Transferrin-Modified Carprofen Platinum(IV) Nanoparticles as Antimetastasis Agents with Tumor Targeting, Inflammation Inhibition, Epithelial-Mesenchymal Transition Suppression, and Immune Activation Properties.

The inflammatory microenvironment is a central driver of tumor metastasis, intimately associated with the promotion of epithelial-mesenchymal transition (EMT) and immune suppression. Here, transferrin-modified carprofen platinum(IV) nanoparticles Tf-NPs@CPF2-Pt(IV) with promising antiproliferative and antimetastatic properties were developed, which activated by inhibiting inflammation, suppressing EMT, and activating immune responses besides causing DNA injury. The nanoparticles released the active ingredient CPF2-Pt(IV) in a sustained manner and offered enhanced pharmacokinetic properties compared to free CPF2-Pt(IV) in vivo. Additionally, they possessed satisfactory tumor targeting effects via the transferrin motif. Serious DNA damage was induced with the upregulation of γ-H2AX and P53, and the mitochondria-mediated apoptotic pathway Bcl-2/Bax/caspase3 was initiated. Inflammation was alleviated by inhibiting COX-2 and MMP9 and decreasing inflammatory cytokines TNF-α and IL-6. Subsequently, the EMT was reversed by inhibiting the Wnt/ß-catenin pathway. Furthermore, the antitumor immunity was provoked by blocking the immune checkpoint PD-L1 and increasing CD3+ and CD8+ T lymphocytes in tumors.

Decreased formulation pH and protein preheating treatment enhance the interaction, storage stability, and bioaccessibility of caseinate-bound lutein/zeaxanthin.

Heat treatment and pH are crucial factors in the formulation and processing of food and beverages; thus, a thorough understanding of the impact of these factors on the interactions between bioactive constituents and proteins is essential to developing effective protein-based delivery systems. This study explores the influences of pH (ranged from 1.5 to 7.5) and preheating treatment on the characteristics of caseinates-lutein (LU)/zeaxanthin (ZX) complexes and evaluates the potential application of caseinates as protective carriers in xanthophyll-fortified beverages. The properties and interactions of caseinates and two xanthophylls were systematically investigated utilizing a range of spectroscopic techniques, including ultraviolet-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS), fluorescence spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. Caseinates were bound to LU/ZX with a binding constant of the order 105 M-1. Furthermore, ZX exhibited a higher affinity for caseinates than LU. In particular, the decreased pH level of complex formulation and the preheating of caseinates at 85 °C strengthened the binding affinity between LU/ZX and caseinates. The caseinate-LU/ZX complexes effectively improved the chemical stability of LU/ZX and achieved a bioaccessibility rate of over 70 %. This study provides a guide for developing commercially available xanthophyll-fortified beverages and further expanding the application of caseinates as encapsulation carriers for extremely hydrophobic nutrients in the food industry.

Ursodeoxycholic Acid Platinum(IV) Conjugates as Antiproliferative and Antimetastatic Agents: Remodel the Tumor Microenvironment through Suppressing JAK2/STAT3 Signaling.

Tumor microenvironment (TME) is a pivotal factor driving the tumor metastasis and leading to the failure of tumor therapy. Here, a series of ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling the TME through suppressing JAK2/STAT3 signaling was developed. A candidate was screened out, which displayed potent antiproliferative and antimetastatic performance both in vitro and in vivo. It displayed superior pharmacokinetic properties compared to cisplatin. Serious DNA injury was induced, and then mitochondria-mediated apoptosis was initiated through the Bcl-2/Bax/Caspase3 pathway. The JAK2/STAT3 and TGF-ß1 signaling pathways were remarkably inhibited, and pro-death autophagy was subsequently promoted. The inflammatory and hypoxic TME was suppressed by downregulating COX-2, MMP9, and HIF-1α, which resulted in inhibited angiogenesis in tumors by inhibiting the HIF-1α/VEGFA axis. Additionally, the immunosuppressive TME was reversed by blocking the immune checkpoint PD-L1, further improving the density of CD3+ and CD8+ tumor-infiltrating lymphocytes, and promoting macrophage polarization from M2- to M1-type.

A hydroxychloroquine platinum(IV) conjugate displaying potent antimetastatic activities by suppressing autophagy to improve the tumor microenvironment.

Protective autophagy is a promising target for antitumor drug exploration. A hydroxychloroquine (HCQ) platinum(IV) complex with autophagy suppressing potency was developed, which displayed potent antitumor activities with a TGI rate of 44.2% against 4T1 tumors in vivo and exhibited a rather lower toxicity than cisplatin. Notably, it exhibited satisfactory antimetastatic activities toward lung pulmonary metastasis models with an inhibition rate of 49.6% and was obviously more potent than CDDP, which has an inhibition rate of 21.6%. Mechanism detection revealed that it caused serious DNA damage and upregulated the expression of γ-H2AX and p53. More importantly, the incorporation of an autophagy inhibitor HCQ endowed the platinum(IV) complex with potent autophagy impairing properties by perturbing the lysosomal function in tumor cells, which promoted apoptosis synergistically with DNA injury. Then, the impaired autophagy further led to the suppression of hypoxia and inflammation in the tumor microenvironment by downregulating ERK1/2, HIF-1α, iNOS, caspase1 and COX-2. Adaptive immune response was improved by inhibiting the immune checkpoint PD-L1 and further increasing CD4+ and CD8+ T cells in tumors. Then, tumor metastasis was effectively inhibited by restraining angiogenesis through inhibiting VEGFA, MMP-9, and CD34.

Ciclopirox platinum(IV) conjugates suppress tumors by promoting mitophagy and provoking immune responses.

Mitophagy is an important target for antitumor drugs development. A series of ciclopirox (CPX) platinum(IV) hybrids targeting PTEN induced putative kinase 1 (PINK1)/Parkin mediated mitophagy were designed and prepared as antitumor agents. The dual CPX platinum(IV) complex with cisplatin core was screened out as a candidate, which displayed promising antitumor activities both in vitro and in vivo. Mechanistically, it caused serious DNA damage in tumor cells. Then, remarkable mitochondrial damage was induced accompanied by the mitochondrial membrane depolarization and reactive oxygen species generation, which further promoted apoptosis through the Bcl-2/Bax/Caspase3 pathway. Furthermore, mitophagy was ignited via the PINK1/Parkin/P62/LC3 axis, and exhibited positive influence on promoting the apoptosis of tumor cells. The antitumor immunity was boosted by the block of immune check point programmed cell death ligand-1 (PD-L1), which further increased the density of T cells in tumors. Subsequently, the metastasis of tumor cells was inhibited by inhibiting angiogenesis in tumors.

Canadine Platinum(IV) Complexes Targeting Epithelial-Mesenchymal Transition as Antiproliferative and Antimetastatic Agents.

Epithelial-mesenchymal transition (EMT) is a critical process for cancer progression, which is crucial in inhibiting the immunity in tumors and further boosting tumor metastasis. The suppression of EMT represents a promising strategy for inhibiting metastatic tumors. Herein, a series of new canadine platinum(IV) conjugates with potent antiproliferative and antimetastatic activities were developed, which activated by suppressing EMT and provoking immune response in tumors besides causing DNA injury. The complexes could covalently conjugate to DNA and induce mitochondria-mediated apoptosis via Bcl-2/Bax/caspase3 signaling. The EMT process was remarkably inhibited by suppressing the Wnt/ß-catenin pathway, reversing the inflammatory tumor microenvironment, and inhibiting the HIF-1α pathway, which further resulted in the inhibited angiogenesis in tumors. Moreover, the antitumor immunity was elevated by blocking immune checkpoints PD-L1 and CD47 accompanied by the improvement of CD3+ and CD8+ T lymphocytes and the macrophage polarization from M2- toward M1-type simultaneously in tumors.

Non-covalent complexes of lutein/zeaxanthin and whey protein isolate formed at different pH levels: Binding interactions, storage stabilities, and bioaccessibilities.

Lutein (Lut) and zeaxanthin (Zx) are promising healthy food ingredients; however, the low solubilities, stabilities, and bioavailabilities limit their applications in the food and beverage industries. A protein-based complex represents an efficient protective carrier for hydrophobic ligands, and its ligand-binding properties are influenced by the formulation conditions, particularly the pH level. This study explored the effects of various pH values (2.5-9.5) on the characteristics of whey protein isolate (WPI)-Lut/Zx complexes using multiple spectroscopic techniques, including ultraviolet-visible (UV-Vis), fluorescence, and Fourier transform infrared (FTIR) spectroscopies and dynamic light scattering (DLS). UV-Vis and DLS spectra revealed that Lut/Zx were present as H-aggregates in aqueous solutions, whereas WPI occurred as nanoparticles. The produced WPI-Lut/Zx complexes exhibited binding constants of 104-105 M-1, which gradually increased with increasing pH from 2.5 to 9.5. FTIR spectra demonstrated that pH variations and Lut/Zx addition caused detectable changes in the secondary WPI structure. Moreover, the WPI-Lut/Zx complexes effectively improved the physicochemical stabilities and antioxidant activities of Lut/Zx aggregates during long-term storage and achieved bioaccessibilities above 70% in a simulated gastrointestinal digestion process. The comprehensive data obtained in this study offer a basis for formulating strategies that can be potentially used in developing commercially available WPI complex-based xanthophyll-rich foods.

Multi-spectroscopic and molecular docking studies for the pH-dependent interaction of ß-lactoglobulin with (-)-epicatechin gallate and/or piceatannol: Influence on antioxidant activity and stability.

(-)-Epicatechin gallate (ECG) and piceatannol (PIC) are commonly polyphenols with excellent biological activities. ß-Lactoglobulin (BLG) is a food-grade globule protein and its morphologies are sensitive to pH. This study used experimental and computational methods to determine the interaction of single or combined ECG and PIC with BLG at different pHs. The static quenching process was determined through fluorescence and ultraviolet-visible spectroscopy. Compared with ECG, PIC could significantly bind to BLG with higher affinity. Their binding affinity for BLG with different morphologies followed the tendency of monomer > dimer > tetramer. The negative contribution of van der Waals forces, electrostatic interactions, and hydrogen bonds to ΔHo exceeded the positive contribution of hydrophobic interactions in the spontaneous and exothermic process. The reduced binding affinity in the ternary systems demonstrated the competitive binding between ECG and PIC on BLG, and the hinder effect of ECG or PIC was enhanced with increasing pH. Molecular docking studies revealed the same binding sites of ECG and PIC on various conformations of BLG and identical driven forces as thermodynamic results. Tryptophan and tyrosine were the main participators in the BLG + ECG and BLG + PIC systems, respectively. The conformational changes in the binary and ternary systems could be ascertained through synchronous fluorescence, circular dichroism, and dynamic light scattering. Furthermore, the effects of pH and BLG encapsulation on the antioxidant capacity and stability of ECG or PIC were also implemented. ECG or PIC was the most stable in the (BLG + PIC) + ECG system at pH 6.0. This study could clarify the interaction mechanism between ECG/PIC and BLG and elucidate the pH effect on their binding information. The results will provide basic support for their usage in food processing and applications.

Off-pump versus on-pump coronary artery bypass grafting in elderly patients at 30 days: a propensity score matching study.

BACKGROUND: Elderly patients are at increased risk of perioperative morbidity and mortality after conventional on-pump coronary artery bypass grafting (ONCABG). This study was to determine whether such high-risk population would benefit from off-pump coronary artery bypass grafting (OPCABG). METHODS: A retrospective analysis was performed on patients aged 65 years or older who underwent isolated coronary artery bypass grafting for the first time in Wuhan Union Hospital from January 2015 to January 2021. We used propensity score matching to adjust for differences in baseline characteristics between the ONCABG and OPCABG groups. Morbidity and mortality within 30 days after surgery were compared between the two groups. All operations were performed by experienced cardiac surgeons. RESULTS: A total of 511 patients (ONCABG 202, OPCABG 309) were included. After 1:1 matching, the baseline characteristics of the two groups were comparable (ONCABG 173, OPCABG 173). The OPCABG group had higher rate of incomplete revascularization (13.9% vs. 6.9%; P = .035) than the ONCABG group. However, OPCABG reduced the risk of postoperative renal insufficiency (15.0% vs. 30.1%; P = .001) and reoperation for bleeding (0.0% vs. 3.5%; P = .030). There were no significant differences in early postoperative mortality, myocardial infarction, stroke, and other outcomes between the two groups. CONCLUSIONS: OPCABG is an alternative revascularization method for elderly patients. It reduces the risk of early postoperative renal insufficiency and reoperation for bleeding.

Series of Desloratadine Platinum(IV) Hybrids Displaying Potent Antimetastatic Competence by Inhibiting Epithelial-Mesenchymal Transition and Arousing Immune Response.

Metastasis is the major obstacle to the survival of cancer patients. Herein, a series of new desloratadine platinum(IV) conjugates with promising antiproliferative and antimetastatic activities were developed and evaluated. The candidate complex caused significant DNA damage and stimulated mitochondrial apoptosis through the Bcl-2/Bax/caspase3 pathway. Then, it suppressed the epithelial-mesenchymal transition (EMT) process in tumors effectively through NMT-1/HPCAL1 and ß-catenin signaling. Subsequently, the angiogenesis was inhibited with the downregulation of key proteins HIF-1α, VEGFA, MMP-9, and CD34. Moreover, the antitumor immunity was effectively aroused by the synergism of EMT reversion and decrease of the histamine level; then, the macrophage polarization from M2- to M1-type and the increase of CD4+ and CD8+ T cells were triggered simultaneously in tumors.

A High MCT-Based Ketogenic Diet Suppresses Th1 and Th17 Responses to Ameliorate Experimental Autoimmune Encephalomyelitis in Mice by Inhibiting GSDMD and JAK2-STAT3/4 Pathways.

SCOPE: Inflammation and pyroptosis play important roles in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In this study, we evaluated the therapeutic potential of ketogenic diet (KD) in EAE. METHODS AND RESULTS: The administration of KD reduces demyelination and microglial activation in the spinal cord of EAE mice. Meanwhile, KD decreases the levels of Th1 and Th17 associated cytokines/transcription factors production (T-bet, IFN-γ, RORγt, and IL-17) and increases those of Th2 and Treg cytokines/transcription factors (GATA3, IL-4, Foxp3, and IL-10) in the spinal cord and spleen. Corresponding, KD reduces the expression of chemokines in EAE, which those chemokines associate with T-cell infiltration into central nervous system (CNS). In addition, KD inhibits the GSDMD activation in microglia, oligodendrocyte, CD31+ cells, CCR2+ cells, and T cells in the spinal cord. Moreover, KD significantly decreases the ratios of p-JAK2/JAK2, p-STAT3/STAT3, and p-STAT4/STAT4, as well as GSDMD in EAE mice. CONCLUSIONS: this study demonstrates that KD reduces the activation and differentiation of T cells in the spinal cord and spleen and prevents T cell infiltration into CNS of EAE via modulating the GSDMD and STAT3/4 pathways, suggesting that KD is a potentially effective strategy in the treatment of MS.

A series of ligustrazine platinum(IV) complexes with potent anti-proliferative and anti-metastatic properties that exert chemotherapeutic and immunotherapeutic effects.

The development of novel anticancer drugs with antiproliferative and antimetastatic activities is of great importance in the pharmaceutical field. Herein, a series of ligustrazine (LSZ) platinum(IV) complexes with chemotherapeutic and immunotherapeutic effects were designed, prepared and evaluated as antitumor agents for the first time. Complex 4 with potent antitumor activities both in vitro and in vivo was screened out as a candidate. Notably, it displays significantly more effective anti-metastatic activities than the platinum(II) drugs cisplatin and oxaliplatin. Mechanism detection discloses that it causes serious DNA damage and increases the expression of γ-H2AX and P53. Then, the apoptosis of tumor cells is promoted by activating the mitochondrial apoptotic pathway Bcl-2/Bax/caspase-3 and causing autophagy via modulating LC3-I/II and P62 expression. Furthermore, the immune therapeutic responses are significantly elevated by blocking HIF-1α, ERK 1/2 and COX-2 pathways to reduce PD-L1 expression, and further increasing CD3+ and CD8+ T cells to elevate T cell immunity in tumors. Tumor metastasis is blocked by the synergistic functions of DNA damage, hypoxia modulation and immune activation.

Impact of hypromellose acetate succinate and Soluplus® on the performance of ß-carotene solid dispersions with the aid of sorbitan monolaurate: In vitro-in vivo comparative assessment.

Solid dispersions (SDs) possess the potential to enhance the bioavailability of insoluble active pharmaceutical ingredients (APIs) by effectively converting them into amorphous state. However, SDs have a tendency to recrystallize unless appropriate excipients are employed. The objective of this study was to evaluate the ability of hypromellose acetate succinate HF (HPMCAS-HF) and Soluplus® to inhibit the recrystallization of ß-carotene and improve its in vivo bioavailability through the fabrication of ternary ß-carotene solid dispersions (SDs) with the aid of specific surfactant. Due to rapid micellization, the dissolution profiles of ß-carotene SDs based on HPMCAS-HF/Span 20 (5:5, w/w) or Soluplus®/Span 20 (6:4, w/w) combinations exhibited significant improvement, which were almost 7-10 times higher than ß-carotene bulk powder. DSC and PXRD analysis indicated a notable reduction in the crystallinity degree of ß-carotene within the SDs. The stability study demonstrated a half-life of ß-carotene in the SDs exceeding 30 days. Additionally, the in vivo pharmacokinetics analysis confirmed that the cellulose derivatives/surfactant combinations significantly enhanced the bioavailability of ß-carotene by 1.37-fold and 2.3-fold, respectively. Notably, the HPMCAS-HF/Span 20 combination exhibited superior performance. Consequently, the HPMCAS-HF/Span 20 combination held potential for the advancement of an effective drug delivery system for ß-carotene.

Design, Synthesis, and Activity Evaluation of Novel Dual-Target Inhibitors with Antifungal and Immunoregulatory Properties.

Dual-target (CYP51/PD-L1) plays an important role in the process of fungal proliferation and immune suppression. A series of novel quinazoline compounds with dual-target inhibition function was constructed using the skeleton growth method, and their structures were synthesized, characterized, and evaluated. Among them, the perfected compounds (L11, L20, L21) were selected for further study, which exhibited remarkable biological activity against different fungal strains (MIC50, 0.25-2.0 µg/mL) in vitro. On the one hand, these compounds inhibited CYP51 activity, induced ROS aggregation, and mitochondrial damage; this ultimately caused fungal lysis and death. On the other hand, they also effectively activated the body's immune ability by blocking the interaction between PD-L1 and PD-1, slowed down the inflammatory reaction, and accelerated the recovery process of fungal infections.

Construction and Evaluation of Novel Dual-function Antifungal Inhibitors and Covalent Organic Framework Carriers Based on the Infection Microenvironment.

In this study, PD-L1 and CYP51 were selected as key dual-target enzymes, which play an important role in the process of fungal proliferation and immune suppression. A series of novel bifonazole dual-target compounds were designed through the method of fragment combination. Their chemical structure was synthesized, characterized, and evaluated. Among them, the compounds (10c-1, 14a-2, 17c-2) exhibited excellent antifungal and antidrug-resistant fungal activity in vitro. In particular, the preferred compound 14a-2 with high-efficiency dual-target inhibitor ability could block the fungal proliferation and activate the organism's immune efficacy. Moreover, the corresponding covalent organic framework carrier was also successfully constructed to improve its bioavailability. This significantly accelerated the body's recovery process from fungal infection in vivo. In summary, this study expanded the scientific frontier of antifungal drugs and provided a feasible candidate pathway for clinical treatment of fungal infections.

Large-scale automatic extraction of agricultural greenhouses based on high-resolution remote sensing and deep learning technologies.

Widely used agricultural greenhouses are critical in the development of facility agriculture because of not only their huge capacity in food and vegetable supplies, but also their environmental and climatic effects. Therefore, it is important to obtain the spatial distribution of agricultural greenhouses for agricultural production, policy making, and even environmental protection. Remote sensing technologies have been widely used in greenhouse extraction mainly in small or local regions, while large-scale and high-resolution (~ 1-m) greenhouse extraction is still lacking. In this study, agricultural greenhouses in an important agricultural province (Shandong, China) are extracted by the combination of high-resolution remote sensing images from Google Earth and deep learning algorithm with high accuracy (94.04% for mean intersection over union over test set). The results demonstrated that the agricultural greenhouses cover an area of 1755.3 km2, accounting for 1.11% of the total province and 2.31% of total cultivated land. The spatial density map of agricultural greenhouses also suggested that the facility agriculture in Shandong has obviously regional aggregation characteristics, which is vulnerable in both environment and economy. The results of this study are useful and meaningful for future agriculture planning and environmental management.

Mechanical Performances Analysis and Prediction of Short Plant Fiber-Reinforced PLA Composites.

Plant fiber-reinforced polylactic acid (PLA) exhibits excellent mechanical properties and environmental friendliness and, therefore, has a wide range of applications. This study investigated the mechanical properties of three short plant fiber-reinforced PLA composites (flax, jute, and ramie) using mechanical testing and material characterization techniques (SEM, FTIR, and DSC). Additionally, we propose a methodology for predicting the mechanical properties of high-content short plant fiber-reinforced composite materials. Results indicate that flax fibers provide the optimal reinforcement effect due to differences in fiber composition and microstructure. Surface pretreatment of the fibers using alkali and silane coupling agents increases the fiber-matrix interface contact area, improves interface performance, and effectively enhances the mechanical properties of the composite. The mechanical properties of the composites increase with increasing fiber content, reaching the highest value at 40%, which is 38.79% higher than pure PLA. However, further increases in content lead to fiber agglomeration and decreased composite properties. When the content is relatively low (10%), the mechanical properties are degraded because of internal defects in the material, which is 40.42% lower than pure PLA. Through Micro-CT technology, the fiber was reconstructed, and it was found that the fiber was distributed mainly along the direction of injection molding, and the twin-screw process changes the shape and length of the fiber. By introducing the fiber agglomeration factor function and correcting the Halpin-Tsai criterion, the mechanical properties of composite materials with different contents were successfully predicted. Considering the complex stress state of composite materials in actual service processes, a numerical simulation method was established based on transversely isotropic material using the finite element method combined with theoretical analysis. The mechanical properties of high-content short plant fiber-reinforced composite materials were successfully predicted, and the simulation results showed strong agreement with the experimental results.

Ketogenic diet attenuates neuroinflammation and induces conversion of M1 microglia to M2 in an EAE model of multiple sclerosis by regulating the NF-κB/NLRP3 pathway and inhibiting HDAC3 and P2X7R activation.

Multiple sclerosis (MS) is an autoimmune disorder characterized by demyelination and neurodegeneration in the central nervous system (CNS); severe symptoms lead MS patients to use complementary treatments. Ketogenic diet (KD) shows wide neuroprotective effects, but the precise mechanisms underlying the therapeutic activity of KD in MS are unclear. The present study established a continuous 24 days experimental autoimmune encephalomyelitis (EAE) mouse model with or without KD. The changes in motor function, pathological hallmarks of EAE, the status of microglia, neuroinflammatory response and intracellular signaling pathways in mice were detected by the rotarod test, histological analysis, real-time PCR (RT-PCR) and western blotting. Our results showed that KD could prevent motor deficiency, reduce clinical scores, inhibit demyelination, improve pathological lesions and suppress microglial activation in the spinal cord of EAE mice. Meanwhile, KD shifted microglial polarization toward the protective M2 phenotype and modified the inflammatory milieu by downregulating the production of pro-inflammatory cytokines, including TNF-α, IL-1ß and IL-6, as well as upregulating the release of anti-inflammatory cytokines such as TGF-ß. Furthermore, KD decreased the expression levels of CCL2, CCR2, CCL3, CCR1, CCR5, CXCL10 and CXCR3 in the spinal cord and spleen with reduced monocyte/macrophage infiltration in the CNS. In addition, KD inhibits NLRP3 activation in the microglia, as revealed by the significantly decreased co-expression of NLRP3+ and Iba-1+ in the KD + EAE group. Further studies demonstrated that KD suppresses inflammatory response and M1 microglial polarization by inhibiting the TLR4/MyD88/NF-κB/NLRP3 pathway, the JAK1/STAT1 pathway, HDAC3 and P2X7R activation, as well as up-regulation of JAK3/STAT6.

Prediction of Suitable Habitat Distribution of Cryptosphaeria pullmanensis in the World and China under Climate Change.

Years of outbreaks of woody canker (Cryptosphaeria pullmanensis) in the United States, Iran, and China have resulted in massive economic losses to biological forests and fruit trees. However, only limited information is available on their distribution, and their habitat requirements have not been well evaluated due to a lack of research. In recent years, scientists have utilized the MaxEnt model to estimate the effect of global temperature and specific environmental conditions on species distribution. Using occurrence and high resolution ecological data, we predicted the spatiotemporal distribution of C. pullmanensis under twelve climate change scenarios by applying the MaxEnt model. We identified climatic factors, geography, soil, and land cover that shape their distribution range and determined shifts in their habitat range. Then, we measured the suitable habitat area, the ratio of change in the area of suitable habitat, the expansion and shrinkage of maps under climate change, the direction and distance of range changes from the present to the end of the twenty-first century, and the effect of environmental variables. C. pullmanensis is mostly widespread in high-suitability regions in northwestern China, the majority of Iran, Afghanistan, and Turkey, northern Chile, southwestern Argentina, and the west coast of California in the United States. Under future climatic conditions, climate changes of varied intensities favored the expansion of suitable habitats for C. pullmanensis in China. However, appropriate land areas are diminishing globally. The trend in migration is toward latitudes and elevations that are higher. The estimated area of possible suitability shifted eastward in China. The results of the present study are valuable not only for countries such as Morocco, Spain, Chile, Turkey, Kazakhstan, etc., where the infection has not yet fully spread or been established, but also for nations where the species has been discovered. Authorities should take steps to reduce greenhouse gas emissions in order to restrict the spread of C. pullmanensis. Countries with highly appropriate locations should increase their surveillance, risk assessment, and response capabilities.

Spectroscopic, calorimetric and cytotoxicity studies on the combined binding of daunorubicin and acridine orange to a DNA tetrahedron.

Chemotherapy-phototherapy (CTPT) combination drugs co-loaded by targeted DNA nanostructures can achieve controlled drug delivery, reduce toxic side effects and overcome multidrug resistance. Herein, we constructed and characterized a DNA tetrahedral nanostructure (MUC1-TD) linked with the targeting aptamer MUC1. The interaction of daunorubicin (DAU)/acridine orange (AO) alone and in combination with MUC1-TD and the influence of the interaction on the cytotoxicity of the drugs were evaluated. Potassium ferrocyanide quenching analysis and DNA melting temperature assays were used to demonstrate the intercalative binding of DAU/AO to MUC1-TD. The interactions of DAU and/or AO with MUC1-TD were analyzed by fluorescence spectroscopy and differential scanning calorimetry. The number of binding sites, binding constant, entropy and enthalpy changes of the binding process were obtained. The binding strength and binding sites of DAU were higher than those of AO. The presence of AO in the ternary system weakened the binding of DAU to MUC1-TD. In vitro cytotoxicity studies demonstrated that the loading of MUC1-TD augmented the inhibitory effects of DAU and AO and the synergistic cytotoxic effects of DAU + AO on MCF-7 cells and MCF-7/ADR cells. Cell uptake studies showed that the loading of MUC1-TD was beneficial in promoting the apoptosis of MCF-7/ADR cells due to its enhanced targeting to the nucleus. This study has important guiding significance for the combined application of DAU and AO co-loaded by DNA nanostructures to overcome multidrug resistance.