In this study, a series of 4,5-bis(substituted phenyl)-4H-1,2,4-triazol-3-amine compounds was designed, synthesised, and evaluated to determine their potential as anti-lung cancer agents. According ...to the results of screening of lung cancer cell lines A549, NCI-H460, and NCI-H23 in vitro, most of the synthesised compounds have potent cytotoxic activities with IC
50
values ranging from 1.02 to 48.01 µM. Particularly, compound 4,5-bis(4-chlorophenyl)-4H-1,2,4-triazol-3-amine (BCTA) was the most potent anti-cancer agent, with IC
50
values of 1.09, 2.01, and 3.28 µM against A549, NCI-H460, and NCI-H23 cells, respectively, meaning many-fold stronger anti-lung cancer activity than that of the chemotherapeutic agent 5-fluorouracil. We also explored the effects of BCTA on apoptosis in lung cancer cells by flow cytometry and western blotting. Our results indicated that BCTA induced apoptosis by upregulating proteins BAX, caspase 3, and PARP. Thus, the potential application of compound BCTA as a drug should be further examined.
An outstanding compound BCTA (4,5-bis(4-chlorphenyl)-4H-1,2,4-triazol-3-amine) was found to possess more potent anticancer activity against several lung cancer cells than the reference drugs 5-FU. The effects of BCTA on apoptosis and necrosis in A549 cells were analysed by Hoechst/propidium iodide (PI) double staining and early and late apoptosis were analysed by Annexin V/PI flow cytometry. Further Western bloting results revealed that BCTA could induce cell apoptosis by down-regulting Bcl-2 protein.
Hepatocellular carcinoma (HCC) generally arises from a background of liver cirrhosis (LC). Patients with cirrhosis and suspected HCC are recommended to undergo serum biomarker tests and imaging ...diagnostic evaluation. However, the performance of routine diagnostic methods in detecting early HCC remains unpromising.
Here, we conducted a large-scale, multicenter study of 1675 participants including 490 healthy controls, 577 LC patients, and 608 HCC patients from nine clinical centers across nine provinces of China, profiled gene mutation signatures of cell-free DNA (cfDNA) using Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) through detecting 931 mutation sites across 21 genes.
An integrated diagnostic model called "Combined method" was developed by combining three mutation sites and three serum biomarkers. Combined method outperformed AFP in the diagnosis of HCC, especially early HCC, with sensitivities of 81.25% for all stages and 66.67% for early HCC, respectively. Importantly, the integrated model exhibited high accuracy in differentiating AFP-negative, AFP-L3-negative, and PIVKA-II-negative HCCs from LCs.
•miR-1 suppresses the malignant properties of HCC in vitro and in vivo.•miR-1 and API-5 are inversely expressed in human primary HCC tissues.•miR-1 negatively regulates API-5 expression via binding ...to its 3′UTR.•miR-1 promotes apoptosis of hepatoma cells by directly targeting API-5.
Although microRNA-1 (miR-1) is a known liver cancer suppressor, the role of miR-1 in apoptosis of hepatoma cells has remained largely unknown. Our study shows that ectopic miR-1 overexpression induced apoptosis of liver hepatocellular carcinoma (HepG2) cells. Apoptosis inhibitor 5 (API-5) was found to be a potential regulator of miR-1 induced apoptosis, using a bioinformatics approach. Furthermore, an inverse relationship between miR-1 and API-5 expression was observed in human liver cancer tissues and adjacent normal liver tissues. Negative regulation of API-5 expression by miR-1 was demonstrated to promote apoptosis of HepG2 cells. Our study provides a novel regulatory mechanism of miR-1 in the apoptosis of hepatoma cells.
Smoking is a well-known risk factor of reproductive health. However, the effect of paternal smoking on fertility has been less extensively examined. We conducted a cross-sectional study in a ...mountainous area of South-West China to assess the effect of male smoking on couples' fertility. A total of 8200 couples aged 18-49 years in the study area were invited to participate in the study. An in-person interview was performed to collect demographic characteristics of the couples, and husbands' life style factors including smoking and drinking habits. Information on time to pregnancy (TTP) was collected retrospectively. Infertility was defined as failure to achieve clinical pregnancy after regular unprotected intercourse for ≥12 months. Logistic regression model was used to estimate the association between male smoking and infertility. A total of 7025 couples were included in the final analysis. After adjusting for potential confounders, the couples were more likely to suffer from infertility if the husbands smoked (adjusted odds ratio aOR =1.28, 95% CI: 1.08-1.52) before the first pregnancy. After the analyses were performed according to husbands' smoking duration, an increased risk started at a relatively longer smoking duration of 5-10 years (aOR = 1.58, 95% CI: 1.26-1.99) and a stronger association (aOR = 3.34, 95% CI: 2.45-4.56) was observed in the group of ≥10 years. Similar patterns were found for the number of cigarettes smoked per day and the total amount of cigarettes smoked. From our findings, we conclude that male smoking may have an adverse impact on couples' infertility.
We have previously observed that knockout of Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol transporter essential for intestinal cholesterol absorption, reduces the output of dry stool in mice. As ...the food intake remains unaltered in NPC1L1-knockout (L1-KO) mice, we hypothesized that NPC1L1 deficiency may alter the gut microbiome to reduce stool output. Consistently, here we demonstrate that the phyla of fecal microbiota differ substantially between L1-KO mice and their wild-type controls. Germ-free (GF) mice have reduced stool output. Inhibition of NPC1L1 by its inhibitor ezetimibe reduces stool output in specific pathogen-free (SPF), but not GF mice. In addition, we show that GF versus SPF mice have reduced intestinal absorption and increased fecal excretion of cholesterol, particularly after treatment with ezetimibe. This negative balance of cholesterol in GF mice is associated with reduced plasma and hepatic cholesterol, and likely caused by reduced expression of NPC1L1 and increased expression of ABCG5 and ABCG8 in small intestine. Expression levels of other genes in intestine and liver largely reflect a state of cholesterol depletion and a decrease in intestinal sensing of bile acids. Altogether, our findings reveal a broad role of microbiota in regulating whole-body cholesterol homeostasis and its response to a cholesterol-lowering drug, ezetimibe.
Considering the global issues of resource depletion and climate change, the need for sustainable development is more significant than ever. This study focuses on China and examines the complex ...dynamics of green growth and natural resource exploitation through the prism of intellectual property conflicts and prospects to strike a balance between sustainable development and economic growth from 2000 to 2020. Advanced econometric techniques are essential to this research, such as the Cross-sectional Augmented Dickey-Fuller (CADF) test, the Cross-sectional Im, Pesaran, and Shin (CIPS) test, and the Cross-sectionally Augmented Distributed Lag (CS-ARDL) model. The study clarifies how important it is for intellectual property rights to spur innovation in environmentally friendly resource extraction techniques. It also evaluates the impact of taxes on the energy sector on China's energy transition rate, weighing the need for economic growth against environmental protection. This study thoroughly explains the opportunities and challenges related to intellectual property in green growth. It also offers important insights and strategies for academics, industry stakeholders, and policymakers who navigate the intricate landscape of sustainable resource exploitation.
•This study focuses on China and examines the complex dynamics of green growth and natural resource.•The study clarifies how important it is for intellectual property rights to spur innovation.•This study thoroughly explains the opportunities and challenges related to intellectual property.
Asymmetric catalysis: A highly enantioselective and efficient procedure for the amino alcohol–zinc‐catalyzed addition of 1,3‐diynes to various aromatic, α,β‐unsaturated, and aliphatic aldehydes has ...been developed. The present catalytic system was successfully applied in the concise synthesis of natural products such as (S)‐strongylodiols A and B (see scheme).
Cell penetrating peptides (CPPs) are promising tools for transducing presynthesized therapeutic molecules which possess low membrane permeability. The poor efficiency of cellular uptake and ...unexpected cellular localization are still the main obstacles to the development of drug delivery by using CPPs. In this study, we investigated the effect of a penetration enhancer, dimethylsulfoxide (DMSO), on the penetrating efficiency of a synthetic TAT peptide or the TAT fusion protein. FITC-labeled TAT and TAT-GFP were added to 10% DMSO or 100
μM chloroquine pretreated cells, fluorescence uptake into culturing cells was observed using fluorescence microscopy, FACS or quantitatively analyzed by a fluorescence spectrum. 10% DMSO treatment markedly increased internalization of TAT into cells and appeared in a well-distributed pattern throughout the cytosol and nucleus without membrane perforating or detectable cytotoxicity, the enhancement effect by 10% DMSO was reduced by endocytosis inhibitors including ammonium chloride and sodium azide. 10% DMSO also enhanced TAT-Apoptin induced apoptosis of carcinoma cells. These findings implicated that DMSO can be a novel delivery enhancer appropriate for CPP penetration.
Addition of dimethylsulfoxide (DMSO) significantly enhances the internalization efficiency of arginine-rich cell penetrating peptides (CPPs) and fusion protein.
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Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains ...unpromising.
A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage Ⅰ cohort (510 HCCs and 2074 LCs) and Stage Ⅱ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage Ⅰ cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage Ⅱ cohort.
PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% 95% CI: 39.66%–62.84% at 95.53% 95% CI: 94.62%–96.38% specificity for PreCar Score; sensitivity of 23.68% 95% CI: 14.99%–35.07% at 99.37% 95% CI: 98.91%–99.64% specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening.
Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care.
A full list of funding bodies that contributed to this study can be found in Acknowledgments section.
Interception effects of an ecological ditch, used to control agricultural non-point source pollution in subtropical China, on nitrogen transport in surface runoff were studied by monthly measuring ...the runoff volume and concentrations of ammonium nitrogen (NH₄⁺-N), nitrate nitrogen (NO₃⁻-N) and total nitrogen (TN) at the ditch inlet and outlet from 2013 to 2014. In addition, differences of NH₄⁺-N, NO₃⁻-N and TN removal were compared between 2013 and 2014. The results showed that the study ecological ditch worked effectively in N removal with average NH₄⁺-N, NO₃⁻-N and TN removal rates of 77.8%, 58.3%, and 48.7%; and their interception rates were 38.4, 59.6, and 171.1 kg · a⁻¹, respectively. The average proportion of NH₄⁺-N and NO₃⁻-N in TN was 47.5% at inlet, and 33.6% at outlet, which was significantly lower than that at inlet (P < 0.01). All hydrophytes in the ecological ditch were replaced by Myriophyllum aquaticum in 2014, which led to the increased average NO₃⁻-N and TN removal rates of 30.5% and 18.2%, r
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