Bovine serum albumin-based and dual-responsive targeted hollow mesoporous silica nanoparticles for breast cancer therapy.

Combination therapy is an effective way to alleviate the shortcoming of monotherapy and enhances therapeutic efficacy. Herein, a distinctive hollow mesoporous silica nanoparticle (HMSNs) encapsulated with folic acid-modified bovine serum albumin (BSA-FA), denoted as HBF, was engineered for tumor targeting and dual-responsive release of loaded-therapeutic agents MD (methylene blue (MB) and doxorubicin (DOX)). The BSA molecule as a ''gatekeeper'' prevents premature drug leakage and actively unloads the cargos through BSA detachment in response to intracellular glutathione (GSH). Folic acid (FA) promotes the specific intracellular delivery of the drug to folate receptor (FR)-expressing cancer cells to improve the efficacy of chemo-photodynamic therapy (PDT). In vitro drug release profiles showed that the drug carrier could achieve pH/redox-responsive drug release from MD@HBF owing to the cleavage of the imine bonds between HMSNs-CHO and BSA-FA and BSA intramolecular disulfide bond. Additionally, a series of biological evaluations, such as cell uptake experiments, toxicity experiments, and in vivo therapeutic assays indicated that MD@HBF possesses the features of accurately targeting FR-expressing 4T1 cells to induce cells apoptosis in vitro, exhibits outstanding tumor cell synergistic killing efficiency of chemo-photodynamic therapy (combination index CI = 0.325), and inhibits tumors growth. These results demonstrated that the strategy of combining HMSNs with stimuli-responsive biodegradable protein molecules could provide a new potential direction toward the ''on-demand'' drug release for precision chemo-photodynamic therapy in cancer treatment.

An infection-microenvironment-targeted and responsive peptide-drug nanosystem for sepsis emergency by suppressing infection and inflammation.

Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation. Nevertheless, current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens. Omiganan, an antimicrobial peptide, has shown promise for neutralizing endotoxins and eliminating diverse pathogens. However, its clinical application is hindered by safety and stability concerns. Herein, we present a nanoscale drug delivery system (Omi-hyd-Dex@HA NPs) that selectively targets infectious microenvironments (IMEs) and responds to specific stimuli for efficient intervention in sepsis. The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid (HA). The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes, but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase. The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation. In multiple tissue infection and sepsis animal models, Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction, thereby preventing subsequent fatal complications and significantly improving survival outcomes. The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.

Synergistic effect of reductions in multiple gaseous precursors on secondary inorganic aerosols in winter under a meteorology-based redistributed daily NH3 emission inventory within the Beijing-Tianjin-Hebei region, China.

Secondary inorganic aerosols (SIA) account for 20-60% of the total fine particulates in the Beijing-Tianjin-Hebei (BTH) region of China, indicating an urgent need to clarify the relationship among such compounds. The purpose of this study was to quantify the relationship between emissions of NH3, NOx, SO2, VOCs and SIA concentrations during a severe winter haze episode using an air quality model and a meteorology-based redistributed NH3 emission inventory within the BTH region. The results showed that the model performance regarding the NH3 simulations in January by the four emission inventories improved after the redistribution of daily NH3 emissions, with an increase of 0.02-0.13 in R, a 9-56% decrease in NMB, and a 7-51% decrease in NME. The updated simulations reproduced the daily observations of SIA, SO2, and NO2 well. A total of 125 sets of sensitivity simulations showed that a synergistic reduction in NH3 and VOCs was more efficient in terms of SIA control than simply reducing SO2 or NOx in the BTH region. If only NOx emissions were reduced, the SIA concentration would first increase and then decrease, and it could decline by another 0.86-8.03% in parallel with an equal NH3 emission cut. SIA could be reduced by approximately 22.68% with the most stringent inorganic precursors' control. Moreover, VOCs emission reductions could lead to a decrease in SIA, and the impact of VOCs on SIA was similar to that of NH3. The collaborative control of both inorganic precursors and VOCs was more effective than single-factor control measures for decreasing SIA, and the decline rate was approximately 29.26% under minimum emission conditions. This improved effectiveness was obtained because VOCs mitigation effectively decreases the ozone concentration, which in turn influences SIA formation. Finally, on the premise of a 60% SO2 cut, the reduction scheme NH3:VOCs:NOx = 4:4:1 was suggested for SIA control.

Agricultural ammonia emissions and its impact on PM2.5 concentrations in the Beijing-Tianjin-Hebei region from 2000 to 2018.

Ammonia (NH3) discharged from agricultural activities to the atmosphere plays a crucial role in the formation of secondary inorganic aerosols. This study analyzed the temporal-spatial development of agricultural NH3 emissions from 2000 to 2018 in the Beijing-Tianjin-Hebei (BTH) region and assessed the effects of reducing PM2.5 by removing agricultural NH3 using an air quality model. The results showed that the interannual agricultural NH3 emissions in the BTH region exhibited a stairs trend from 2000 to 2018, with an average of 971.63 Gg. In particular, agricultural NH3 emissions in the BTH region reached a maximum in summer when the temperature was high and were more concentrated in the southern plains compared to the northern areas. Under the reduction scenario (RS), the agricultural NH3 emissions in the BTH region in 2015, 2016, 2017, and 2018 were reduced by 2.95%, 4.10%, 18.75%, and 10.21%, resulting in a reduction of 0.5%, 0.5%, 2.5%, and 1.2% of annual mean PM2.5 concentration, respectively, compared with the baseline scenario (BS). Furthermore, agricultural NH3 emissions contributed 12.6, 12.1, 11.9, and 11.3 µg m-3 to PM2.5 concentrations in 2015, 2016, 2017, and 2018 under the zero-emission scenario (ZS), respectively. However, the contribution rates exhibited a slightly increasing trend from 20.5% in 2015 to 24.6% in 2018. These findings could provide a new understanding of agricultural NH3 emission trends and their impacts on PM2.5 concentration based on actual NH3 mitigation ratios in recent years, thereby guiding the formulation of future control strategies.

A Sequentially Responsive Nanosystem Breaches Cascaded Bio-barriers and Suppresses P-Glycoprotein Function for Reversing Cancer Drug Resistance.

Cancer chemotherapy is challenged by multidrug resistance (MDR) mainly attributed to overexpressed transmembrane efflux pump P-glycoprotein (P-gp) in cancer cells. Improving drug delivery efficacy while co-delivering P-gp inhibitors to suppress drug efflux is an often-used nanostrategy for combating MDR, which is however challenged by cascaded bio-barriers en route to cancer cells and P-gp inhibitors' adverse effects. To effectively breach the cascaded bio-barriers while avoiding P-gp inhibitors' adverse effects, a stealthy, sequentially responsive doxorubicin (DOX) delivery nanosystem (RCMSNs) is fabricated, composed of an extracellular-tumor-acidity-responsive polymer shell (PEG-b-PLLDA), pH/redox dual-responsive mesoporous silica nanoparticle-based carriers (MSNs-SS-Py), and cationic ß-cyclodextrin-PEI (CD-PEI) gatekeepers. The PEG-b-PLLDA corona makes RCMSNs stealthy with prolonged blood circulation time. Once tumors are reached, extracellular acidity degrades PEG-b-PLLDA, reversing nanosystem's surface charges to be positive, which drastically improves RCMSNs' tumor accumulation, penetration, and cellular internalization. Within cancer cells, CD-PEI gatekeepers detach to allow DOX unloading in response to intracellular acidity and glutathione and functionally act as a P-gp inhibitor, dampening P-gp's efflux activity by impairing ATP production. Thus, the resultant high-efficacy drug delivery along with reduced P-gp function cooperatively reverses MDR in vitro. Importantly, in preclinical tumor models, DOX@RCMSNs potently suppress MDR tumor growth without eliciting systemic toxicity, demonstrating their potential of clinical translation.

Prediction and mitigation potential of anthropogenic ammonia emissions within the Beijing-Tianjin-Hebei region, China.

Large ammonia (NH3) emissions contribute approximately 8-30% to the fine particle pollution in China and highlight the need for understanding the emission trends and mitigation effects of NH3 in the future. The purpose of this study is to predict the NH3 emissions and analyze the mitigation potential up to year 2040 by scenario analysis based on the established new NH3 emission inventory from anthropogenic sources for the Beijing-Tianjin-Hebei (BTH) region. The results showed that the total NH3 emission in the BTH region was estimated at 966.14 Gg in 2016. Under the Business-as-Usual (BAU) scenario, the total NH3 emissions in 2030 and 2040 would increase by 13% and 26% compared with 2016 levels, with average annual growth rates of 0.9% and 1.0%, respectively. Livestock will continue to dominate NH3 emissions in the future, with the proportions of total emissions increasing from 57% in 2016 to 64% in 2030 and 68% in 2040. The share of the second-largest NH3 emission source, synthetic fertilizer application, will decrease from 36% in 2016 to 31% in 2030 and 27% in 2040. Among five other sources, the largest change occurred in waste disposal, increasing notably by 3.31 times from 2016 to 2040 owing to rapid urbanization. Under the Combined Options (CO) scenario, the total NH3 emissions could be reduced by as much as 34% by 2030 and 50% by 2040 compared with the BAU scenario, which is attributed to livestock (24% in 2030, 37% in 2040) and synthetic fertilizer application (10% in 2030, 13% in 2040), respectively. This study can give a reliable estimation of anthropogenic NH3 emission in the BTH region during 2020-2040 and provide a valuable reference for effective mitigation measures and control strategies for policy makers.

Estimation and prediction of pollutant emissions from agricultural and construction diesel machinery in the Beijing-Tianjin-Hebei (BTH) region, China☆.

Both agricultural and construction machinery are important non-road sources of atmospheric pollution, with total hydrocarbons (THC), nitrogen oxides (NOx) and particulate matter (PM) emissions accounting for more than 60% of the total emissions from all non-road mobile sources in China. However, there exist relatively few efforts to establish the emission inventory for these machineries. This study attempted to estimate and predict air pollutant emissions from agricultural and construction diesel machinery, using the Beijing-Tianjin-Hebei (BTH) region as the case study area. The results show that total emissions of PM10, PM2.5, THC, NOX, CO and SO2 in 2015 were 41.10, 38.80, 86.14, 520.41, 379.01 and 17.32 Kt respectively. The contribution of agricultural machinery was slightly higher than that of construction machinery, accounting for 60-71% of the total. Moreover, emissions of various pollutants (except SO2) from agricultural machinery were mainly distributed in central Hebei (Cangzhou, Shijiazhuang and Baoding), while emissions from construction machinery were mainly distributed in Beijing and Tianjin. The prediction suggest that the total emissions of agricultural and construction diesel machinery in the BTH region would increase by 6% in 2020 and 9% in 2025. Moreover, pollutant emissions from construction machinery would contribute from 29% to 40% in 2015 to 34%-61% in 2025. These results could provide important information for making effective mitigation measures of non-road mobile sources.

Functional extracellular vesicles engineered with lipid-grafted hyaluronic acid effectively reverse cancer drug resistance.

Multidrug resistance (MDR) is a key issue accounting for ineffectiveness of cancer chemotherapy. Numerous multifunctional nanocarriers have been developed to increase drug delivery efficacy and inhibit drug efflux for overcoming cancer drug resistance. However, limited success has been achieved in clinic because of nanocarriers' complicated multi-step fabrication procedures and their undesired side toxicity as well as potential immunogenicity. Here, hyaluronic acid (HA) functionalized extracellular vesicles (EVs) are generated as natural vehicles to efficiently deliver doxorubicin (DOX) and reverse MDR. The EVs isolated from noncancerous HEK293T cells (hEVs) reduce P-glycoprotein (P-gp) expression in drug resistant MCF7/ADR cells. To acquire tumor-targeting capability, hEVs are modified with lipidomimetic chains-grafted HA (lipHA) by a simple incubation. Owing to CD44-mediated cancer-specific targeting and P-gp suppressive capability, the HA-functionalized hEVs (lipHA-hEVs) remarkably promote the intracellular DOX accumulation in drug resistant breast cancer cells. In preclinical MDR tumor models, lipHA-hEVs deeply penetrate into tumor tissue and effectively transport DOX into tumor local, while eliminating DOX's systemic toxicity. Importantly, DOX@lipHA-hEVs inhibited MDR tumor growth by 89% and extend animal survival time by approximately 50%. Thus, our engineered tumor-targeting hEVs are promising natural carriers for overcoming cancer MDR.

Identification of microRNAs and their targets responding to low-potassium stress in two barley genotypes differing in low-K tolerance.

MicroRNAs (miRNAs) have diverse and crucial roles in plant growth and development, including in the response to abiotic stresses. Although plant responses to K deficiency are well documented at the physiological and transcriptional levels, the miRNA-mediated post-transcriptional pathways are still not clearly elucidated. In this study, high-throughput sequencing and degradome analysis were performed using two barley genotypes differing in low-K tolerance (XZ149, tolerant and ZD9, sensitive), to determine the genotypic difference in miRNAs profiling. A total of 270 miRNAs were detected in the roots of XZ149 and ZD9 at 2 d and 10 d after low-K treatment, of which 195 were commonly found in both genotypes. Their targets were further investigated by bioinformatics prediction and degradome sequencing approach. The results showed that ata-miR1432-5p might act as a regulator participating in Ca2+ signaling pathways in response to low-K stress. The difference in the miR444/MADS-box model as well as pathways mediated by miR319/TCP4 and miR396/GRF could be attributed to high tolerance to low-K stress in XZ149. In addition, other conserved and novel miRNAs families associated with low-K tolerance were also detected. The current results provide molecular evidence for understanding the possible involvement of miRNAs in the regulation of low-K tolerance.

TRIM28 protects CARM1 from proteasome-mediated degradation to prevent colorectal cancer metastasis.

TRIM28 (Tripartite motif-containing protein 28), a member of TRIM family, is aberrantly expressed and reportedly has different functions in many types of human cancer. However, the biological roles of TRIM28 and related mechanism in colorectal cancer (CRC) remain unclear. Here, we showed that TRIM28 was downregulated in colorectal cancer compared with normal mucosa, especially at advanced stages, and acted as an independent prognostic factor of favorable outcome. Functional studies demonstrated that TRIM28 restrained CRC migration and invasion in vitro and in vivo. Mechanistically, we reported that CARM1 (co-activator-associated arginine methyltransferase1) was a critical player downstream of TRIM28. TRIM28 interacted with CARM1, and protected CARM1 from proteasome-mediated degradation through physical protein-protein interaction to suppress CRC metastasis. Further, TRIM28 suppressed the migration and invasion of CRC cells through inhibiting WNT/ß-catenin signaling in a CARM1-dependent manner, but independent of CARM1's methyltransferase activity. The protein expression of CARM1 was positively correlated with TRIM28 in CRC tissues. Patients with high levels of TRIM28 and CARM1 had improved prognosis, whereas patients with low TRIM28 and CARM1 expression had the poor outcomes. Thus, our study reveals an inhibitory role of TRIM28 in CRC metastasis, which was achieved through a TRIM28-CARM1-WNT/ß-catenin axis. This work provides potential prognostic and therapeutic targets for CRC treatment.

Root and leaf metabolite profiles analysis reveals the adaptive strategies to low potassium stress in barley.

BACKGROUND: Potassium (K) deficiency in arable land is one of the most important factors affecting crop productivity. Development of low K (LK) tolerant crop cultivars is regarded as a best economic and effective approach for solving the issue of LK. In previous studies, we found a wider variation of LK tolerance in the Tibetan wild barley accessions than cultivated barley. However, the mechanism of LK tolerance in wild barley is still elusive. RESULTS: In this study, two wild barley genotypes (XZ153, LK tolerant and XZ141, LK sensitive) and one cultivar (LuDaoMai, LK tolerant) was used to investigate metabolome changes in response to LK stress. Totally 57 kinds of metabolites were identified in roots and leaves of three genotypes at 16 d after LK treatment. In general, accumulation of amino acids and sugars was enhanced in both roots and leaves, while organic acids were reduced under LK stress compared to the control. Meanwhile, the concentrations of the negatively charged amino acids (Asp and Glu) and most organic acids was reduced in both roots and leaves, but more positively charged amino acids (Lys and Gln) were increased in three genotypes under LK. XZ153 had less reduction than other two genotypes in biomass and chlorophyll content under LK stress and showed greater antioxidant capacity as reflected by more synthesis of active oxygen scavengers. Higher LK tolerance of XZ153 may also be attributed to its less carbohydrate consumption and more storage of glucose and other sugars, thus providing more energy for plant growth under LK stress. Moreover, phenylpropanoid metabolic pathway mediated by PAL differed among three genotypes, which is closely associated with the genotypic difference in LK tolerance. CONCLUSIONS: LK tolerance in the wild barley is attributed to more active phenylpropanoid metabolic pathway mediated by PAL, energy use economy by reducing carbohydrate consumption and storage of glucose and other sugars, and higher antioxidant defense ability under LK stress.

Methotrexate-Loaded Extracellular Vesicles Functionalized with Therapeutic and Targeted Peptides for the Treatment of Glioblastoma Multiforme.

Despite promising in vitro evidence for effective glioblastoma treatment, most drugs are hindered from entering the central nervous system because of the presence of the blood-brain barrier (BBB). Thus, successful modification of drug delivery and novel therapeutic strategies are needed to overcome this obstacle. Extracellular vesicles (EVs), cell-derived membrane-encapsulated structures with diameters ranging from 50 to 1000 nm, have been explored as the drug delivery system to deliver their cargo to the brain tissue. Moreover, tumor targeting and selective drug delivery has been facilitated by engineering their parent cells to secrete modified EVs. However, the method suffers from many shortcomings including poor repeatability and complex and time-consuming operations. In this context, we present an easy-to-adapt and highly versatile methodology to modify EVs with an engineered peptide capable of recognition and eradication of glioma. On the basis of molecular recognition between phospholipids on EV lipid bilayer membranes and ApoA-I mimetic peptides, we have developed methotrexate (MTX)-loaded EVs functionalized with therapeutic [Lys-Leu-Ala (KLA)] and targeted [low-density lipoprotein (LDL)] peptides. In vitro experiments demonstrated that EVs decorated with LDL or KLA-LDL could obviously ameliorate their uptake by human primary glioma cell line U87 and permeation into three-dimensional glioma spheroids in contrast to blank EVs, and consequently, the treatment outcome of the payload is improved. Both ex vivo and in vivo imaging experiments revealed that peptide LDL could obviously promote EV extravasation across the BBB and distribution in the glioma site. Furthermore, compared with the mice administrated with MTX and MTX@EVs, MTX@EVs-KLA-LDL-treated mice showed the longest median survival period. In conclusion, functionalizing with the peptide onto EV surfaces may provide a substantial advancement in the application of EVs for selective target binding as well as therapeutic effects for brain tumor treatment.

Dual-Stimuli-Responsive, Polymer-Microsphere-Encapsulated CuS Nanoparticles for Magnetic Resonance Imaging Guided Synergistic Chemo-Photothermal Therapy.

Integrating biomedical imaging and multimodal therapies into one platform for enhanced anticancer efficacy is of great significance. Herein, a core/shell structured nanotheranostic (CuS@copolymer) for magnetic resonance imaging (MRI)-guided chemo-photothermal therapy was simply prepared via emulsifier-free emulsion polymerization with the full participation of hydrophilic CuS NPs, styrene (St), N-isopropylacrylamide (NIPAm), methacrylic acid (MAA), and polymerizable rare earth complex (Gd(AA)3phen). The synthesized multifunctional microspheres with excellent biocompatibility exhibited high loading capacity (15.3 wt %) for DOX·HCl and excellent drug release under low pH and high temperature. The photosensitive CuS cores which can simultaneously efficiently absorb near-infrared (NIR) light and convert NIR light to fatal heat, leading to a synergistic therapeutic effect combined photothermal therapy (PTT) with chemotherapy. Moreover, the temperature sensitive copolymer attached onto the CuS nanoparticles was able to be productively infected by the thermal effect and give rise to a highly controllable DOX release. Furthermore, the CuS@copolymer/DOX showed an enhanced therapeutic efficacy against 4T1 cells than separate photothermal therapy or chemotherapy. Additionally, the drug delivery procedure could be visualized by in vivo MR images and the longitudinal relaxivity (r1) was calculated to be 10.72 mM-1 s-1. These results suggest the CuS@copolymer microspheres highly attractive candidates for biomedical applications.

Bio-inspired synthesis of PEGylated polypyrrole@polydopamine nanocomposites as theranostic agents for T1-weighted MR imaging guided photothermal therapy.

Polypyrrole nanoparticle (PPy) based theranostic agents for magnetic resonance imaging (MRI) guided photothermal therapy (PTT) have received increasing attention in recent years. However, the limitations of cost and biocompability still offer us opportunities to improve these agents. Considering the versatile character of polydopamine (PDA), PEGylated PPy@Fe3+-chelated PDA nanocomposites (PPDEs) were designed and prepared in an easy way. PPDE with a uniform core-shell structure could be obtained by adjusting the ratio of dopamine and PPys. In this nanocomplex, the shells confer the nanoparticles with good biocompability and MRI signal enhancing ability. Moreover, the PPy cores play a role in photothermal ablation of tumors. Compared with pure PDA nanoparticles, the PPDEs have higher NIR absorbance and better photothermal capability benefitting from the high photothermal conversion of the cores. Additionally, the obtained PPDEs provide significant MRI signal enhancement for both in vitro and in vivo imaging with high longitudinal relaxivity (r1 = 5.055 mM-1 s-1). After intravenous injection, the PPDEs exhibited valid tumor accumulation, as revealed by MRI and verified by biodistribution analysis. Under NIR irradiation, the PPDEs showed highly effective photothermal ablation of 4T1 cells. Notably, excellent biocompability of the PPDEs was confirmed by a relevant MTT assay and histologic analysis. This work achieved an example of exploiting the inherent advantages of PPy and PDA within a single unit and exploring its potential for T1 MRI-guided PTT.

Metabolic analysis of two contrasting wild barley genotypes grown hydroponically reveals adaptive strategies in response to low nitrogen stress.

Nitrogen (N) is an essential macronutrient for plants. The increasingly severe environmental problems caused by N fertilizer application urge alleviation of N fertilizer dependence in crop production. In previous studies, we identified the Tibetan wild barley accessions with high tolerance to low nitrogen (LN). In this study, metabolic analysis was done on two wild genotypes (XZ149, tolerant and XZ56, sensitive) to understand the mechanism of LN tolerance, using a hydroponic experiment. Leaf and root samples were taken at seven time points within 18 d after LN treatment, respectively. XZ149 was much less affected by low N stress than XZ56 in plant biomass. A total of 51 differentially accumulated metabolites were identified between LN and normal N treated plants. LN stress induced tissue-specific changes in carbon and nitrogen partitioning, and XZ149 had a pattern of energy-saving amino acids accumulation and carbon distribution in favor of root growth that contribute to its higher LN tolerance. Moreover, XZ149 is highly capable of producing energy and maintaining the redox homeostasis under LN stress. The current results revealed the mechanisms underlying the wild barley in high LN tolerance and provided the valuable references for developing barley cultivars with LN tolerance.