Synthesis and evaluation of pentacyclic triterpenoids conjugates as novel HBV entry inhibitors targeting NTCP receptor.

Chronic liver diseases caused by hepatitis B virus (HBV) are the accepted main cause leading to liver cirrhosis, hepatic fibrosis, and hepatic carcinoma. Sodium taurocholate cotransporting polypeptide (NTCP), a specific membrane receptor of hepatocytes for triggering HBV infection, is a promising target against HBV entry. In this study, pentacyclic triterpenoids (PTs) including glycyrrhetinic acid (GA), oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) were modified via molecular hybridization with podophyllotoxin respectively, and resulted in thirty-two novel conjugates. The anti-HBV activities of conjugates were evaluated in HepG2.2.15 cells. The results showed that 66% of the conjugates exhibited lower toxicity to the host cells and had significant inhibitory effects on the two HBV antigens, especially HBsAg. Notably, the compounds BA-PPT1, BA-PPT3, BA-PPT4, and UA-PPT3 not only inhibited the secretion of HBsAg but also suppressed HBV DNA replication. A significant difference in the binding of active conjugates to NTCP compared to the HBV PreS1 antigen was observed by SPR assays. The mechanism of action was found to be the competitive binding of these compounds to the NTCP 157-165 epitopes, blocking HBV entry into host cells. Molecular docking results indicated that BA-PPT3 interacted with the amino acid residues of the target protein mainly through π-cation, hydrogen bond and hydrophobic interaction, suggesting its potential as a promising HBV entry inhibitor targeting the NTCP receptor.

Acetylshikonin induces apoptosis through the endoplasmic reticulum stress-activated PERK/eIF2α /CHOP axis in oesophageal squamous cell carcinoma.

Acetylshikonin (AS) is an active component of Lithospermum erythrorhizon Sieb. et Zucc that exhibits activity against various cancers; however, the underlying mechanisms of AS against oesophageal squamous carcinoma (ESCC) need to be elusive. The research explores the anti-cancer role and potential mechanism of AS on ESCC in vitro and in vivo, providing evidences for AS treatment against ESCC. In this study, we firstly demonstrated that AS treatment effectively inhibits cell viability and proliferation of ESCC cells. In addition, AS significantly induces G1/S phage arrest and promotes apoptosis in ESCC cell lines. Further studies reveal that AS induces ER stress, as observed by dose- and time-dependently increased expression of BIP, PDI, PERK, phosphorylation of eIF2α , CHOP and splicing of XBP1. CHOP knockdown or PERK inhibition markedly rescue cell apoptosis induced by AS. Moreover, AS treatment significantly inhibits ESCC xenograft growth in nude mice. Elevated expression of BIP and CHOP is also observed in xenograft tumours. Taken together, AS inhibits proliferation and induces apoptosis through ER stress-activated PERK/eIF2α /CHOP pathway in ESCC, which indicates AS represents a promising candidate for ESCC treatment.

Observation of the validity of the upper lip bite test in predicting difficult intubation.

The upper lip bite test (ULBT) is considered an effective method for predicting difficult airways, but data on the ULBT for predicting difficult tracheal intubation are lacking. This study aimed to examine the clinical utility of the ULBT in predicting difficult endotracheal intubation. We conducted an observational case-cohort study of adult patients undergoing elective surgery and requiring endotracheal intubation for general anesthesia. Difficult airway assessment was performed on the recruited patients before the operation, including the ULBT, mouth opening, thyromental distance, modified Mallampati test, and body mass index. The primary outcome was the incidence of difficult tracheal intubation. The receiver operating characteristic curve analysis was used to compare the performance of variables in predicting difficult tracheal intubation. We successfully recruited 2522 patients for analysis and observed 64 patients with difficult tracheal intubation. When predicting difficult tracheal intubation, grade 2 ULBT had a sensitivity of 0.75 and a specificity of 0.54, and grade 3 had a sensitivity of 0.28 and a specificity of 0.75. Compared with mouth opening, the area under the receiver operating characteristic curve of the ULBT was lower in predicting difficult tracheal intubation (0.69 [95% confidence interval: 0.67-0.71] vs. 0.84 [95% confidence interval: 0.82-0.87], P < 0.05).Clinical Trials Registry: ChiCTR-ROC-16009050, principal investigator: Weidong Yao.

Development and validation of a screening method for difficult tracheal intubation based on geometric simulation and computer technology.

BACKGROUND: The anatomical characteristics of difficult airways can be analysed geometrically. This study aims to develop and validate a geometry-assisted difficult airway screening method (GADAS method) for difficult tracheal intubation. METHODS: In the GADAS method, a geometric simulated model was established based on computer graphics. According to the law of deformation of the upper airway on laryngoscopy, the expected visibility of the glottis was calculated to simulate the real visibility on laryngoscopy. Validation of the new method: Approved by the Ethics Committee of Yijishan Hospital of Wannan Medical College. Adult patients who needed tracheal intubation under general anaesthesia for elective surgery were enrolled. The data of patients were input into the computer software to calculate the expected visibility of the glottis. The results of tracheal intubation were recorded by anaesthesiologists. The primary observation outcome was the screening performance of the expected visibility of the glottis for difficult tracheal intubation. RESULTS: The geometric model and software of the GADAS method were successfully developed and are available for use. We successfully observed 2068 patients, of whom 56 patients had difficult intubation. The area under the receiver operating characteristic curve of low expected glottis visibility for predicting difficult laryngoscopy was 0.96 (95% confidence interval [CI]: 0.95-0.96). The sensitivity and specificity were 89.3% (95% CI: 78.1-96.0%) and 94.3% (95% CI: 93.2%-95.3), respectively. CONCLUSIONS: It is feasible to screen difficult-airway patients by applying computer techniques to simulate geometric changes in the upper airway.

The value of multiparameter combinations for predicting difficult airways by ultrasound.

BACKGROUND: Based on the upper airway anatomy and joint function parameters examined by ultrasound, a multiparameter ultrasound model for difficult airway assessment (ultrasound model) was established, and we evaluated its ability to predict difficult airways. METHODS: A prospective case-cohort study of difficult airway prediction in adult patients undergoing elective surgery with endotracheal intubation under general anesthesia, and ultrasound phantom examination for difficult airway assessment before anesthesia, including hyomental distance, tongue thickness, mandibular condylar mobility, mouth opening, thyromental distance, and modified Mallampati tests, was performed. Receiver operating characteristic (ROC) curve analysis was used to evaluate the effectiveness of the ultrasound model and conventional airway assessment methods in predicting difficult airways. RESULTS: We successfully enrolled 1000 patients, including 51 with difficult laryngoscopy (DL) and 26 with difficult tracheal intubation (DTI). The area under the ROC curve (AUC) for the ultrasound model to predict DL was 0.84 (95% confidence interval [CI]: 0.82-0.87), and the sensitivity and specificity were 0.75 (95% CI: 0.60-0.86) and 0.82 (95% CI: 0.79-0.84), respectively. The AUC for predicting DTI was 0.89 (95% CI: 0.87-0.91), and the sensitivity and specificity were 0.85 (95% CI: 0.65-0.96) and 0.81 (95% CI: 0.78-0.83), respectively. Compared with mouth opening, thyromental distance, and modified Mallampati tests, the ultrasound model predicted a greater AUC for DL (P < 0.05). Compared with mouth opening and modified Mallampati tests, the ultrasound model predicted a greater AUC for DTI (P < 0.05). CONCLUSIONS: The ultrasound model has good predictive performance for difficult airways. TRIAL REGISTRATION: This study is registered on chictr.org.cn (ChiCTR-ROC-17013258); principal investigator: Jianling Xu; registration date: 06/11/2017).

Predicting difficult intubation: the hyomental distance ultrasound evaluation is superior to the thyromental distance.

BACKGROUND: Hyomental distance (HMD), an anatomical feature of the upper airway, can be measured precisely by ultrasonography. But the sensitivity and specificity of HMD compared to thyromental distance (TMD) to predict difficult airways is still unknown. METHODS: A case-cohort study was conducted. The written informed consent was obtained. Elective surgery adult patients undergoing general anaesthesia and tracheal intubation were recruited. The other inclusion criteria were: no maxillofacial deformity, trauma, airway stenosis, known difficult airway. The exclusion criteria were: tracheal intubations or operations were canceled, or patients' data were missing. HMD ultrasound measurements of patients in a sniffing position and other usual airway evaluations were performed before general anaesthesia induction. The primary outcome was the intubation difficulty level. Predictive values were calculated. RESULTS: We successfully enrolled 2357 patients (62 difficult intubation patients) in the cohort study for analysis. The area under the receiver operating characteristic curve (AUC) of the HMD and TMD for predicting difficult intubation was 0.86 (95% CI, 0.84-0.87) and 0.77 (95% CI, 0.75-0.78) respectively (comparison: P < 0.001). With an optimal cut-off value of HMD ≤ 4.9 cm, we observed a sensitivity and specificity of 0.90 (95% CI, 0.80-0.96) and 0.73 (95% CI, 0.71-0.75). Meanwhile, with TMD ≤ 7.0 cm, the sensitivity and specificity were 0.77 (95% CI, 0.65-0.87) and 0.65 (95% CI, 0.63-0.67) respectively. CONCLUSION: In comparison to TMD, HMD measured by ultrasound was more sensitive in predicting difficult intubation.

Inhibition of BRD4 triggers cellular senescence through suppressing aurora kinases in oesophageal cancer cells.

Oesophageal cancer is one of the most frequent solid malignancies and the leading cause of cancer-related death around the world. It is urgent to develop novel therapy strategies to improve patient outcomes. Acetylation modification of histones has been extensively studied in epigenetics. BRD4, a reader of acetylated histone and non-histone proteins, has involved in tumorigenesis. It has emerged as a promising target for cancer therapy. BRD4 inhibitors, such as JQ1, have exerted efficacious anti-proliferation activities in diverse cancers. However, the effects of JQ1 on oesophageal cancer are still not fully described. Here, we demonstrate that JQ1 suppresses cell growth and triggers cellular senescence in KYSE450 cells. Mechanistically, JQ1 up-regulates p21 level and decreases cyclin D1 resulting in G1 cycle arrest. The inhibitory effects of JQ1 on KYSE450 cells are independent on apoptosis. It activates cellular senescence by increasing SA-ß-gal activity. BRD4 knockdown by shRNA recapitulates cellular senescence. We also display that administration of JQ1 decreases recruitment of BRD4 on the promoter of aurora kinases A and B. Inhibitors targeting at AURKA/B phenocopy JQ1 treatment in KYSE450 cells. These results identify a novel action manner of BRD4 in oesophageal cancer, which strengthens JQ1 as a candidate drug in oesophageal cancer chemotherapy.

Relationship between polycyclic aromatic hydrocarbons and rheumatoid arthritis in US general population, NHANES 2003-2012.

The purpose of this study was to explore the association between urinary concentrations of polycyclic aromatic hydrocarbon (PAH) metabolites and the prevalence of rheumatoid arthritis (RA). Cross-sectional data were analyzed from the National Health and Nutrition Examination Survey (NHANES) 2003-2012 using levels of nine monohydroxylated urinary PAH metabolites as exposure. Multivariable logistic regression was used to examine the association between urinary biomarkers of PAHs and RA. All of the models were adjusted for age, sex, race, education level, marital status, smoking, BMI, physical activity, energy, diabetes, and survey cycle. Ultimately, 6,072 adults (3,108 men and 2,964 women) 20 years of age or older were analyzed. In the quartile analyses, compared with the lowest quartile, increased RA prevalence was observed in the participants with the highest quartile of 2-hydroxynapthalene (OR = 1.89, 95% CI = 1.28-2.78), 3-hydroxyfluorene (OR = 1.55, 95% CI = 1.07-2.25), 2-hydroxyfluorene (OR = 1.51, 95% CI = 1.02-2.24), 3-hydroxyphenanthrene (OR = 1.50, 95% CI = 1.09-2.07), and 9-hydroxyfluorene (OR = 1.60, 95% CI = 1.10-2.33) in a fully adjusted model, respectively. In the subgroup analysis of current smokers, compared with the participants with lower urinary PAH scores, those with higher scores had a dramatically increased prevalence of RA (OR = 15.46, 95% CI = 3.11-76.75) in the adjusted model. There was a significant interaction between all of the urinary PAH metabolite levels and smoking status in the relationship with RA (P < 0.05). High levels of urinary PAH metabolites are positively associated with RA prevalence in the US general population. PAH exposure and smoking may potentially interact to increase the prevalence of RA. Further prospective studies are needed to clarify the possible effect of PAHs on RA.

Distribution, sources and health risk assessment of contaminations in water of urban park: A case study in Northeast China.

This case study was performed to determine whether the pollutants in water of urban park could bring health risk to human engaging in water-related activities such as swimming and provide evidence demonstrating the critical need for strengthened recreational water resources management of urban park. TN, NH4+-N, TP, Cu, Mn, Zn, Se, Pb, As, Cd and Cr(VI) contents were determined to describe the spatial distribution of contaminations; sources apportionment with the method of correlation analysis, factor analysis and cluster analysis were followed by health risk assessment for swimmers of different age groups. The results reveal that element contents in all sites do not exceed Chinese standard for swimming area and European Commission standard for surface water; all detected elements except Cr(VI) have a tendency to accumulate in the location of lake crossing bridge; Mn and Zn are considered to have the same pollution source including geogenic and anthropogenic sources by multivariable analysis. Carcinogenic risks of different age groups descend in the same order with non-carcinogenic risks. Among all elements, Zn and Mn contribute the lowest non-carcinogenic risk (5.1940E-06) and the highest non-carcinogenic risk (7.9921E-04) through skin contact pathway, respectively. The total average personal risk for swimmers in swimming area is 1.9693E-03, and this site is not suitable for swimming. Overall, it is possible that swimmers are exposed to risk via the dermal route when carrying out water-related activities, it is recommended that necessary precautions and management should be taken in other similar locations around the world.

Ecological risk assessment of heavy metals in soils surrounding oil waste disposal areas.

More attention is being devoted to heavy metal pollution because heavy metals can concentrate in higher animals through the food chain, harm human health and threaten the stability of the ecological environment. In this study, the effects of heavy metals (Cu, Cr, Zn, Pb, Cd, Ni and Hg) emanating from oil waste disposal on surrounding soil in Jilin Province, China, were investigated. A potential ecological risk index was used to evaluate the damage of heavy metals and concluded that the degree of potential ecological damage of heavy metals can be ranked as follows: Hg > Cd > Pb > Cu > Ni > Cr > Zn. The average value of the potential ecological harm index (Ri) is 71.93, thereby indicating light pollution. In addition, this study researched the spatial distribution of soil heavy metals by means of ArcGIS (geographic information system) spatial analysis software. The results showed that the potential ecological risk index (R) of the large value was close to the distance from the oil waste disposal area; it is relatively between the degree of heavy metals in soil and the distance from the waste disposal area.

Effects and risk evaluation of oil spillage in the sea areas of Changxing Island.

This paper evaluated the oil spillage risk in the waters near the island of Changxing in Dalian (China) based on the established risk assessment index. Four wind regimes (windless, northerly wind, westerly wind and southerly wind) were selected as weather conditions for the dynamic prediction of oil drift. If an oil spill occurs near the Koumen (a place near the island of Changxing), the forecast and evaluation are conducted based on a three-dimensional mathematical model of oil spillage, and the results obtained show the scope of the affected area when winds from various directions are applied. The oil spillage would, under various conditions, flow into the northern and western sea area of Changxing Island Bay, namely the Dalian harbor seal National Nature Reserve, and create adverse effects on the marine ecological environment. The rationality of combining the established oil spillage risk comprehensive index system with model prediction is further confirmed. Finally, preventive measures and quick fixes are presented in the case of accidental oil spillages. The most effective method to reduce environment risk is to adopt reasonable preventive measures and quick fixes.

Blood lead and cadmium levels in children: A study conducted in Changchun, Jilin Province, China.

OBJECTIVES: Exposure to lead and cadmium in developing countries is considered to be a public health emergency. The present study was designed to investigate children's exposure to lead and cadmium in Changchun, China. METHODS: A total of 1619 blood samples were collected at random from 1426 children between one and 14 years of age, and 204 adults from Changchun, China. Blood lead and cadmium levels were determined using atomic absorption spectrophotometry. RESULTS: The average blood lead level in children was 60.29 µg/L, with boys exhibiting higher blood lead levels than girls. The average blood cadmium level in children was 1.26 µg/L, and differences were not observed between boys and girls. CONCLUSIONS: Children from Changchun exhibited relatively low blood lead and cadmium levels compared with children from other cities, and higher lead and lower cadmium levels than adults. This may be related to leaded gasoline environmental pollution and children's hand-to-mouth activities.

OBJECTIFS: L'exposition au plomb et au cadmium est considérée comme une urgence de santé publique dans les pays en développement. La présente étude était conçue pour examiner l'exposition des enfants de Changchun, en Chine, au plomb et au cadmium. MÉTHODOLOGIE: Les chercheurs ont colligé au hasard un total de 1 619 prélèvements de sang auprès de 1 426 enfants de un à 14 ans et de 204 adultes de Changchun, en Chine. Ils ont déterminé leur taux de plomb et de cadmium dans le sang au moyen de la spectrophotométrie d'absorption atomique. RÉSULTATS: La plombémie moyenne des enfants s'élevait à 60,29 µg/L et était plus élevée chez les garçons que chez les filles. Le taux moyen de cadmium dans le sang des enfants s'élevait à 1,26 µg/L et n'était pas différent entre les garçons et les filles. CONCLUSIONS: Les enfants de Changchun présentaient un taux relativement faible de plomb et de cadmium dans le sang par rapport aux enfants d'autres villes, et un taux plus élevé de plomb et plus faible de cadmium que les adultes. Ce phénomène peut être lié à la pollution environnementale par l'essence au plomb et au fait que les enfants portent beaucoup leurs mains à leur bouche.