Triphenylphosphonium-linked derivative of hecogenin with enhanced antiproliferative activity: Design, synthesis, and biological evaluation.

Hecogenin (HCG), a steroidal sapogenin, possesses good antitumor properties. However, the application of HCG for cancer treatment has been hindered primarily by its moderate potency. In this study, we incorporated triphenylphosphonium cation (TPP+) at the C-3 and C-12 positions through different lengths of alkyl chains to target mitochondria and enhance the efficacy and selectivity of the parent compound. Cytotoxicity screening revealed that most of the target compounds exhibited potent antiproliferative activity against five human cancer cell lines (MKN45, A549, HCT-116, MCF-7, and HepG2). Structure-activity relationship studies indicated that the TPP+ group significantly enhanced the antiproliferative potency of HCG. Among these compounds, 3c demonstrated remarkable potency against MKN45 cells with an IC50 value of 0.48 µM, significantly more effective than its parent compound HCG (IC50 > 100 µM). Further investigations into the mechanism of action revealed that 3c induced apoptosis of MKN45 cells through the mitochondrial pathway. In a zebrafish xenograft model, 3c inhibited the proliferation of MKN45 cells. Overall, these results suggest that 3c, with potent antiproliferative activity, may serve as a valuable scaffold for developing new antitumor agents.

The Graphene Quantum Dots Gated Nanoplatform for Photothermal-Enhanced Synergetic Tumor Therapy.

Currently, the obvious side effects of anti-tumor drugs, premature drug release, and low tumor penetration of nanoparticles have largely reduced the therapeutic effects of chemotherapy. A drug delivery vehicle (MCN-SS-GQDs) was designed innovatively. For this, the mesoporous carbon nanoparticles (MCN) with the capabilities of superior photothermal conversion efficiency and high loading efficiency were used as the skeleton structure, and graphene quantum dots (GQDs) were gated on the mesopores via disulfide bonds. The doxorubicin (DOX) was used to evaluate the pH-, GSH-, and NIR-responsive release performances of DOX/MCN-SS-GQDs. The disulfide bonds of MCN-SS-GQDs can be ruptured under high glutathione concentration in the tumor microenvironment, inducing the responsive release of DOX and the detachment of GQDs. The local temperature of a tumor increases significantly through the photothermal conversion of double carbon materials (MCN and GQDs) under near-infrared light irradiation. Local hyperthermia can promote tumor cell apoptosis, accelerate the release of drugs, and increase the sensitivity of tumor cells to chemotherapy, thus increasing treatment effect. At the same time, the detached GQDs can take advantage of their extremely small size (5-10 nm) to penetrate deeply into tumor tissues, solving the problem of low permeability of traditional nanoparticles. By utilizing the photothermal properties of GQDs, synergistic photothermal conversion between GQDs and MCN was realized for the purpose of synergistic photothermal treatment of superficial and deep tumor tissues.

Combination immunotherapy of PEG-modified preladenant thermosensitive liposomes and PD-1 inhibitor effectively enhances the anti-tumor immune response and therapeutic effects.

Immunotherapy is a promising cancer treatment strategy. In contrast, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors are associated with low response rates and are only useful in a small group of cancer patients. A combination of treatments may be effective for overcoming this clinical issue. Preladenant is an adenosine (ADO) receptor inhibitor that can block the ADO pathway and improve the tumor microenvironment (TME), thereby enhancing the immunotherapeutic effect of PD-1 inhibitors. However, its poor water solubility and low targeting limit its clinical applications. We designed a PEG-modified thermosensitive-liposome (pTSL) loaded with ADO small molecule inhibitor preladenant (P-pTSL) to overcome these problems and enhance the effect of PD-1 inhibitor on breast cancer immunotherapy. The prepared P-pTSL was round and uniformly distributed with a particle size of (138.9 ± 1.22) nm, PDI: 0.134 ± 0.031, and zeta potential (-10.1 ± 1.63) mV; preladenant was released slowly at 37 °C but released fast at 42 °C from P-pTSL, which was 76.52 ± 0.44%. P-pTSL has good long-term and serum stability and excellent tumor-targeting ability in mice. Moreover, the combination with PD-1 inhibitor significantly enhanced the anti-tumor effect, and the improvement of related factors in serum and lymph was more obvious under the condition of 42 °C thermotherapy in vitro.

Preparation of Lamivudinyl palmitate nanoemulsome for liver-targeting delivery.

The water solubility and side effects of lamivudine limit its application for the treatment of viral hepatitis type B and human immunodeficiency virus. In order to increase the solubility of LA and improve the in vivo membrane permeability of the drug, LA was modified with hexadecane acid to prepare the prodrug lamivudine palmitic acid (LAP) and loaded into nanoemulsome (NES). LAP-NES was prepared by the thin film dispersion method. The LAP-NES showed the sustained release performance up to 72h in pH 7.4 PBS. Moreover, the pharmacokinetics of LAP-NES after tail vein injection in rats and the biodistribution characteristics were evaluated. The tmax of LAP-NES was 2.5h. The t1/2, clearance rate and average retention time of LAP-NES obviously prolonged compared with free LAP. The tissue biodistribution behavior of NES in vivo showed the good targeting in the liver and spleen, with the maximum at 4h and then the fluorescence slowly decreased until 72h. LAP-NES could significantly delay the release of LA in vivo, effectively prolong the elimination time and had obvious liver-targeting ability. In summary, LAP-NES shows great potential for liver-targeting delivery to increase the therapeutic effect and decrease the side effects of LA.

Biomimetic Antidote Nanoparticles: a Novel Strategy for Chronic Heavy Metal Poisoning.

Chronic lead poisoning has become a major factor in global public health. Chelation therapy is usually used to manage lead poisoning. Dimercaptosuccinic acid (DMSA) is a widely used heavy metal chelation agent. However, DMSA has the characteristics of poor water solubility, low oral bioavailability, and short half-life, which limit its clinical application. Herein, a long-cycle slow-release nanodrug delivery system was constructed. We successfully coated the red blood cell membrane (RBCM) onto the surface of dimercaptosuccinic acid polylactic acid glycolic acid copolymer (PLGA) nanoparticles (RBCM-DMSA-NPs), which have a long cycle and detoxification capabilities. The NPs were characterized and observed by particle size meters and transmission electron microscopy. The results showed that the particle size of RBCM-DMSA-NPs was approximately 146.66 ± 2.41 nm, and the zeta potential was - 15.34 ± 1.60 mV. The homogeneous spherical shape and clear core-shell structure of the bionic nanoparticles were observed by transmission electron microscopy. In the animal tests, the area under the administration time curve of RBCM-DMSA-NPs was 156.52 ± 2.63 (mg/L·h), which was 5.21-fold and 2.36-fold that of free DMSA and DMSA-NPs, respectively. Furthermore, the median survival of the RBCM-DMSA-NP treatment group (47 days) was 3.61-fold, 1.32-fold, and 1.16-fold for the lead poisoning group, free DMSA, and DMSA-NP groups, respectively. The RBCM-DMSA-NP treatment significantly extended the cycle time of the drug in the body and improved the survival rate of mice with chronic lead poisoning. Histological analyses showed that RBCM-DMSA-NPs did not cause significant systemic toxicity. These results indicated that RBCM-DMSA-NPs could be a potential candidate for long-term chronic lead exposure treatment.

Study of the isomeric Maillard degradants, glycosylamine and Amadori rearrangement products, and their differentiation via MS2 fingerprinting from collision-induced decomposition of protonated ions.

RATIONALE: The focus of this work was to study glycosylamine and Amadori rearrangement products (ARPs), the two major degradants in the Maillard reactions of pharmaceutical interest, and utilize their MS2 fingerprints by liquid chromatography/high-resolution tandem mass spectrometry (LC/HRMS2 ) to quickly distinguish the two isomeric degradants. These two types of degradants are frequently encountered in the compatibility and stability studies of drug products containing primary or secondary amine active pharmaceutical ingredients (APIs), which are formulated with excipients consisting of reducing sugar functionalities. METHODS: Vortioxetine was employed as the primary model compound to react with lactose to obtain the glycosylamine and ARP degradants of the Maillard reaction, and their MS2 spectra (MS2 fingerprints) were obtained by LC/MS2 . Subsequently, the two degradants were isolated via preparative HPLC and their structures were confirmed by one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) determination. RESULTS: The MS2 fingerprints of the two degradants display significantly different profiles, despite the fact that many common fragments are observed. Specifically, protonated glycosylamine shows a prominent characteristic fragment of [Mvort + C2 H3 O]+ at m/z 341 (Mvort is the vortioxetine core), while protonated ARP shows a prominent characteristic fragment of [Mvort + CH]+ at m/z 311. Further study of the Maillard reactions between several other structurally diverse primary/secondary amines and lactose produced similar patterns. CONCLUSIONS: The study suggests that the characteristic MS2 fragment peaks and their ratios may be used to differentiate the glycosylamine and ARP degradants, the two isomeric degradants of the Maillard reaction, which are commonly encountered in finished dosage forms of pharmaceutical products containing primary and secondary amine APIs.

Novel biomimetic nanostructured lipid carriers for cancer therapy: preparation, characterization, and in vitro/in vivo evaluation.

Nanostructured lipid carriers (NLC) have become a research hotspot, wherein cancer-targeting effects are enhanced and side effects of chemotherapy are overcome. Usually, accelerated blood clearance (ABC) occurs after repeated injections, without changing the immunologic profile, despite PEGylation which prolongs the circulation function. To overcome these problems, we designed a red blood cell-membrane-coated NLC (RBCm-NLC), which was round-like, with a particle size of 60.33 ± 3.04 nm and a core-shell structure. Its stability was good, the drug paclitaxel (PTX) release from RBCm-PTX-NLC was less than 30% at pH7.4 and pH6.5, and the integrity of RBC membrane surface protein was maintained before and after preparation. Additionally, in vitro assays showed that, with the RBCm coating, the cellular uptake of the NLC by cancer cells was significantly enhanced. RBCm-NLC can avoid recognition by macrophage cells and prolong circulation time in vivo. In S180 tumor-bearing mice, the DiR-labeled RBCm-NLC group showed a stronger fluorescence signal and longer retention in tumor tissues, indicating a prompt tumor-targeting effect and extended blood circulation. Importantly, RBCm-PTX-NLC enhanced the antitumor effect and extended the survival period significantly in vivo. In summary, biomimetic NLC offered a novel strategy for drug delivery in cancer therapy.

Structure Elucidation and Mechanistic Study of a New Dimeric Degradant in Ropinirole Hydrochloride Extended-Release Tablets.

PURPOSE: The goal of the study was to elucidate the structure of a new degradant (1,3'-Dimer), generated in the stability testing of ropinirole extended-release tablets, and the formation mechanism of 1,3'-Dimer and its isomer (3,3'-Dimer). METHODS: The strategy of combining LC-PDA/UV-MSn (n = 1, 2) and NMR in conjunction with mechanism-based forced degradation study was employed to identify the structure of the unknown degradant and the formation mechanism of this dimeric degradant as well as its isomer, 3,3'-Dimer. The forced degradation was conducted by treating ropinirole API with formaldehyde under alkaline catalysis. A compatibility study between ropinirole and lactose was also performed. RESULTS: The degradant was isolated from the forced degradation sample and characterized by LC-PDA/UV-MSn as well as NMR measurement. The impurity was identified as a new dimeric degradant of ropinirole connected by a methylene bridge via the 1- and 3'-position of each ropinirole unit (i.e., 1,3'-Dimer of ropinirole), which is an isomer of a known dimeric degradant of ropinirole, namely 3,3'-Dimer. CONCLUSIONS: The newly occurred unknown degradant in ropinirole extended-release tablets was elucidated as the methylene-bridged 1,3'-Dimer of ropinirole. Based on the mechanistic study, 1,3'-Dimer and its isomer (3,3'-Dimer) were both formed by the reaction of ropinirole with residual formaldehyde present or formed in lactose, a main excipient of the formulation.

Spatiotemporal variations of the start of thermal growing season for grassland on the Qinghai-Tibetan Plateau during 1961-2014.

The start of thermal growing season (STGS) is an important indicator for climate change effects on regional plant growth and development. This study comprehensively investigated and compared the spatiotemporal variations in STGS at 0 °C (STGS_0), 5 °C (STGS_5), and 10 °C (STGS_10) thresholds for grassland on the Qinghai-Tibetan Plateau (QTP) during 1961-2014. Although elevation was the predominant influencing factor of the spatial variations of STGSs, the effect of latitude should not be ignored at the low-elevation regions, especially for the STGS with a low-temperature threshold (e.g., STGS_0). With the decrease of temperature thresholds, the effect of elevation became weaker, while the effect of latitude became stronger. Significant advancing trends were observed in all the three STGSs, with greater advancing rate for STGS_0 (0.23 days·year-1) than that of STGS_5 (0.15 days·year-1) and STGS_10 (0.16 days·year-1). More obvious advancing trends were found after 1980, which coincided with more rapid climate warming. The advancing trends weakened after 1998 when climate warming hiatus occurred. Since positive and negative impacts may be simultaneously induced by the advanced STGSs, more observations are still needed to analyze their impacts on the growth and development of alpine grassland on the QTP.

A Comparative Study of the Use of Mesoporous Carbon and Mesoporous Silica as Drug Carriers for Oral Delivery of the Water-Insoluble Drug Carvedilol.

Mesoporous carriers have been extensively applied to improve the dissolution velocity and bioavailability of insoluble drugs. The goal of this work was to compare the drug-loading efficiency (LE) and drug-dissolution properties of mesoporous silica nanoparticles (MSN) and mesoporous carbon nanoparticles (MCN) as drug vectors oral delivery of water-insoluble drugs. For this purpose, MSN and MCN with similar particle size, surface area, and mesoporous diameter were prepared to precisely evaluate the effects of different textures on the drug-loading and dissolution behavior of insoluble drugs. Carvedilol (CAR), a Bio-pharmaceutic Classification System (BCS) class II drug, was loaded in the MSN and MCN by the solvent adsorption method and solvent evaporation method with different carrier-drug ratios. The carboxylated MCN (MCN-COOH) had a higher LE for CAR than MSN for both the two loading methods due to the strong adsorption effect and π-π stacking force with CAR. In vitro drug dissolution study showed that both MSN and MCN-COOH could improve the dissolution rate of CAR compared with the micronized CAR. In comparison to MSN, MCN-COOH displayed a slightly slower dissolution profile, which may be ascribed to the strong interaction between MCN-COOH and CAR. Observation of cell cytotoxicity and gastrointestinal mucosa irritation demonstrated the good biocompatibility of both MSN and MCN-COOH. The present study encourages further research of different carriers to determine their potential application in oral administration.

Hyaluronic acid-coated single-walled carbon nanotubes loaded with doxorubicin for the treatment of breast cancer.

Hyaluronic acid (HA)-modified amino single-walled carbon nanotubes (NH2-SWCNTs) were developed for targeted delivery of doxorubicin (DOX) to improve breast cancer treatment. HA, which specifically binds to the CD44 receptor, was non-covalently coated on NH2-SWCNTs through simply electrostatic adsorption. The formed SWCNTs-DOX-HA complexes were characterized in terms of morphology, particle size and zeta potential by different techniques. The DOX loading percentage on the SWCNTs-DOX-HA complexes was 81.5±1.0 %. In vitro release study showed that the release of DOX was pH-triggered and was faster at a lower pH 5.5 (tumor cell microenvironment) than that under physiological conditions (pH 7.4), which was beneficial for intracellular drug release. The SWCNTs-DOX-HA showed a significantly improved intracellular delivery of DOX in CD44 overexpressing MDA-MB-231 cells by flow cytometry and confocal microscopy. Of particular importance, the SWCNTs-DOX-HA complexes were better than the unmodified SWCNTs-DOX on inhibiting proliferation and inducing apoptosis of cells. In addition, the migration of MDA-MB-231 cells was significantly blocked by SWCNTs-DOX-HA. In the cancer cell spheroids assay, SWCNTs-DOX-HA exhibited notable effect to inhibit the growth of cancer cell spheroids. All these results indicated that this developed SWCNTs-DOX-HA complexes hold a great promise to be used as an efficient nano-sized anticancer drug formulation for tumor-targeted treatment.

Doubly charged trimeric cluster ions: effective in mutual chiral recognition of tadalafil and three proton pump inhibitors.

Mutual chiral recognition of four stereoisomers of tadalafil and three pairs of enantiomers of proton pump inhibitors (PPIs) including pantoprazole, lansoprazole, and omeprazole, as well as quantitative analysis of enantiomeric excess is achieved on the basis of the competitive fragmentation of doubly charged trimeric NiII cluster ions. Compared with a singly charged trimeric cluster ion, a doubly charged trimeric cluster ion was proved efficient in the recognition of chiral drugs with one or multiple chiral centers, due to its rich fragmentation ions. Upon collision-induced dissociation (CID), the cluster ion [NiII(PPIs)(tadalafil)2]2+ yielded two diagnostic ions [tadalafil + H]+ and [tadalafil - benzo[d][1,3]dixoloe]+ through electrospray ionization quadrupole time-of-flight mass spectrometry. The abundance ratio of the two fragment ions relied mainly on the configuration of PPIs and tadalafil, and therefore the chiral selectivity (Rchiral) of one enantiomer relative to the others is different. The chiral recognition of all four stereoisomers of tadalafil was achieved by using S configuration PPIs as references, and S-omeprazole showed the best selectivity. The Rchiral values for R,R/S,S, R,S/S,R, R,R/R,S and R,R/S,R-tadalafils were 1.47, 1.17, 2.37, and 2.10, respectively. In a reciprocal process, the Rchiral was 1.36 and 1.31 for R/S-pantoprazole and R/S-lansoprazole, respectively, by using R,R-tadalafil as a reference. Although omeprazole is a racemic drug, it can also be discriminated with S-omeprazole. Calibration curves were constructed with favorable correlation coefficients (r2 > 0.991) by relating the ln(Rchiral) values to the isomeric composition in a mixture. The sensitivity of the methodology allows mixtures to be analyzed for the enantiomeric excess (ee) by recording the ratios of fragment ion abundances in a mass spectrum. The sensitivity of the methodology allowed the determination of enantiomeric impurities of 5% molar composition in individual compounds present in mixtures; the diastereoisomeric impurity of R,R-tadalafil could be quantified even at 1%. We believe that the developed method not only has scientific significance in qualitative and quantitative chiral analyses of tadalafil and PPIs, but also provides great opportunity for enabling the discrimination on a wide range of chiral drugs.

Preparation of novel porous starch microsphere foam for loading and release of poorly water soluble drug.

BACKGROUND: Organic porous material is a promising carrier for enhancing the dissolution of poorly water soluble drug. The aim of the present study was to enhance dissolution and oral bioavailability of lovastatin (LV) by preparing a porous starch microsphere foam (PSM) using a novel method, meanwhile, looking into the mechanism of improving dissolution of LV. METHODS: PSM was prepared by the W/O emulsion-freeze thawing method. The porous structure of PSM was characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. The adsorption role of nanopores on the drug dissolution and physical state of LV was systematically studied by instrumental analysis, and in vitro and in vivo drug dissolution studies. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate carrier cytotoxicity. RESULTS: The SEM images of PSM showed nanometer-sized pores. Physical state characterization indicated that porous structure effectively limited the degree of crystallinity of LV. The results of in vitro and in vivo tests testified that PSM accelerated the release of LV and enhanced its oral bioavailability in comparison with crude LV and commercial capsules. The loaded PSM powder indicated a good physical stability under storage for 12 months. MTT assay shows PSM has no toxicity for Caco-2 cell. CONCLUSION: The preparation was a promising method to produce small and uniform PSM with markedly enhanced dissolution rate and oral bioavailability due to the spatial confinement effect of porous structure. The present work demonstrates the significant potential for the use of PSM as a novel delivery system for poorly water soluble drugs.

Regional differences in the impact paths of climate on aboveground biomass in alpine grasslands across the Qinghai-Tibet Plateau.

Alpine grasslands on the Qinghai-Tibet Plateau (QTP) play an essential role in water conservation, biodiversity protection and climate feedback, with aboveground biomass (AGB) serving as a crucial indicator of grassland health and functionality. To date, studies have independently explored the phenological differences, cumulative effects, and spatial variability of climatic impacts on biomass/productivity in alpine grasslands. Nevertheless, the cascading effects regarding climate and phenology on AGB still present knowledge gaps. Here, using peak AGB measurements, remote sensing and gridded climate data in the QTP alpine grasslands during 2002-2018, we systematically analyzed the impact paths of climatic variables (i.e., cumulative precipitation, CP; growing degree-days, GDD) and phenology-mediated paths (start and peak date of the growing season, SOS and POS) on AGB and their regional differences. During the preseason (pre60) or the growing season (sos-pos), climate primarily directly impacted variations in AGB across different climatic regions, although a phenology-mediated path by which climate indirectly affected AGB existed (i.e., GDDsos-pos → POS → AGB). Three general patterns were revealed: In the plateau temperate arid regions, an increase in CPpre60 significantly promoted AGB (path coefficient w = 0.61-0.71), whereas an increase in GDDpre60 inhibited AGB (w = -0.42 ~ -0.47); In the plateau sub-cold regions, increases in both CPsos-pos and GDDsos-pos significantly promoted AGB, respectively (w = 0.46-0.81 and w = 0.37-0.70); Similarly, in the plateau temperate arid or semi-arid regions, increases in CPsos-pos also significantly promoted the AGB (w = 0.56-0.73). This study highlights that the water and heat accumulation mainly exert direct impacts on alpine grassland AGB across various climatic regions and phenological stages, providing insights into the mechanism driving AGB by climate and phenology during spring and summer.

Grazing affects ecosystem traits by regulating plateau pika activities at the landscape scale.

The mechanism underlying the effects of livestock grazing on grassland ecosystem traits has been greatly discussed. However, as a common small burrowing mammal on the Tibetan Plateau grasslands, the plateau pika's (Ochotona curzoniae) influence on alpine grassland ecosystem traits has rarely been investigated, especially beyond the plot scale. In this study, we flew an unmanned aerial vehicle (UAV) over a grassland landscape under grazing and nongrazing treatments. Mounted visible spectral remote sensing, in combination with field surveys, was utilized to explore how livestock and pika grazing modify grassland ecosystem traits at the landscape scale on the Tibetan Plateau (TP). Using object-oriented classification and partial least squares regression, we retrieved the pika burrow distribution and grassland ecosystem traits. Then, the relationships among livestock grazing, pika burrowing and ecosystem traits were evaluated. The results indicated that livestock grazing reduces the alpine meadow community height by 0.13 cm and the species number by 0.25 while increasing the vegetation coverage by 9.69 % and the aboveground biomass (AGB) by 10.07 g/m2. A lower statue grassland community with greater coverage caused by livestock grazing promotes pika burrowing. Pika burrow density increases 100/ha per 1.70 % increase in vegetation coverage, a 1.87 g/m2 increase in AGB or a 0.08 m decrease in community height. Under livestock grazing, both community structure and nutrients are more strongly associated with pika burrow density. The structural equation model demonstrated that livestock grazing regulates pika burrow density by moderating structural value and subsequently affecting nutritional value. Pika burrowing activity explains 40 % of the total variation in nutritional value. Our findings revealed an intrinsic linkage between mammal activities and alpine grassland ecosystems, which can provide guidelines for grassland management through pika population control by adjusting grazing intensity on the TP.

Regional inequalities of future climate change impact on rice (Oryza sativa L.) yield in China.

The implications of climate change for rice yield have significant repercussions for food security, particularly in China, where rice cultivation is diverse, involving various cropping intensities, management practices, and climate conditions across numerous regions. The regional discrepancies in the impact of climate change on rice yield in China, however, are yet to be fully understood. Using the ORYZA(v3) model and future climate data from 2025 to 2084, gathered from ten climate models and three climate change scenarios (RCP2.6, RCP4.5, and RCP8.5), we conducted an investigation into these regional discrepancies. Our findings suggest a projected average decline in rice yield ranging from 3.7 % to 16.4 % under both rainfed and fully irrigated conditions across different scenarios. Central, eastern, and northwestern China could face the most significant climate change impacts on both rainfed and irrigated rice, with yield reductions reaching 41.5 %. In contrast, low levels of climate change under the RCP2.6 scenario may benefit northeastern (2.4 %) and southern (1.0 %) regions for rainfed and irrigated rice, respectively. Fertilization effects from elevated CO2 could counterbalance climate change's negative impact, resulting in yield increases in all Chinese rice-growing regions, excluding the northwest. The primary factor influencing rice yield changes in all regions under the RCP4.5 and RCP8.5 scenarios was temperature. However, precipitation, solar radiation, and relative humidity had notable and sometimes dominant effects, especially under the RCP2.6 scenario. These results highlight the divergent, even contradictory, rice yield responses to climate change across China, underlining the need to account for regional differences in large-scale impact studies. The study's findings can inform future policy decisions regarding ensuring regional and national food security in China.

Polysialic acid-functionalized liposomes for efficient honokiol delivery to inhibit breast cancer growth and metastasis.

To improve the anti-metastasis effects of honokiol (HNK) on breast cancer, we designed cationic liposomes (Lip) in which HNK was encapsulated into Lip, and its surface was modified with negatively charged polysialic acid (PSA-Lip-HNK) for efficient treatment of breast cancer. PSA-Lip-HNK possessed a homogeneous spherical shape and high encapsulation efficiency. In vitro 4T1 cell experiments indicated that PSA-Lip-HNK increased cellular uptake and cytotoxicity via the endocytosis pathway mediated by PSA and selectin receptors. Furthermore, the significant antitumor metastasis impact of PSA-Lip-HNK was confirmed by wound healing and cell migration and invasion. Enhanced in vivo tumor accumulation of the PSA-Lip-HNK was observed in 4T1 tumor-bearing mice by living fluorescence imaging. For in vivo antitumor experiments using 4T1 tumor-bearing mice, PSA-Lip-HNK exhibited a higher tumor growth and metastasis inhibition compared with unmodified liposomes. Therefore, we believe that PSA-Lip-HNK well combined biocompatible PSA nano-delivery and chemotherapy, providing a promising drug delivery approach for metastatic breast cancer therapy.

Customized multi-stimuli nanovehicles with dissociable 'bomblets' for photothermal-enhanced synergetic tumor therapy.

Recently, the therapeutic effect of chemotherapy has been obviously impaired due to premature drug release, low tumor penetration, and multidrug resistance of nanoplatforms. In this paper, a novel multiple-sensitive drug delivery system (MC-ss-CDs) was developed by gating long-wavelength emitting carbon dots (CDs) on the openings of mesoporous carbon nanoparticles (MC) through disulfide bonds. The MC with excellent photothermal transition efficiency and high drug storage capacity for doxorubicin (DOX) was used as the delivery carrier. The CDs had multiple functions, including intelligent switching to hinder unwanted release, photothermal therapy (PTT) agents to improve the heat generation effect of MCs and bioimaging trackers to monitor drug delivery. The disulfide bonds, as the linkers between MC carriers and CDs, are stable under normal physical conditions and relatively labile under high GSH concentrations in the cytoplasm of tumor cells. After arriving at the tumor microenvironment, DOX/MC-ss-CDs can rapidly break into DOX/MC and CDs under high GSH concentrations. DOX/MC could realize efficient integration of PTT and chemotherapy on the surface of the tumor by stimuli-responsive DOX release and synergetic heating of MC and CDs. The small-sized CDs with excellent penetrating ability could effectively enter the deep tumor and realize NIR-triggered photothermal ablation. The DOX/MC-ss-CDs showed a chemophotothermal effect with a combination index of 0.38 in vitro and in vivo. Therefore, the DOX/MC-ss-CDs could be employed as a trackable nanovehicle for synergistic chemotherapy and PTT at different depths.

[Division of winter wheat yield estimation by remote sensing based on MODIS EVI time series data and spectral angle clustering].

Crop yield estimation division is the basis of crop yield estimation; it provides an important scientific basis for estimation research and practice. In the paper, MODIS EVI time-series data during winter wheat growth period is selected as the division data; JiangSu province is study area; A division method combined of advanced spectral angle mapping(SVM) and K-means clustering is presented, and tested in winter wheat yield estimation by remote sensing. The results show that: division method of spectral angle clustering can take full advantage of crop growth process that is reflected by MODIS time series data, and can fully reflect region differences of winter wheat that is brought by climate difference. Compared with the traditional division method, yield estimation result based on division result of spectral angle clustering has higher R2 (0.702 6 than 0.624 8) and lower RMSE (343.34 than 381.34 kg x hm(-2)), reflecting the advantages of the new division method in the winter wheat yield estimation. The division method in the paper only use convenient obtaining time-series remote sensing data of low-resolution as division data, can divide winter wheat into similar and well characterized region, accuracy and stability of yield estimation model is also very good, which provides an efficient way for winter wheat estimation by remote sensing, and is conducive to winter wheat yield estimation.