Regulation of VEGF gene expression by bisacridine derivative through promoter i-motif for cancer treatment.

BACKGROUND: Vascular endothelial growth factor (VEGF) is overexpressed in most malignant tumors, which has important impact on tumor angiogenesis and development. Its gene promoter i-motif structure formed by C-rich sequence can regulate gene expression, which is a promising new target for anti-tumor therapy. METHODS: We screened various compounds and studied their effects on VEGF through extensive experiments, including SPR, MST, TO displacement, FRET, CD, ESI-MS, NMR, MTT, clone formation, qPCR, Western blot, dual-luciferase reporter assay, immunofluorescence, cell scrape, apoptosis, transwell assay, and animal model. RESULTS: After extensive screening, bisacridine derivative B09 was found to have selective binding and stabilization to VEGF promoter i-motif, which could down-regulate VEGF gene expression. B09 showed potent inhibition on MCF-7 and HGC-27 cell proliferation and metastasis. B09 significantly inhibited tumor growth in xenograft mice model with HGC-27 cells, showing decreased VEGF expression analyzed through immunohistochemistry. CONCLUSION: B09 could specifically regulate VEGF gene expression, possibly through interacting with promoter i-motif structure. As a lead compound, B09 could be further developed for innovative anti-cancer agent targeting VEGF.

Life-Course Health Risk Assessment of PM2.5 Elements in China: Exposure Disparities by Species, Source, Age, Gender, and Location.

Key stages in people's lives have particular relevance for their health; the life-course approach stresses the importance of these stages. Here, we applied a life-course approach to analyze the health risks associated with PM2.5-bound elements, which were measured at three sites with varying environmental conditions in eastern China. Road traffic was found to be the primary source of PM2.5-bound elements at all three locations, but coal combustion was identified as the most important factor to induce both cancer risk (CR) and noncancer risk (NCR) across all age groups due to the higher toxicity of elements such as As and Pb associated with coal. Nearly half of NCR and over 90% of CR occurred in childhood (1-6 years) and adulthood (>18 years), respectively, and females have slightly higher NCR and lower CR than males. Rural population is found to be subject to the highest health risks. Synthesizing previous relevant studies and nationwide PM2.5 concentration measurements, we reveal ubiquitous and large urban-rural environmental exposure disparities over China.

Syntheses and evaluation of acridone derivatives as anticancer agents targeting Kras promoter i-motif structure.

Two series of novel acridone derivatives were designed and synthesized, with their anticancer activity evaluated. Most of these compounds showed potent antiproliferative activity against cancer cell lines. Among them, compound C4 with dual 1,2,3-triazol moieties exhibited the most potent activity against Hep-G2 cells with IC50 value determined to be 6.29 ± 0.93 µM. Subsequent experiments showed that C4 could bind to and destabilize Kras gene promoter i-motif structure without significant interaction with its corresponding G-quadruplex. C4 could down-regulate Kras expression in Hep-G2 cells, possibly due to its interaction with the Kras i-motif. Further cellular studies indicated that C4 could induce apoptosis of Hep-G2 cells, possibly related to its effect on mitochondrial dysfunction. These results indicated that C4 could be further developed as a promising anticancer agent.

Regulation of c-Kit gene transcription selectively by bisacridine derivative through promoter dual i-motif structures.

BACKGROUND: c-Kit protein is a signal transduction protein involved in multiple signal pathways, which play an important role in a variety of cellular events such as cell proliferation, apoptosis and differentiation. Special DNA secondary structures on the promoter of c-Kit gene, including G-quadruplex and i-motif structures, could act as "molecular switch" for gene transcriptional regulation, which are potentially important target for development of new anti-cancer drugs. METHODS: We screened and evaluated the effect of compounds on c-Kit through several experiments, including SPR, FRET, CD, MST, NMR, dual-luciferase reporter assay, Western blot, qPCR, immunofluorescence, MTT assay, colony formation, cell scrape, cell apoptosis, cell cycle analysis, and transwell assay. RESULTS: After extensive screening, we found that bisacridine derivative B05 had selective binding and stabilization to dual i-motif structures on c-Kit gene promoter, which could down-regulate c-Kit gene transcription and translation, resulting in inhibition of cell proliferation and metastasis. B05 exhibited potent anti-tumor activity on HGC-27 cells, and strongly suppressed tumor growth in HGC-27 xenograft mice model. CONCLUSIONS: B05 could interact with c-Kit promoter dual i-motif structures with excellent selectivity, which make it possible for selective regulation of gene transcription and translation. B05 could be further developed for selective anti-cancer agent targeting c-Kit promoter i-motifs. GENERAL SIGNIFICANCE: i-Motifs on different proto-oncogene promoters are diversified, and especially binding of dual i-motifs on the same promoter simultaneously could significantly down-regulate gene transcription with decreased dosage, and therefore increasing the selectivity. This new strategy shed bight light on development of selective DNA-targeting ligands.

Functionalised penetrating peptide-chondroitin sulphate­gold nanoparticles: Synthesis, characterization, and applications as an anti-Alzheimer's disease drug.

The purpose of this study was to construct a transmembrane peptide-chondroitin sulphate­gold nanoparticle (TAT-CS@Au) delivery system and investigate its activity as an anti-Alzheimer's disease (AD) drug. We successfully prepared TAT-CS@Au nanoparticles, investigated their anti-AD effects, and explored the possible mechanisms in in vitro models. TAT-CS@Au exhibited excellent cellular uptake and transport capacity, effectively inhibited the accumulation of Aß1-40, and significantly reduced Aß1-40-induced apoptosis in SH-SY5Y cells. Furthermore, TAT-CS@Au significantly reduced oxidative stress damage and cholinergic injury induced by Aß1-40 by regulating intracellular concentrations of reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and acetylcholine (ACh). Western blotting results demonstrated that TAT-CS@Au inhibited aberrant tau phosphorylation (Ser199, Thr205, Ser404, and Ser396) through GSK3ß inactivation. TAT-CS@Au decreased the levels of inflammatory factors, specifically TNF-α, IL-6, and IL-1ß, by inhibiting NF-κB nuclear translocation by activating MAPK signalling pathways. Overall, these results indicate that TAT-CS@Au exhibits excellent transmembrane ability, inhibits Aß1-40 accumulation, antagonises oxidative stress, reduces aberrant tau phosphorylation, and suppresses the expression of inflammatory factors. TAT-CS@Au may be a multi-target anti-AD drug with good cell permeability, providing new insights into the design and research of anti-AD therapeutics.

Impacts of springtime biomass burning in Southeast Asia on atmospheric carbonaceous components over the Beibu Gulf in China: Insights from aircraft observations.

Limited by the scarcity of in situ vertical observation data, the influences of biomass burning in Southeast Asia on major atmospheric carbonaceous compositions in downwind regions have not been thoroughly studied. In this study, aircraft observations were performed to obtain high time-resolved in situ vertical distributions of black carbon (BC) as well as carbon monoxide (CO) and carbon dioxide (CO2). Four types of profiles were revealed: Mode I (from 2000 to 3000 m, the BC, CO and CO2 concentrations were enhanced), Mode II (with increasing altitude, the BC, CO and CO2 concentrations almost decreased), Mode III (inhomogeneous vertical BC, CO and CO2 profiles with BC peaks were observed from 2500 to 3000 m) and Mode IV (the BC, CO and CO2 concentrations increased above 1500 m). Furthermore, simulations were conducted to calculate radiative forcing (RF) caused by BC and study the heating rate (HR) of BC in combination with the vertical BC profiles. A larger BC distribution in the atmosphere resulted in a sharp RF change from negative to positive values, imposing a nonnegligible influence on the atmospheric temperature profile, with maximum HR values ranging from 0.4 to 5.8 K/day. The values of the absorption Ångström exponent (AAE) were 1.46 ± 0.11 and 1.48 ± 0.17 at altitudes from 1000 to 2000 and 2000-3000 m, respectively. The average BC light absorption coefficient at the 370 nm wavelength (α BC (370)) accounted for 50.3 %-76.8 % of the α (370), while the brown carbon (BrC) light absorption coefficient at the 370 nm wavelength (α BrC (370)) contributed 23.2 %-49.7 % to the α (370) at altitudes of 1000-2000 m. At altitudes of 2000-3000 m, α BC (370) and α BrC (370) contributed 43.8 %-88.2 % and 11.8 %-56.2 % to the α (370), respectively. These findings show that calculations that consider the surface BC concentration but ignore the vertical BC distribution could result in massive uncertainties in estimating the RF and HR caused by BC. This study helped achieve a deeper understanding of the influences of biomass burning over the region of Southeast Asia on the profiles of atmospheric carbonaceous compositions and atmospheric BC absorption and its warming effect.

Exploring the variation of black and brown carbon during COVID-19 lockdown in megacity Wuhan and its surrounding cities, China.

Absorbing carbonaceous aerosols, i.e. black and brown carbon (BC and BrC), affected heavily on climate change, regional air quality and human health. The nationwide lockdown measures in 2020 were performed to against the COVID-19 outbreak, which could provide an important opportunity to understand their variations on light absorption, concentrations, sources and formation mechanism of carbonaceous aerosols. The BC concentration in Wuhan megacity (WH) was 1.9 µg m-3 during lockdown, which was 24% lower than those in the medium-sized cities and 26% higher than those in small city; in addition, 39% and 16-23% reductions occurred compared with the same periods in 2019 in WH and other cities, respectively. Fossil fuels from vehicles and industries were the major contributors to BC; and compared with other periods, minimum contribution (64-86%) mainly from fossil fuel to BC occurred during the lockdown in all cities. Secondary BrC (BrCsec) played a major role in the BrC light absorption, accounting for 65-77% in WH during different periods. BrCsec was promoted under high humidity, and decreased through the photobleaching of chromophores under higher Ox. Generally, the lockdown measures reduced the BC concentrations significantly; however, the variation of BrCsec was slight.

An investigation into the impact of variations of ambient air pollution and meteorological factors on lung cancer mortality in Yangtze River Delta.

Lung cancer (LC) mortality, as one of the top cancer deaths in China, has been associated with increased levels of exposure to ambient air pollutants. In this study, different lag times on weekly basis were applied to study the association of air pollutants (PM2.5, PM10, and NO2) and LC mortality in Ningbo, and in subpopulations at different age groups and genders. Furthermore, seasonal variations of pollutant concentrations and meteorological variables (temperature, relative humidity, and wind speed) were analysed. A generalised additive model (GAM) using Poisson regression was employed to estimate the effect of single pollutant model on LC mortality in Yangtze River Delta using Ningbo as a case study. It was reported that there were statistically significant relationships between lung cancer mortality and air pollutants. Increases of 6.2% (95% confidence interval [CI]: 0.2% to 12.6%) and 4.3% (95% CI: 0.1% to 8.5%) weekly total LC mortality with a 3-week lag time were linked to each 10 µg/m3 increase of weekly average PM2.5 and PM10 respectively. The association of air pollutants (PM2.5, PM10 and NO2) and LC mortality with a 3-week lag time was also found statistically significant during periods of low temperature (T < 18 °C), low relative humidity (H < 73.7%) and low wind speed (u < 2.8 m/s), respectively. The female population was found to be more susceptible to the exposure to air pollution than the male population. In addition, the population with an age of 50 years or above was shown to be more sensitive to ambient air pollutant. These outcomes indicated that increased risk of lung cancer mortality was evidently linked to exposure to ambient air pollutant on a weekly basis. The impact of weekly variation on the LC mortality and air pollutant levels should be considered in air pollution-related health burden analysis.

Characteristics, sources, and health risks of PM2.5-bound trace elements in representative areas of Northern Zhejiang Province, China.

This study aimed to characterize PM2.5-bound trace elements in Northern Zhejiang Province (NZP), one of the most economically prosperous regions in China, and assess the associated health risks for the general populations. A year-long sampling campaign was conducted at four sites representative of urban, suburban, and rural areas of NZP. The average of the sum of twenty trace elements in PM2.5 was 2.8 ± 0.4 µg m-3, dominated by K, Al, Fe, Mg, Zn, and V (>100 ng m-3). The highest total elements' concentration occurred in winter, followed by autumn, spring, and summer. Enrichment factors and principal component analysis (PCA) revealed that the major sources of trace elements in NZP were fossil fuel combustion, biomass burning, crustal dust, traffic, and industrial emissions. Elevated concentrations of certain elements reflected featured sources in different areas, e.g., V and Ni from heavy oil combustion in the port city, and Cu, Fe and Ba from traffic emissions in urban areas. Arsenic (As) represented the major non-cancer risk driver as its hazard quotient was 8.7. The cumulative cancer risk from all the carcinogenic elements was 1.7 × 10-3 in NZP, exceeding the upper limit (10-4) of the acceptable risk range. As and Cr contributed 33% and 66%, respectively, and thus were regarded as cancer risk drivers. The high health risks from PM2.5-bound elements warrant future actions to control their emissions in this region. Priorities should target industrial operations and coal combustion emissions, as informed by the risk drivers.

Preparation and in vitro evaluation of multi-target-directed selenium-chondroitin sulfate nanoparticles in protecting against the Alzheimer's disease.

The purpose of this study was to ascertain the effect of selenium-chondroitin sulfate nanoparticles (CS@Se) on multi-target-directed therapy for the treatment of Alzheimer's disease (AD). CS@Se nanoparticles were successfully synthesized, and their therapeutic effects were studied in in vitro AD models. CS@Se effectively inhibited amyloid-ß (Aß) aggregation and protected SH-SY5Y cells from Aß1-42-induced cytotoxicity. Moreover, CS@Se significantly decreased okadaic acid-induced actin cytoskeleton instability in SH-SY5Y cells. In addition, CS@Se decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the levels of glutathione peroxidase (GSH-Px). The Western blot results indicated that CS@Se attenuated the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of GSK-3ß. In summary, this study demonstrated that CS@Se could inhibit the aggregation of Aß, reduce damage to the cytoskeleton, mitigate oxidative stress and attenuate the hyperphosphorylation of tau protein. CS@Se might be a potent multi-functional agent for the treatment of AD and thus warrants further research and evaluation.

Ambient volatile organic compounds in a suburban site between Beijing and Tianjin: Concentration levels, source apportionment and health risk assessment.

Volatile organic compounds (VOCs) have vital implications for secondary pollutants, atmospheric oxidation and human health. Ambient VOCs were investigated using an online system, gas chromatography-mass spectrometry/flame ionization detector (GC-MS/FID), at a suburban site in Xianghe in the North China Plain from 6 November 2017 to 29 January 2018. Positive matrix factorization (PMF) receptor model was applied to identify the major VOC contributing sources. Four-step health risk assessment method was used to estimate risks of all risk-posing VOC species. A total of 101 VOCs were quantified, and the mean concentration of total VOCs was 61.04 ±â€¯65.18 ppbv. The VOCs were dominated by alkanes (38.76%), followed by alkenes, aromatics, halocarbons, OVOCs, acetylene and acetonitrile. The results of PMF revealed that vehicle exhaust, industrial emissions, liquefied petroleum gas & natural gas, solvent utilization and secondary and long-lived species contributed 31.0%, 26.4%, 18.6%, 13.6% and 10.4%, respectively, to the total VOCs. Pollutant-specific and source-specific noncarcinogenic and carcinogenic risk estimates were conducted, which showed that acrolein and vehicle exhaust had evident noncarcinogenic risks of 4.9 and 0.9, respectively. The carcinogenic risks of specific species (1,3-butadiene, acetaldehyde, benzene, chloroform and 1,2-dichloroethane) and identified sources were above the United States Environmental Protection Agency (USEPA) acceptable level (1.0 × 10-6) but below the tolerable risk level (1.0 × 10-4). Vehicle exhaust was the largest contributor (56.2%) to noncarcinogenic risk, but solvent utilization (32.6%) to carcinogenic risk. Moreover, with the evolution of pollution levels, almost all VOC species, contributions of alkenes, aromatics, solvent utilization and vehicle exhaust, and pollutant-specific and source-specific risks increased continuously and noticeably. Collectively, our findings unraveled the importance of alkenes, aromatics, solvent utilization and vehicle exhaust in the evolution of pollution levels. Future studies should consider targeting these VOC groups and sources when focusing on effective reduction strategies and assessing public health risks.

Preparation, characterisation and in vitro and in vivo evaluation of CD44-targeted chondroitin sulphate-conjugated doxorubicin PLGA nanoparticles.

The purpose of this study was to ascertain the effect of chondroitin sulphate-modified doxorubicin (Dox) nanoparticles on enhancing the tumour-targeting effect and tumour growth inhibition effect of doxorubicin both in vitro and in vivo. The chondroitin sulphate-doxorubicin conjugate and its poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CS-Dox-PLGA) were successfully synthesised, and then characterized by Fourier-transform infrared spectroscopy (FTIR), proton magnetic resonance (1HNMR), thermogravimetric analysis/differential scanning calorimetry (TGA/DSC), transmission electron microscope (TEM), zeta potential and laser light scattering. Taking advantage of the enhanced permeability and CD44-mediated endocytosis, CS-Dox-PLGA showed excellent capacity for penetrating the peripheral tumour barrier and into the nucleus of tumour cells. The CS-Dox-PLGA cellular uptake was improved and exhibited a significantly higher level of cytotoxicity in U251 cells. After intravenous administration, the CS-Dox-PLGA showed good pharmacokinetic properties and excellent U251-induced tumour inhibition with low cardiac toxicity. Therefore, CS-Dox-PLGA with low cardiac toxicity and good anti-tumour ability might be a better choice for Dox in clinical practice.

Quantification of the impact of aerosol on broadband solar radiation in North China.

PM2.5 plays a key role in the solar radiation budget and air quality assessments, but observations and historical data are relatively rare for Beijing. Based on the synchronous monitoring of PM2.5 and broadband solar radiation (Rs), a logarithmic function was developed to describe the quantitative relationship between these parameters. This empirical parameterization was employed to calculate Rsn from PM2.5 with normalized mean bias (NMB) -0.09 and calculate PM2.5 concentration from Rsn with NMB -0.12. Our results indicate that this parameterization provides an efficient and straightforward method for estimating PM2.5 from Rs or Rs from PM2.5.

Characterization of black carbon in an urban-rural fringe area of Beijing.

Measuring black carbon (BC) is critical to understand the impact of combustion aerosols on air quality and climate change. In this study, BC was measured in 2014 at a unique community formed with rapid economic development and urbanization in an urban-rural fringe area of Beijing. Hourly BC concentrations were 0.1-33.5 µg/m3 with the annual average of 4.4 ± 3.7 µg/m3. BC concentrations had clear diurnal, weekly, and seasonal variations, and were closely related with atmospheric visibility. The absorption coefficient of aerosols increased while its contribution to extinction coefficient decreased with the enhancement of PM2.5 concentration. The high mass absorption efficiency (MAE) of EC was attributed to a combination of coal combustion, vehicular emission and rapidly coating by water-soluble ions and organic carbon (OC). BC concentrations followed a typical lognormal pattern, with over 88% samples in 0.1-10.0 µg/m3. Low BC levels were mostly bounded up with winds from north and northwest. Coal combustion and biomass burning were closely associated with severe haze pollution events. Firework discharge had significant UV absorption contribution. During the Asia-Pacific Economic Cooperation (APEC) forum in November 2014, air quality obviously improved due to various control strategies.

[Comparison of Monitoring Methods of Organic Carbon and Element Carbon in Atmospheric Fine Particles].

Accurate measurement of organic carbon (OC) and elemental carbon (EC) in atmospheric fine particulate is an important scientific basis for studying the formation and source apportionment of carbonaceous aerosol. The selection of different analysis programs will lead to difference in the OC and EC concentrations, and further result in the misjudgment of the results. The OC and EC concentrations observed using three temperature protocols including RT-Quartz ( R) , NIOSH 5040 (N) and Fast-TC (F) were compared and analyzed in combination with the degree of air pollution in Beijing. The results showed that there was no significant difference in the TC (TC = OC + EC), OC and EC concentrations observed using R, N and F protocols and certain deviation was found among the TC (TC = OC + EC) , OC and EC concentrations. For TC, the results observed using R protocol were 5% lower than those using N protocol; hut 1% higher than those using F protocol. For OC, the results obtained using R were 9% lower than those using N protocol and 1% higher than those using F protocol. For EC, the results obtained using R were 20% higher than those using N protocol and 11% lower than those using F protocol. The variation coefficients for TC, OC and EC obtained based on R protocol were less than the other two temperature protocols under different air quality degrees. The slopes of regression curves of TC, OC and EC between on-line analysis using R protocol and off-line analysis were 1.21,1. 14 and 1.35, respectively. The correlation coefficients of TC, OC and EC were 0.99, 0.99 and 0.98, respectively. In contrast with the Black carbon ( BC) concentrations monitored by multi-angle absorption spectrophotometer (MAAP), the EC concentrations measured by on-line OC/EC analyzer using R protocol were obviously lower. When the BC concentrations were less than or equal to 8 gg*m3, the EC/BC ratio was 0.39. While the EC/BC ratio was 0.88, when the BC concentrations were greater than 8 ggm3. The variation trends of EC and BC concentrations were similar, while systematic error existed between the results obtained using those two instruments.