Fluoride exposure confers NRF2 activation in hepatocyte through both canonical and non-canonical signaling pathways.

Due to the high abundance in the Earth's crust and industrial application, fluoride is widely present in our living environment. However, excessive fluoride exposure causes toxicity in different organs. As the most important detoxification and excretion organ, liver is more easily involved in fluoride toxicity than other organs, and oxidative stress is considered as the key mechanism related with fluoride hepatotoxicity. In this study, we mainly investigated the role of nuclear factor erythroid-derived 2-like 2 (NRF2, a core transcription factor in oxidative stress) in fluoride exposure-induced hepatotoxicity as well as the related mechanism. Herein, liver cells (BNL CL.2) were treated with fluoride in different concentrations. The hepatotoxicity and NRF2 signaling pathway were analyzed respectively. Our results indicated that excessive fluoride (over 1 mM) resulted in obvious toxicity in hepatocyte and activated NRF2 and NRF2 target genes. The increased ROS generation after fluoride exposure suppressed KEAP1-induced NRF2 ubiquitylation and degradation. Meanwhile, fluoride exposure also led to blockage of autophagic flux and upregulation of p62, which contributed to activation of NRF2 via competitive binding with KEAP1. Both pharmaceutical activation and genetic activation of NRF2 accelerated fluoride exposure-induced hepatotoxicity. Thus, the upregulation of NRF2 in hepatocyte after fluoride exposure can be regarded as a cellular self-defense, and NRF2-KEAP1 system could be a novel molecular target against fluoride exposure-induced hepatotoxicity.

Effect of long-term nursing intervention on quality of life and social support of patients with coronary heart disease after percutaneous coronary intervention.

OBJECTIVE: To assess the effect of long-term nursing intervention on the quality of life and social support of patients after percutaneous coronary intervention (PCI). METHODS: A randomised controlled trial was designed. A total of 60 patients with coronary heart disease treated with PCI were randomly divided into the control group and the intervention group. The patients in the control group received routine nursing care, while the patients in the intervention group received long-term nursing intervention. The Simplified Quality of Life Scale-Quality of Life Scale, the Coronary Heart Disease Self-Management Scale, and the Social Support Rating Scale were used to collect and analyse the data. RESULTS: After the intervention, the scores for quality of life, social support and self-management in the intervention group were higher than those in the control group, and the differences were statistically significant (p < 0.05). CONCLUSION: Long-term nursing intervention can improve the quality of life and sense of social support of patients with coronary heart disease after PCI.

Comparative genomic characterization of multidrug-resistant Citrobacter spp. strains in Fennec fox imported to China.

BACKGROUND: To investigate the antimicrobial profiles and genomic characteristics of MDR-Citrobacter spp. strains isolated from Fennec fox imported from Sudan to China. METHODS: Four Citrobacter spp. strains were isolated from stool samples. Individual fresh stool samples were collected and subsequently diluted in phosphate buffered saline as described previously. The diluted fecal samples were plated on MacConkey agar supplemented with 1 mg/l cefotaxime and incubated for 20 h at 37 °C. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) was used for identification. Antimicrobial susceptibility testing was performed using the broth microdilution method. Whole-genome sequencing was performed on an Illumina Novaseq-6000 platform. Acquired antimicrobial resistance genes and plasmid replicons were detected using ResFinder 4.1 and PlasmidFinder 1.3, respectively. Comparative genomic analysis of 277 Citrobacter genomes was also performed. RESULTS: Isolate FF141 was identified as Citrobacter cronae while isolate FF371, isolate FF414, and isolate FF423 were identified as Citrobacter braakii. Of these, three C. braakii isolates were further confirmed to be extended-spectrum ß-lactamases (ESBL)-producer. All isolates are all multidrug resistance (MDR) with resistance to multiple antimicrobials. Plasmid of pKPC-CAV1321 belong to incompatibility (Inc) group. Comparative genomics analysis of Citrobacter isolates generated a large core-genome. Genetic diversity was observed in our bacterial collection, which clustered into five main clades. Human, environmental and animal Citrobacter isolates were distributed into five clusters. CONCLUSIONS: To our knowledge, this is the first investigation of MDR-Citrobacter from Fennec Fox. Our phenotypic and genomic data further underscore the threat of increased ESBL prevalence in wildlife and emphasize that increased effort should be committed to monitoring the potentially rapid dissemination of ESBL-producers with one health perspective.

Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro.

After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential antiviral agents. SARS-CoV-2 3CLpro is essential for processing the viral polyproteins into mature non-structural proteins, making it an attractive target for developing antiviral agents. Here we show that Vitamin K3 screened from the FDA-Approved Drug Library containing an array of 1,018 compounds has potent inhibitory activity against SARS-CoV-2 3CLpro with the IC50 value of 4.78 ± 1.03 µM, rather than Vitamin K1, K2 and K4. Next, the time-dependent inhibitory experiment was carried out to confirm that Vitamin K3 could form the covalent bond with SARS-CoV-2 3CLpro. Then we analyzed the structure-activity relationship of Vitamin K3 analogues and identified 5,8-dihydroxy-1,4-naphthoquinone with 9.8 times higher inhibitory activity than Vitamin K3. Further mass spectrometric analysis and molecular docking study verified the covalent binding between Vitamin K3 or 5,8-dihydroxy-1,4-naphthoquinone and SARS-CoV-2 3CLpro. Thus, our findings provide valuable information for further optimization and design of novel inhibitors based on Vitamin K3 and its analogues, which may have the potential to fight against SARS-CoV-2.

Design, Synthesis, and Structure-Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase.

Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC50 =0.30 µM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R1 ) and hydrophobic interactions of phenyl moiety (R3 ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolones-type PL inhibitors for biomedical applications.

Discovery of natural alkaloids as potent and selective inhibitors against human carboxylesterase 2.

Human Carboxylesterase 2A (hCES2A), one of the most important serine hydrolases, plays crucial roles in the hydrolysis and the metabolic activation of a wide range of esters and amides. Increasing evidence has indicated that potent inhibition on intestinal hCES2A may reduce the excessive accumulation of SN-38 (the hydrolytic metabolite of irinotecan with potent cytotoxicity) in the intestinal tract and thereby alleviate the intestinal toxicity triggered by irinotecan. In this study, more than sixty natural alkaloids have been collected and their inhibitory effects against hCES2A are assayed using a fluorescence-based biochemical assay. Following preliminary screening, seventeen alkaloids are found with strong to moderate hCES2A inhibition activity. Primary structure-activity relationships (SAR) analysis of natural isoquinoline alkaloids reveal that the benzo-1,3-dioxole group and the aromatic pyridine structure are beneficial for hCES2A inhibition. Further investigations demonstrate that a steroidal alkaloid reserpine exhibits strong hCES2A inhibition activity (IC50 = 0.94 µM) and high selectivity over other human serine hydrolases including hCES1A, dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE) and thrombin. Inhibition kinetic analyses demonstrated that reserpine acts as a non-competitive inhibitor against hCES2A-mediated FD hydrolysis. Molecular docking simulations demonstrated that the potent inhibition of hCES2A by reserpine could partially be attributed to its strong σ-π and S-π interactions between reserpine and hCES2A. Collectively, our findings suggest that reserpine is a potent and highly selective inhibitor of hCES2A, which can be served as a promising lead compound for the development of more efficacious and selective alkaloids-type hCES2A inhibitors for biomedical applications.

The removal of uranium using novel temperature sensitive urea-formaldehyde resin: adsorption and fast regeneration.

A novel adsorbent of temperature sensitive urea-formaldehyde (TS-UF) resin was synthesized by base/acid two-step synthetic strategy with low formaldehyde/urea mole ratio of 0.8. The sorption kinetics of TS-UF resin obeys the pseudo-second-order model, and the adsorption is an endothermic process. The Langmuir model can well describe the sorption isotherms, through which the Qmax is calculated to be 99.2 mg/g for uranium (VI) at pH 6.0 and T = 298 K. The characterized results show that the functional groups -NH- and -CH2OH in TS-UF resin have been involved in uranium sorption via chemical interaction. The temperature sensitive property of TS-UF resin significantly accelerates the regeneration of TS-UF resin, which can be fast regenerated within 15 min at its low critical solution temperature 333 K and exhibits high removal efficiency of uranium (VI) (>90%) over 5 cycles. Therefore, TS-UF resin can be as a promising sorbent for the uranium (VI) removal from wastewater due to its low-cost, easy-fabrication, high-efficiency and fast regeneration. This work can not only boost the exploration of novel adsorbent materials, but also promote the investigations of the regeneration and reusability of adsorbents.

[Occurrence Characteristics and Health Risks of PAHs on the Surface of Buildings and Devices in the Coking Plant].

The occurrence characteristics of polycyclic aromatic hydrocarbons (PAHs) on the surfaces of buildings and devices in a typical coking plant were analyzed with the samples from different functional zones and materials. The health risk of PAHs was also evaluated. The results showed that PAHs concentrations ranged from 8.00×10-2-1.98×102 µg·dm-2, and 22.0% wiping samples exceeded the World Trade Center Task Group(WTCTG)standard (1.45 µg·dm-2), the highest rate beyond the standard in the samples was 135. The functional zones with the high PAHs concentration were mainly located in the coking and refinery zone. The PAHs concentration on the surfaces of buildings in the coking zone was 12.1 µg·dm-2, which was the highest in all functional zones. Among the surface materials, the antirust paint contained the highest concentrations of PAHs and were over the standard rate, whereas the glass had the lowest adsorption ability for PAHs. The US Superfund Risk Assessment Method was used to evaluate the health risk of PAHs. The evaluation results showed that PAHs in the coking and refinery zones were a risk for carcinogenicity, the total carcinogenic risk value to the exposed population (3.78×10-6-1.32×10-5) was higher than the lower limit of the US EPA standard (10-6). The results could provide the scientific basis for environmental management and remediation of contaminated sites.

Sensitive detection of polycyclic aromatic hydrocarbons with gold colloid coupled chloride ion SERS sensor.

A simple surface-enhanced Raman spectroscopy (SERS) sensor based on an undecorated gold-colloid substrate was developed for the rapid and effective detection of polycyclic aromatic hydrocarbons (PAH). The SERS enhancement of the bare Au nanoparticles for PAH was achieved by adjusting chemical reduction conditions and Cl- content. The strongest SERS response of this system was achieved with 2.0 mL of trisodium citrate (1%) and 80 µL of NaCl (1 M). With this simple SERS sensor, qualitative and quantitative determination of trace-level naphthalene (NaP), phenanthrene (PHE) and pyrene (PYR) were achieved using a portable Raman spectrometer at detection limits of 1.38 µg L-1, 0.23 µg L-1, and 0.45 µg L-1, respectively. Plots of SERS intensity vs. PAH concentrations were linear, with correlation coefficients (R2) ranging from 0.8729 to 0.9994. More importantly, the SERS sensor was able to accurately identify each PAH in complex mixtures. This SERS technique shows great promise for the rapid and direct detection of aromatic hydrocarbons organic pollutants in field.

Catalyst-free visible-light-induced condensation to synthesize bis(indolyl)methanes and biological activity evaluation of them as potent human carboxylesterase 2 inhibitors.

A mild strategy for visible-light-induced synthesis of bis(indolyl)methanes was developed using aromatic aldehydes and indole as substrates. This reaction could be performed at room temperature under catalyst- and additive-free conditions to synthesize a series of bis(indolyl)methanes in good to excellent yields. In addition, all synthesized bis(indolyl)methanes together with ß-substituted indole derivatives synthesized according to our previous work, were evaluated for their inhibitory effect against human carboxylesterase (CES1 and CES2). Primary structure-activity relationship analysis of all tested compounds showed that the modifications of ß-substituted indole at the ß-site with another indolyl group led to a significant enhancement of the inhibitory effect on CES2, and the bisindolyl structure is essential for CES2 inhibition. These results demonstrated that these bis(indolyl)methanes are potent and selective CES2 inhibitors, which might be helpful for medicinal chemists to design and develop more potent and selective CES2 inhibitors for biomedical applications.

Mathematical modeling identified c-FLIP as an apoptotic switch in death receptor induced apoptosis.

Apoptosis is an essential process to get rid of injured or unwanted cells. In this study, we proposed a mathematical modeling for death receptor mediated apoptosis to investigate the role of c-FLIP in controlling the balance between apoptosis and survival. In order to get insight into how NF-kappa B mediated pro-survival pathway affects the outcome of our modeling, we implemented reduced models without taking such regulation into consideration. Our simulation revealed that c-FLIP could act as a pivotal death or life switch and this switch-like behavior is bistable, irreversible, and robust. We introduce a new term, probability apoptosis, to delineate the likelihood in occurrence of apoptosis events. This simulation system is plausible and may offer several valuable clinical indications for the abnormal apoptosis related disease, such as cancer.