Identification and high-throughput quantification of baicalein and its metabolites in plasma and urine

Ethnopharmacological relevance: Scutellaria baicalensis Georgi. contains varieties of function compounds, and it has been used as traditional drug for centuries. Baicalein is the highest amount of flavonoid found in Scutellaria baicalensis Georgi., which exerts various pharmacological activities and might be a promising drug to treat COVID-19. Aim of the study: The present work aims to investigate the metabolism of baicalein in humans after oral administration, and study the pharmacokinetics of BA and its seven metabolites in plasma and urine. Materials and methods: The metabolism profiling and the identification of baicalein metabolites were performed on HPLC-Q-TOF. Then a column-switching method named MPX™-2 system was applied for the high-throughput quantificationof BA and seven metabolites. Results: Seven metabolites were identified using HPLC-Q-TOF, including sulfate, glucuronide, glucoside, and methyl-conjugated metabolites. Pharmacokinetic study found that BA was extensively metabolized in vivo, and only 5.65% of the drug remained intact in the circulatory system after single dosing. Baicalein-7-O-sulfate and baicalein-6-O-glucuronide-7-O-glucuronide were the most abundant metabolites. About 7.2% of the drug was excreted through urine and mostly was metabolites. Conclusion: Seven conjugated metabolites were identified in our assay. A high-throughput HPLC-MS/MS method using column switch was established for quantifying BA and its metabolites. The method has good sensitivity and reproducibility, and successfully applied for the clinical pharmacokinetic study of baicalein and identified metabolites. We expect that our results will provide a metabolic and pharmacokinetic foundation for the potential application of baicalein in medicine. © 2022

Enhanced sulfur in the upper troposphere and lower stratosphere in spring 2020

Sulfur compounds in the upper troposphere and lower stratosphere (UTLS) impact the atmosphere radiation budget, either directly as particles or indirectly as precursor gas for new particle formation. In situ measurements in the UTLS are rare but are important to better understand the impact of the sulfur budget on climate. The BLUESKY mission in May and June 2020 explored an unprecedented situation. (1) The UTLS experienced extraordinary dry conditions in spring 2020 over Europe, in comparison to previous years, and (2) the first lockdown of the COVID-19 pandemic caused major emission reductions from industry, ground, and airborne transportation. With the two research aircraft HALO and Falcon, 20 flights were conducted over central Europe and the North Atlantic to investigate the atmospheric composition with respect to trace gases, aerosol, and clouds. Here, we focus on measurements of sulfur dioxide (SO2) and particulate sulfate (SO42-) in the altitude range of 8 to 14.5 km which show unexpectedly enhanced mixing ratios of SO2 in the upper troposphere and of SO42- in the lowermost stratosphere. In the UT, we find SO2 mixing ratios of (0.07±0.01) ppb, caused by the remaining air traffic, and reduced SO2 sinks due to low OH and low cloud fractions and to a minor extent by uplift from boundary layer sources. Particulate sulfate showed elevated mixing ratios of up to 0.33 ppb in the LS. We suggest that the eruption of the volcano Raikoke in June 2019, which emitted about 1 Tg SO2 into the stratosphere in northern midlatitudes, caused these enhancements, in addition to Siberian and Canadian wildfires and other minor volcanic eruptions. Our measurements can help to test models and lead to new insights in the distribution of sulfur compounds in the UTLS, their sources, and sinks. Moreover, these results can contribute to improving simulations of the radiation budget in the UTLS with respect to sulfur effects.

Chemical characteristics and sources of PM2.5 in Hohhot, a semi-arid city in northern China: insight from the COVID-19 lockdown

A knowledge gap exists concerning how chemical composition and sources respond to implemented policy control measures for aerosols, particularly in a semi-arid region. To address this, a single year's offline measurement was conducted in Hohhot, a semi-arid city in northern China, to reveal the driving factors of severe air pollution in a semi-arid region and assess the impact of the COVID-19 lockdown measures on chemical characteristics and sources of PM2.5. Organic matter, mineral dust, sulfate and nitrate accounted for 31.5 %, 14.2 %, 13.4 % and 12.3 % of the total PM2.5 mass, respectively. Coal combustion, vehicular emission, crustal source and secondary inorganic aerosols were the main sources of PM2.5 in Hohhot, at 38.3 %, 35.0 %, 13.5 %, and 11.4 %, respectively. Due to the coupling effect of emission reduction and improved atmospheric conditions, the concentration of secondary inorganic components, organic matter and elemental carbon declined substantially from the pre-lockdown (pre-LD) period to the lockdown (LD) and post-lockdown (post-LD) periods. The source contribution of secondary inorganic aerosols increased (from 21.1 % to 37.8 %), whereas the contribution of vehicular emission reduced (from 35.5 % to 4.4 %) due to lockdown measures. The rapid generation of secondary inorganic components caused by unfavorable meteorological conditions during lockdown led to serious pollution. This study elucidates the complex relationship between air quality and environmental policy.

Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?

Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous viruses use heparan sulfates as receptors to infect cells; in this group are HSV, HPV, and SARS-CoV-2. Other viruses require the cell to express sialic acids, as is the case in influenza A viruses and adenoviruses. This review aims to present, in a general way, the participation of glycoconjugates in viral entry, and therapeutic strategies focused on inhibiting the interaction between the virus and the glycoconjugates. Interestingly, there are few studies that suggest the participation of both glycoconjugates in the viruses addressed here. Considering the biological redundancy that exists between heparan sulfates and sialic acids, we propose that it is important to jointly evaluate and design strategies that contemplate inhibiting the interactions of both glycoconjugates. This approach will allow identifying new receptors and lead to a deeper understanding of interspecies transmission.

PM10 variation, composition, and source analysis in Tuscany (Italy) following the COVID-19 lockdown restrictions

To control the spread of COVID-19, exceptional restrictive measures were taken in March 2020 that imposed a radical change on the lifestyle of millions of citizens around the world, albeit for a short period. The national lockdown, which lasted from 10 March to 18 May 2020 in Italy, was a unique opportunity to observe the variation in air quality in urban environments under conditions comprising almost total traffic restriction and a strong reduction in work activities. In this paper, the data from 17 urban monitoring sites in Tuscany are presented, and the PM and NO2 concentrations in the 2 months before the start of the lockdown and the 2 months after lockdown are compared with the corresponding months of the previous 3 years. The results show that the total loads of PM2.5 and PM10 (particulate matter with an aerodynamic diameter smaller than 2.5 and 10 µm, respectively) decreased, but they did not exhibit significant changes compared to previous years, whereas NO2 underwent a drastic reduction. For three of these sites, the chemical composition of the collected samples was measured using thermal–optical techniques, ion chromatography, and particle-induced X-ray emission analysis, and the application of multivariate positive matrix factorization analysis also allowed for PM10 source identification and apportionment. Using these analyses, it was possible to explain the low sensitivity of PM10 to the lockdown effects as being due to different, sometimes inverse, behaviors of the different sources that contribute to PM. The results clearly indicate a decline in pollution levels related to urban traffic and an increase in the concentration of sulfate for all sites during the lockdown period.

Measurement report: The importance of biomass burning in light extinction and direct radiative effect of urban aerosol during the COVID-19 lockdown in Xi'an, China

Due to the complexity of emission sources, a better understanding of aerosol optical properties is required to mitigate climate change in China. Here, an intensive real-time measurement campaign was conducted in an urban area of China before and during the COVID-19 lockdown in order to explore the impacts of anthropogenic activities on aerosol light extinction and the direct radiative effect (DRE). The mean light extinction coefficient (bext) decreased from 774.7 ± 298.1 Mm-1 during the normal period to 544.3 ± 179.4 Mm-1 during the lockdown period. A generalised additive model analysis indicated that the large decline in bext (29.7 %) was due to sharp reductions in anthropogenic emissions. Chemical calculation of bext based on a ridge regression analysis showed that organic aerosol (OA) was the largest contributor to bext in both periods (45.1 %–61.4 %), and the contributions of two oxygenated OAs to bext increased by 3.0 %–14.6 % during the lockdown. A hybrid environmental receptor model combined with chemical and optical variables identified six sources of bext. It was found thatbext from traffic-related emissions, coal combustion, fugitive dust, the nitrate and secondary OA (SOA) source, and the sulfate and SOA source decreased by 21.4 %–97.9 % in the lockdown, whereas bext from biomass burning increased by 27.1 %, mainly driven by the undiminished need for residential cooking and heating. An atmospheric radiative transfer model was further used to illustrate that biomass burning, rather than traffic-related emissions, became the largest positive effect (10.0 ± 10.9 W m-2) on aerosol DRE in the atmosphere during the lockdown. Our study provides insights into aerosol bext and DRE from anthropogenic sources, and the results imply the importance of controlling biomass burning for tackling climate change in China in the future.

Secondary PM2.5 decreases significantly less than NO2 emission reductions during COVID lockdown in Germany

This study estimates the influence of anthropogenic emission reductions on the concentration of particulate matter with a diameter smaller than 2.5 µm (PM2.5) during the 2020 lockdown period in German metropolitan areas. After accounting for meteorological effects, PM2.5 concentrations during the spring 2020 lockdown period were 5 % lower compared to the same time period in 2019. However, during the 2020 pre-lockdown period (winter), PM2.5 concentrations with meteorology accounted for were 19 % lower than in 2019. Meanwhile, NO2 concentrations with meteorology accounted for dropped by 23 % during the 2020 lockdown period compared to an only 9 % drop for the 2020 pre-lockdown period, both compared to 2019. SO2 and CO concentrations with meteorology accounted for show no significant changes during the 2020 lockdown period compared to 2019. GEOS-Chem (GC) simulations with a COVID-19 emission reduction scenario based on the observations (23 % reduction in anthropogenic NOx emission with unchanged anthropogenic volatile organic compounds (VOCs) and SO2) are consistent with the small reductions of PM2.5 during the lockdown and are used to identify the underlying drivers for this. Due to being in a NOx-saturated ozone production regime, GC OH radical and O3 concentrations increased (15 % and 9 %, respectively) during the lockdown compared to a business-as-usual (BAU, no lockdown) scenario. Ox (equal to NO2+O3) analysis implies that the increase in ozone at nighttime is solely due to reduced NO titration. The increased O3 results in increased NO3 radical concentrations, primarily during the night, despite the large reductions in NO2. Thus, the oxidative capacity of the atmosphere is increased in all three important oxidants, OH, O3, and NO3. PM nitrate formation from gas-phase nitric acid (HNO3) is decreased during the lockdown as the increased OH concentration cannot compensate for the strong reductions in NO2, resulting in decreased daytime HNO3 formation from the OH + NO2 reaction. However, nighttime formation of PM nitrate from N2O5 hydrolysis is relatively unchanged. This results from the fact that increased nighttime O3 results in significantly increased NO3, which roughly balances the effect of the strong NO2 reductions on N2O5 formation. Ultimately, the only small observed decrease in lockdown PM2.5 concentrations can be explained by the large contribution of nighttime PM nitrate formation, generally enhanced sulfate formation, and slightly decreased ammonium. This study also suggests that high PM2.5 episodes in early spring are linked to high atmospheric ammonia concentrations combined with favorable meteorological conditions of low temperature and low boundary layer height. Northwest Germany is a hot-spot of NH3 emissions, primarily emitted from livestock farming and intensive agricultural activities (fertilizer application), with high NH3 concentrations in the early spring and summer months. Based on our findings, we suggest that appropriate NOx and VOC emission controls are required to limit ozone, and that should also help reduce PM2.5. Regulation of NH3 emissions, primarily from agricultural sectors, could result in significant reductions in PM2.5 pollution.

Trends in secondary inorganic aerosol pollution in China and its responses to emission controls of precursors in wintertime

The Chinese government recently proposed ammonia (NH3) emission reductions (but without a specific national target) as a strategic option to mitigate fine particulate matter (PM2.5) pollution. We combined a meta-analysis of nationwide measurements and air quality modeling to identify efficiency gains by striking a balance between controlling NH3 and acid gas (SO2 and NOx) emissions. We found that PM2.5 concentrations decreased from 2000 to 2019, but annual mean PM2.5 concentrations still exceeded 35 µg m-3 at 74 % of 1498 monitoring sites during 2015–2019. The concentration of PM2.5 and its components were significantly higher (16 %–195 %) on hazy days than on non-hazy days. Compared with mean values of other components, this difference was more significant for the secondary inorganic ions SO42-, NO3-, and NH4+ (average increase 98 %). While sulfate concentrations significantly decreased over this period, no significant change was observed for nitrate and ammonium concentrations. Model simulations indicate that the effectiveness of a 50 % NH3 emission reduction for controlling secondary inorganic aerosol (SIA) concentrations decreased from 2010 to 2017 in four megacity clusters of eastern China, simulated for the month of January under fixed meteorological conditions (2010). Although the effectiveness further declined in 2020 for simulations including the natural experiment of substantial reductions in acid gas emissions during the COVID-19 pandemic, the resulting reductions in SIA concentrations were on average 20.8 % lower than those in 2017. In addition, the reduction in SIA concentrations in 2017 was greater for 50 % acid gas reductions than for the 50 % NH3 emission reductions. Our findings indicate that persistent secondary inorganic aerosol pollution in China is limited by emissions of acid gases, while an additional control of NH3 emissions would become more important as reductions of SO2 and NOx emissions progress.

Graphene Sheets with Defined Dual Functionalities for the Strong SARS-CoV-2 Interactions.

Search of new strategies for the inhibition of respiratory viruses is one of the urgent health challenges worldwide, as most of the current therapeutic agents and treatments are inefficient. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic and has taken lives of approximately two million people to date. Even though various vaccines are currently under development, virus, and especially its spike glycoprotein can mutate, which highlights a need for a broad-spectrum inhibitor. In this work, inhibition of SARS-CoV-2 by graphene platforms with precise dual sulfate/alkyl functionalities is investigated. A series of graphene derivatives with different lengths of aliphatic chains is synthesized and is investigated for their ability to inhibit SARS-CoV-2 and feline coronavirus. Graphene derivatives with long alkyl chains (>C9) inhibit coronavirus replication by virtue of disrupting viral envelope. The ability of these graphene platforms to rupture viruses is visualized by atomic force microscopy and cryogenic electron microscopy. A large concentration window (10 to 100-fold) where graphene platforms display strongly antiviral activity against native SARS-CoV-2 without significant toxicity against human cells is found. In this concentration range, the synthesized graphene platforms inhibit the infection of enveloped viruses efficiently, opening new therapeutic and metaphylactic avenues against SARS-CoV-2.

SARS-CoV-2 Inhibition by Sulfonated Compounds.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) depends on angiotensin converting enzyme 2 (ACE2) for cellular entry, but it might also rely on attachment receptors such as heparan sulfates. Several groups have recently demonstrated an affinity of the SARS-CoV2 spike protein for heparan sulfates and a reduced binding to cells in the presence of heparin or heparinase treatment. Here, we investigated the inhibitory activity of several sulfated and sulfonated molecules, which prevent interaction with heparan sulfates, against vesicular stomatitis virus (VSV)-pseudotyped-SARS-CoV-2 and the authentic SARS-CoV-2. Sulfonated cyclodextrins and nanoparticles that have recently shown broad-spectrum non-toxic virucidal activity against many heparan sulfates binding viruses showed inhibitory activity in the micromolar and nanomolar ranges, respectively. In stark contrast with the mechanisms that these compounds present for these other viruses, the inhibition against SARS-CoV-2 was found to be simply reversible.