, that can be attributed to the formation of ONOO-, occur in the reactions of biomolecules with secondary ONOO--derived radical oxidants. Therefore, it is very important to develop a specific fluorescent probe for detecting ONOO- to monitor oxidative stress state. The excitation wavelength and emission wavelength of the probe are 689 nm and 739 nm respectively. In the process of co-incubation with ONOO-, generate a new substance with two internal conjugated structures through a special reaction mechanism, one giving the fluorescence with the excitation wavelength of 347 nm and the emission wavelength of 484 nm with the detection limit of 0.12 µM, and the other that with the excitation wavelength of 433 nm and the emission wavelength of 583 nm with the detection limit of 0.077 µM. The linear dynamic range of the probe is 0-5 µM. Its response is not affected by the other reactive oxygen species, thus can sensitively detect ONOO-. In bioimaging experiments with HepG2 cells, the green and blue cell fluorescence signals (583 nm and 433 nm, respectively) were increased, while the red one (739 nm) was significantly reduced, under lipopolysaccharide (LPS) induced oxidative stress, proving that the probe could sensitively detect ONOO- in living cells. This work provides a new tool for the dynamic changes of ONOO- and oxidative stress processes in biological systems.

Manganese dioxide (MnO2) based nanomaterials for cancer therapies and theranostics.

Today, cancer still poses a serious threat to human, but there is no exact cure. Therefore, exploring to accomplish high therapeutic performance is a challenging and urgent task. Since the nanoparticles unique properties were discovered, they have displayed promising potential for more effective therapies and have been widely used in photodynamic therapy (PDT) and radiation therapy (RT). However, some special properties of the tumour microenvironment (TME) have seriously affected the therapeutic outcomes, so the modulation of the TME becomes critical. Manganese dioxide (MnO2), as a transition metal oxide, has been widely used in biomedical fields with special physical and chemical properties, especially in regulating the TME. Furthermore, MnO2 has widely applications in various cancer treatments, such as PDT, chemodynamic therapy (CDT), immunotherapy, and some specific collaborative treatment. Herein, we reviewed the recent applications of MnO2 modified nanomaterials in tumour therapies and theranostics, including TME regulation, controlled drug loading/delivery/release, and imaging.

Tubulin Inhibitors Binding to Colchicine-Site: A Review from 2015 to 2019.

Due to the three domains of the colchicine-site which is conducive to the combination with small molecule compounds, colchicine-site on the tubulin has become a common target for antitumor drug development, and accordingly, a large number of tubulin inhibitors binding to the colchicine-site have been reported and evaluated over the past years. In this study, tubulin inhibitors targeting the colchicine-site and their application as antitumor agents were reviewed based on the literature from 2015 to 2019. Tubulin inhibitors were classified into ten categories according to the structural features, including colchicine derivatives, CA-4 analogs, chalcone analogs, coumarin analogs, indole hybrids, quinoline and quinazoline analogs, lignan and podophyllotoxin derivatives, phenothiazine analogs, N-heterocycle hybrids and others. Most of them displayed potent antitumor activity, including antiproliferative effects against Multi-Drug-Resistant (MDR) cell lines and antivascular properties, both in vitro and in vivo. In this review, the design, synthesis and the analysis of the structure-activity relationship of tubulin inhibitors targeting the colchicine-site were described in detail. In addition, multi-target inhibitors, anti-MDR compounds, and inhibitors bearing antitumor activity in vivo are further listed in tables to present a clear picture of potent tubulin inhibitors, which could be beneficial for medicinal chemistry researchers.

Rapid and Sensitive Detection of Salmonella in Chickens Using Loop-Mediated Isothermal Amplification Combined with a Lateral Flow Dipstick.

Salmonellosis is a highly contagious bacterial disease that threatens both human and poultry health. Tests that can detect Salmonella in the field are urgently required to facilitate disease control and for epidemiological investigations. Here, we combined loop-mediated isothermal amplification (LAMP) with a chromatographic lateral flow dipstick (LFD) to rapidly and accurately detect Salmonella. LAMP primers were designed to target the Salmonella invA gene. LAMP conditions were optimized by adjusting the ratio of inner to outer primers, MgSO4 concentration, dNTP mix concentration, amplification temperature, and amplification time. We evaluated the specificity of our novel LAMP-LFD method using six Salmonella species and six related non-Salmonella strains. All six of the Salmonella strains, but none of the non-Salmonella strains, were amplified. LAMP-LFD was sensitive enough to detect concentrations of Salmonella enterica subsp. enterica serovar Pullorum genomic DNA as low as 89 fg/µl, which is 1,000 times more sensitive than conventional PCR. When artificially contaminated feed samples were analyzed, LAMP-LFD was also more sensitive than PCR. Finally, LAMP-LFD gave no false positives across 350 chicken anal swabs. Therefore, our novel LAMP-LFD assay was highly sensitive, specific, convenient, and fast, making it a valuable tool for the early diagnosis and monitoring of Salmonella infection in chickens.

Low level of galacto-oligosaccharide in infant formula stimulates growth of intestinal Bifidobacteria and Lactobacilli.

AIM: To investigate the effect of a new infant formula supplemented with a low level (0.24 g/100 mL) of galacto-oligosaccharide (GOS) on intestinal micro-flora (Bifidobacteria, Lactobacilli and E. coli) and fermentation characteristics in term infants, compared with human milk and a standard infant formula without GOS. METHODS: Term infants (n = 371) were approached in this study in three hospitals of China. All infants started breast-feeding. Those who changed to formula-feeding within 4 wk after birth were randomly assigned to one of the two formula groups. Growth and stool characteristics, and side effects that occurred in recruited infants were recorded in a 3-mo follow-up period. Fecal samples were collected from a subpopulation of recruited infants for analysis of intestinal bacteria (culture technique), acetic acid (gas chromatography) and pH (indicator strip). RESULTS: After 3 mo, the intestinal Bifidobacteria, Lactobacilli, acetic acid and stool frequency were significantly increased, and fecal pH was decreased in infants fed with the GOS-formula or human milk, compared with those fed with the formula without GOS. No significant differences were observed between the GOS formula and human milk groups. Supplementation with GOS did not influence the incidence of crying, regurgitation and vomiting. CONCLUSION: A low level of GOS (0.24 g/100 mL) in infant formula can improve stool frequency, decrease fecal pH, and stimulate intestinal Bifidobacteria and Lactobacilli as in those fed with human milk.

[Effects of infant formula containing galacto-oligosaccharides on the intestinal microflora in infants].

OBJECTIVE: To study the effect of a low level of galacto-oligosaccharides (GOS) on intestinal bifidobacteria and lactobacilli, and fermentation characteristics in term infants by comparing with human milk and a standard infant formula without GOS. METHODS: A total of 371 term infants from four hospitals of China were enrolled. The infants started with breast feeding. After 1-2 weeks, some of the infants were changed to feeding with formula milk and then were randomly assigned to two formula-feeding groups: with or without GOS supplementation (2.4 g/L). Growth, stool characteristics, and side effects were recorded in a 3-month-follow-up. Faecal samples were collected for analysis of intestinal bacteria (culture technique), acetic acid (gas chromatography) and pH (indicator strip) at postnatal 3 months. RESULTS: Compared with the formula-feeding group without GOS, the contents of bifidobacteria, lactobacilli and acetic acid and stool frequency increased, and faecal pH decreased significantly in the GOS-formula-feeding and the human milk group. There were no significant differences between the GOS-formula-feeding and the human milk groups. Supplementation with GOS did not lead to an increase in the incidence of crying, regurgitation and vomiting. CONCLUSIONS: A supplementation of low levels of GOS in infant formula seemed to improve stool frequency, decrease faecal pH, and stimulate intestinal bifidobacteria and lactobacilli up to levels as found in breast-fed infants.

Palladium-catalyzed direct C(sp3)-H arylation of indole-3-ones with aryl halides: a novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones.

A novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones via palladium-catalyzed direct C(sp3)-H arylation of indole-3-ones with aryl halides has been developed. Various 2-monoarylated indole-3-ones were readily obtained with yields up to 95%. As a class of important nucleophilic intermediates, 2-monoarylated indole-3-ones can be used for the construction of C2-quaternary indolin-3-one skeletons.

Design, synthesis, and biological evaluation of chrysin derivatives as potential FabH inhibitors.

New series of chrysin derivatives (4a-4t) were designed and synthesized by introducing different substituted piperazines at C-7 position. Their inhibitory effects on FabH were evaluated using two Gram-negative bacterial strains, Escherichia coli and Pseudomonas aeruginosa, and two Gram-positive bacterial strains, Bacillus subtilis and Staphylococcus aureus. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with the control positive drugs. Among them, compound 4s exhibited the most potent inhibitory activity with IC50 values of 5.78 ± 0.24 µm inhibiting E. coli FabH and potent antibacterial activity against S. aureus and E. coli with MIC of 1.25 ± 0.01, 1.15 ± 0.12 µg/mL, respectively, comparing to the control positive drugs penicillin G (7.56 ± 0.30 µm). Docking simulation was performed to position compound 4s into the FabH active site, and the result showed that compound 4s could bind well with the FabH as potent FabH inhibitor.