Therapeutic effects and molecular mechanisms of natural products in thrombosis.

Thrombotic disorders, such as myocardial infarction and stroke, are the leading cause of death in the global population and have become a health problem worldwide. Drug therapy is one of the main antithrombotic strategies, but antithrombotic drugs are not completely safe, especially the risk of bleeding at therapeutic doses. Recently, natural products have received widespread interest due to their significant efficacy and high safety, and an increasing number of studies have demonstrated their antithrombotic activity. In this review, articles from databases, such as Web of Science, PubMed, and China National Knowledge Infrastructure, were filtered and the relevant information was extracted according to predefined criteria. As a result, more than 100 natural products with significant antithrombotic activity were identified, including flavonoids, phenylpropanoids, quinones, terpenoids, steroids, and alkaloids. These compounds exert antithrombotic effects by inhibiting platelet activation, suppressing the coagulation cascade, and promoting fibrinolysis. In addition, several natural products also inhibit thrombosis by regulating miRNA expression, anti-inflammatory, and other pathways. This review systematically summarizes the natural products with antithrombotic activity, including their therapeutic effects, mechanisms, and clinical applications, aiming to provide a reference for the development of new antithrombotic drugs.

[Characteristics of Secondary Inorganic Ions in PM2.5 and Its Influencing Factors in Summer in Zhengzhou].

Nitrate (NO3-), sulfate (SO42-), and ammonium (NH4+) are important components of PM2.5, and studying their characteristics and influencing factors is essential for the continuous improvement of air quality. A series of online instruments were used to analyze the chemical components of PM2.5 in Zhengzhou in the summer of 2020. The results showed that the average ρ(PM2.5) was (28 ±13) µg·m-3, showing a daily variation characteristic of high at night and low during the day. The main concentrations of NO3-, SO42-, and NH4+ were (7.8 ±6.7), (7.2 ±3.7), and (5.5 ±3.1) µg·m-3, accounting for 22%, 21%, and 16% in PM2.5, respectively. The proportions of NO3- (27%) and SO42- (23%) in PM2.5, respectively, increased with the increase in PM2.5 and O3 concentration. In addition, the proportions of NO3- and NH4+ increased under low wind speed, high humidity, low temperature, and rainfall conditions. Moreover, the proportion of NO3- showed a daily variation characteristic of high at night and low during the day, whereas the opposite was true for SO42-. The gas-particle partitioning process of NH4NO3 was the main factor affecting the concentrations of NO3- and NH4+ in PM2.5. Low temperature, high humidity, and high aerosol water content concentrations favored the partitioning of HNO3 and NH3 to the particulate phase. High pH also favored the partitioning of gas-phase HNO3 to NO3-; however, it was not conducive to the partition of NH3 to NH4+. These trends partially explained the increase in the concentration and proportion of NO3- in PM2.5 under different scenarios.

Dual Drug-Loaded Nanoliposomes Encapsulating Curcumin and 5-Fluorouracil with Advanced Medicinal Applications: Self-Monitoring and Antitumor Therapy.

Due to the presence of physiological barriers, it is difficult to achieve the desired therapeutic efficacy of drugs; thus, it is necessary to develop an efficient drug delivery system that enables advanced functions such as self-monitoring. Curcumin (CUR) is a naturally functional polyphenol whose effectiveness is limited by poor solubility and low bioavailability, and its natural fluorescent properties are often overlooked. Therefore, we aimed to improve the antitumor activity and drug uptake monitoring by simultaneously delivering CUR and 5-Fluorouracil (5-FU) in the form of liposomes. In this study, dual drug-loaded liposomes (FC-DP-Lip) encapsulating CUR and 5-FU were prepared by the thin-film hydration method; their physicochemical properties were characterized; and their biosafety, drug uptake distribution in vivo, and tumor cell toxicity were evaluated. The results showed that the nanoliposome FC-DP-Lip showed good morphology, stability, and drug encapsulation efficiency. It showed good biocompatibility, with no side effects on zebrafish embryonic development. In vivo uptake in zebrafish showed that FC-DP-Lip has a long circulation time and presents gastrointestinal accumulation. In addition, FC-DP-Lip was cytotoxic against a variety of cancer cells. This work showed that FC-DP-Lip nanoliposomes can enhance the toxicity of 5-FU to cancer cells, demonstrating safety and efficiency, and enabling real-time self-monitoring functions.

[Evaluation of Changes in PM2.5 Exposure Concentration and Health Risk for Urban Resident in Zhengzhou Based on High Spatial Resolution Grids].

In recent years, complex air pollution with the characteristic pollutant of PM2.5 has remained serious in China. Long term exposure to PM2.5 might harm residential health and can increase premature death from specific diseases. The annual average concentration of PM2.5 in Zhengzhou was much higher than the national secondary standard, which has an extremely negative impact on the health of residents. Based on the high spatial resolution grids of population density established through web-crawling and outdoor monitoring concentrations and urban residential emissions used to evaluate PM2.5 exposure concentration, the exposure concentration of PM2.5 for urban residents of Zhengzhou was assessed, considering both indoor and outdoor exposures. Relevant health risks were quantified with the integrated exposure-response model. Finally, the contributions of various reducing measures and different standards of air quality to the decreases in PM2.5 exposure concentration were analyzed. The results showed that in 2017 and 2019, the time weighted exposure concentrations of PM2.5 for Zhengzhou's urban residents were 74.06 µg·m-3 and 60.64 µg·m-3, respectively, which was decreased by 18.12%. In addition, the mass fractions of the indoor exposure concentrations in the time weighted exposure concentrations were 83.58% and 83.01%, and its contribution to the drop of the time weighted exposure concentrations was 84.06%. In 2017 and 2019, the numbers of premature deaths attributed to PM2.5 exposures for urban residents of Zhengzhou over the age of 25 were 13285 and 10323, respectively, showing a 22.30% decrease. By using these comprehensive measures, PM2.5 exposure concentration for Zhengzhou's urban residents could be reduced by 86.23% at most, and 8902 premature deaths could be avoided.

A long-term high-fat diet influences brain damage and is linked to the activation of HIF-1α/AMPK/mTOR/p70S6K signalling.

High-fat diets (HFDs) are related to the incidence of obesity and diabetes, but the effect of high-fat diet-induced brain damage remains to be clarified. In our study, we found that 24 weeks of a HFD effectively induced obesity and a change in fur color in mice. In addition, the mice also exhibited deficits in learning and memory. We further found that autophagic flux was impaired in mice after HFD feeding. Hypoxia-inducible factor 1α (HIF-1α) expression was significantly increased in HFD-fed mice, and HFD feeding inhibited adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and induced mechanistic target of rapamycin (mTOR) phosphorylation and p70S6K expression. Treatment of HFD-induced BV2 cell model with palmitic acid (PA) was used to further verify a similar result. We concluded that improving tissue hypoxia or enhancing autophagy through the AMPK/mTOR/p70S6K pathway may be a relevant strategy for improving obesity- and ageing-related disorders.

[Spatiotemporal Variations in Fine Particulate Matter and the Impact of Air Quality Control in Zhengzhou].

To study the spatiotemporal variations in fine particulate matter (PM2.5) and the impact of air quality management in autumn and winter in Zhengzhou, five sites were selected to collect PM2.5 samples from the autumn of 2017 to the winter of 2018, and the characteristics of the chemical components were analyzed. The positive matrix factorization (PMF) model was also applied to identify the sources of PM2.5, and the effect of air quality control was evaluated to provide support for air quality control in autumn and winter in the next stage. The PM2.5 concentrations in the four seasons in Zhengzhou were ranked as winter > autumn > spring > summer. The PM2.5 concentration at Zhengzhou University (ZZU) was the highest (8.7% higher than the average concentration), and the PM2.5 concentrations at the other sites were slightly lower than the average concentration. The concentration of water-soluble ions (WSIs) was low in spring and summer and high in autumn and winter. The average proportions of SO42-, NO3-, and NH4+ in the nine WSIs were as high as 22.5%, 43.6%, and 23.4%, respectively. The proportion of Cl- in winter was higher than that in the other seasons owing to coal combustion (6.7% and 6.6% in 2017 and 2018, respectively). Owing to wind and sand, the proportions of Ca2+ and Mg2+ in spring were the highest (4.4% and 0.4%, respectively), and those at the Jiancezhan (JCZ) and ZZU sites were higher than those at the other sites. K+, as a marker of biomass burning, had a higher proportion in spring, autumn, and winter. The proportion of K+ in the spring of 2018 was 1.9%, those in the autumn and winter of 2017 were 1.6% and 2.1%, respectively, and those in the autumn and winter of 2018 were 1.3% and 1.8%, respectively. JCZ, Hangkonggang (HKG), and Xinmi (XM) had higher proportions of NO3-, and the proportions of SO42- were lower. Secondary organic carbon (SOC) pollution was serious in autumn and winter, and the concentration accounted for more than half of the organic carbon (OC). In 2018, the SOC/OC at the JCZ and ZZU sites decreased compared with that in 2017, but that at the other three sites increased significantly, thereby indicating that different air pollutant emissions in these regions had different performances in response to control policies. The chemical composition reconstruction results showed that the proportion of sulfate was highest in summer (25.0%), the contribution of nitrate was higher in autumn (23.1% and 25.1% for 2017 and 2018, respectively) and winter (20.6% and 23.0% for 2017 and 2018, respectively), the proportion of crustal material was higher in spring (18.2%), and the contribution of secondary organic aerosol (SOA) was the highest in winter (14.1% and 20.5% for 2017 and 2018, respectively). SOA had higher contributions at the JCZ and HKG sites (16.9% and 16.4%, respectively), and ZZU was affected more by primary organic aerosol (14.3%) and crustal materials (12.1%). The PMF results showed that secondary inorganic salts (37.5%), SOA (15.4%), traffic (14.9%), industry (4.8%), coal combustion (16.0%), fugitive dust (6.5%), and biomass burning (2.8%) were the main pollution sources of PM2.5 in Zhengzhou. SOA and coal combustion contributed more in winter and fugitive dust contributed more in spring, followed by autumn. Biomass burning contributed more in spring and autumn. The urban sites JCZ and ZZU and the characteristic site HKG near the airport were more affected by traffic sources (16.9%, 16.2%, and 16.0%, respectively) than the other sites. The impact of biomass burning on the non-urban sites XM and HKG was slightly larger (both 2.7%), and the contribution of coal combustion to the suburban site XM was higher (16.8%). Owing to the construction around ZZU, the loading of fugitive dust at ZZU was higher than that at other sites. Comparing the results of the two-year autumn and winter, the contribution of SOA, traffic, and industry increased in the autumn and winter of 2018, whereas the contribution of secondary inorganic salts, coal combustion, and biomass burning decreased and the contribution of fugitive dust in winter also decreased. The results showed that the control strategies in autumn and winter had significant effects on the primary sources, including fugitive dust, coal combustion, and industry, and SOA precursor volatile organic compounds should be targeted for further pollution control.

[Characteristics, Meteorological Influences, and Transport Source of Ozone Pollution in Zhengzhou City].

Based on online monitoring data of air quality and meteorological parameters, the long-term variations, spatial differences, and meteorological influencing factors of ground-level ozone (O3) pollution in Zhengzhou were studied. In addition, the transport pathways and potential source regions of O3 were investigated. The results show that surface O3 concentrations at the city station in Zhengzhou City increased significantly during the period 2014-2018 (P<0.05) with a growth rate of 15.50 µg·(m3·a)-1, and the timespan of exceeding pollutant standards was extended. The monthly O3 variations showed an "M" pattern with the seasonal maximum in summer. The diurnal O3 variations showed a "single-peak" pattern with a diurnal concentrations peak at 15:00-16:00, while the diurnal peak at the rural station was relatively high (130.94 µg·m-3). At the urban station, the exceedance probability of O3 concentrations was relative high when hourly temperature (T) exceeded 23℃, relative humidity (RH) was less than 65%, wind speed (WS) ranged 2.0-4.0 m·s-1, and wind direction was southeast or northeast. Based on the multivariate linear fitting of impact factors on O3, the main controlling factors at the city and industrial sites were also identified as T and RH compared to T and WS at the traffic and suburb sites. Back trajectory analysis and potential sources of O3 during different seasons were significantly different, with the dominant transport trajectories during spring and summer being short-distance and slow-moving airflows from the south and northeast; autumn and winter were characterized by long-distance and quick-moving airflows from the northwest. The high O3 concentrations observed in summer were mainly affected by local photochemical formation and regional transport from Hebei, Shandong, and Anhui Provinces.

Role of Hypoxia Inducible Factor-1α in Alzheimer's Disease.

Amyloid-ß (Aß) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer's disease (AD). Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AßPP processing and Aß generation by promoting ß/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aß, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.

Puerariae Lobatae radix flavonoids and puerarin alleviate alcoholic liver injury in zebrafish by regulating alcohol and lipid metabolism.

Exessive drinking is commonly associated with a wide spectrum of liver injuries. The term alcoholic liver disease (ALD) is generally used to refer to this spectrum of hepatic abnormalities, and the term hepatic steatosis denotes early lesions. Puerariae Lobatae Radix (PLR) is a common traditional Chinese medicine and has been widely used as an efficient treatment for alcohol-induced damage. Flavonoids are the principal components of PLR that could potentially be responsible for the activation of alcohol metabolism and lipid-lowering effects. However, little is known about the mechanisms underlying their activity against alcoholic injury. In this study, PLR flavonoids (PLF) were obtained by microwave extraction. A 2% ethanol solution was used to establish a model of alcoholic fatty liver disease by exposure of zebrafish larvae for 32 h, and then the zebrafish were administered PLF and puerarin. The results showed that PLF and puerarin significantly decreased lipid accumulation and the levels of total cholesterol and triglycerides in zebrafish larvae. Moreover, PLF and puerarin downregulated the expression of genes related to alcohol and lipid metabolism (CYP2y3, CYP3a65, ADH8a, ADH8b, HMGCRB, and FASN), endoplasmic reticulum stress, and DNA damage (CHOP, EDEM1, GADD45αa, and ATF6) and reduced levels of inflammatory factors (IL-1ß, TNF-α) in zebrafish larvae. PLF and puerarin increased the phosphorylation of AMP-activated protein kinase-α (AMPKα) and decreased the total protein level of ACC1. The findings suggested that PLF and puerarin alleviated alcohol-induced hepatic steatosis in zebrafish larvae by regulating alcohol and lipid metabolism, which was closely related to the regulation of the AMPKα-ACC signaling pathway. In conclusion, the study provided a possible therapeutic drug for ALD treatment.

Ameliorating Ribosylation-Induced Amyloid-ß Pathology by Berberine via Inhibiting mTOR/p70S6K Signaling.

BACKGROUND: Berberine (BBR) plays a neuroprotective role in the pathogenesis of Alzheimer's disease (AD), inhibiting amyloid-ß (Aß) production and promoting Aß clearance. Advanced glycation end products (AGEs) promote Aß aggregation and tau hyperphosphorylation. The activation of mTOR signaling occurring at the early stage of AD has a prominent impact on the Aß production. This work focused on whether BBR regulates the production and clearance of ribosylation-induced Aß pathology via inhibiting mTOR signaling. OBJECTIVE: To explore whether BBR ameliorates ribosylation-induced Aß pathology in APP/PS1 mice. METHODS: Western blot and immunofluorescence staining were used to detect the related proteins of the mammalian target of Rapamycin (mTOR) signaling pathway and autophagy, as well as the related kinases of Aß generation and clearance. Tissue sections and Immunofluorescence staining were used to observe Aß42 in APP/PS1 mice hippocampal. Morris water maze test was used to measure the spatial learning and memory of APP/PS1 mice. RESULTS: BBR improves spatial learning and memory of APP/PS1 mice. BBR limits the activation of mTOR/p70S6K signaling pathway and enhances autophagy process. BBR reduces the activity of BACE1 and γ-secretase induced by D-ribose, and enhances Aß-degrading enzymes and Neprilysin, and inhibits the expression of Aß in APP/PS1 mice. CONCLUSION: BBR ameliorates ribosylation-induced Aß pathology via inhibiting mTOR/p70S6K signaling and improves spatial learning and memory of the APP/PS1 mice.

[Evaluation of the Reduction in PM2.5 Concentration During the National Traditional Games of Ethnic Minorities in Zhengzhou].

To evaluate the effect of the implementation of emission reduction measures and the improvement in air quality during the National Traditional Games of Ethnic Minorities in Zhengzhou, a series of online instruments were used to continuously observe air pollutants and components of PM2.5 from August 5 to September 30, 2019. Three cases, including before emission reduction (August 5-24), during emission reduction (August 25 to September 18), and after emission reduction (September 19-30), were classified by the implementation of control measures. The results show that the growing concentration of PM2.5 after the cancellation of emission abatement measures (11.7 µg·m-3) was greater than that during the emission reduction (2.3 µg·m-3) compared to the PM2.5 concentration before emission reduction. This thus indicates that the control measures have a significant effect on reducing particulate matter. The main components of PM2.5 were organic matter, nitrate, ammonium, sulfate, and crustal elements. Compared to the proportion of components in PM2.5 before and during the control periods, organic matter and nitrate increased by 3.9% and 0.9%, respectively, while sulfate, ammonium, and crustal elements decreased by 1.1%, 1.9%, and 2.2%, respectively. The results of source appointment by positive matrix factorization show that secondary sulfate, secondary nitrate, secondary organic aerosols, vehicular emissions, industrial emissions, dust, and coal combustion are the main sources of PM2.5. Emission abatement measures reduced the contributions of primary sources such as dust, coal combustion, and industry by 8.3%, 8.2%, and 8.1%, respectively. In contrast, the contributions of secondary organic and nitrate aerosols increased during the control periods, which suggested that the control measures implemented in Zhengzhou had a weaker emission reduction effect on nitrogen oxide and volatile organic compounds than on primary sources of PM2.5.

[Characteristics and Source Apportionment of Ambient VOCs in Spring in Zhengzhou].

Ambient volatile organic compounds (VOCs) samples were collected at five sites in Zhengzhou during the spring of 2018. VOCs concentrations, the ozone formation potential (OFP), the aerosol formation potential (AFP), and source apportionment using a positive matrix factorization (PMF) model were studied based on chemical composition analysis. The results showed that the averaged concentration of VOCs in Zhengzhou during spring was (30.66±13.60)×10-9, of which the proportion of alkanes was the highest (35.3%) followed by oxygenated VOCs (OVOCs, 25.3%), halocarbons (24.1%), aromatics (10.0%), and alkenes (5.2%). The total OFP was 195.53 µg·m-3 and the contributions of alkanes, alkenes, aromatics, halocarbons, and OVOCs were 25.6%, 17.8%, 38.9%, 5.8%, and 11.9%, respectively. The total AFP was 0.95 µg·m-3 with an 87.6% contribution from aromatics and 12.4% from alkanes. The correlation between major species showed that pentane, isopentane, benzene, and toluene in Qinlinglu (QLL) site and Jingkaiqu (JKQ) site were greatly influenced by motor vehicles, but these were mainly influenced by combustion sources in Zhengzhou University (ZZU) site. The five factors that were identified by the PMF model were vehicle and liquefied petroleum gas (LPG) volatilization source (30.5%), solvent coating source (27.3%), industrial process source (22.1%), aging air mass (14.4%), and biogenic source (5.7%).

The risk factors and prognosis of delayed perihematomal edema in patients with spontaneous intracerebral hemorrhage.

PURPOSE: We hypothesize delayed perihematomal edema (DHE) leads to secondary injury after spontaneous intracerebral hemorrhage (sICH) with a poor prognosis. Hence, we need to investigate the risk factors of DHE and identify whether DHE will predict the poor outcome of sICH. METHODS: We retrospectively recruited 121 patients with sICH admitted to the Department of Neurology from January 2014 to August 2018. After dividing all these patients into DHE group and non-DHE group, we analyzed the potential risk factors and outcome of DHE using a multivariate logistic regression model. RESULTS: We conclude DHE after sICH associates with age, hospitalization time, hematoma shape, blood pressure upon admission, alcohol consumption, blood sodium level, and baseline hematoma volume within 24 hours after symptom onset, among which differences were statistically significant (P < .05). Logistic regression analysis finally identified that age (OR = 0.958, 95% CI = 0.923-0.995) and the baseline hematoma volume (OR = 1.161, 95% CI = 1.089-1.238) were the most significant risk factors for DHE, and moreover, the DHE (OR = 3.062, 95% CI = 1.196-7.839) was also a risk factor for poor prognosis in sICH patients. CONCLUSION: We suggest DHE is a clinical predictor of secondary injury following sICH and poor prognosis. In addition, age and baseline hematoma volume are considered significant high-risk factors for DHE in patients with sICH.