Sheet metal forming prediction is a research frontier in the field of high-end equipment such as automobile and aerospace, especially the anisotropy of sheet metal caused by rolling process. How to balance the prediction accuracy and application convenience of anisotropic constitutive model has not been effectively solved. In this study, by introducing the azimuth of the stress principal axis, the anisotropic parameters determination method for coupling multi-dimensional stress and r-value experimental data was given, and the Hill48 modified model with the prediction accuracy of the high-order yield equation which can be applied to the associated flow criterion was established. The modified model improved the ability to characterize different stress states according to the characteristics of sheet metal forming, and the asymmetric stress state between uniaxial and symmetric biaxial stress states was described by interpolation functions. Hill48 modified model was developed to ABAQUS/VUMAT finite element code to simulate the deep drawing process of cylindrical cup and square box. The results show that the developed model can clearly reveal the influence of different stress states on the forming parts, and significantly improve the forming prediction accuracy. This study provides an idea for overcoming the problem of anisotropic yield model considering both application convenience and prediction accuracy, and has important theoretical significance and application value for the development of forming technology of complex components.

Currently, intraperitoneal (IP) chemoimmunotherapy offers synergistic effect, pharmacokinetic advantages and reduced systemic toxicity, achieving significant progress in peritoneal metastatic ovarian cancer (OC). However, its efficacy is limited by poor drug retention, lack of targeting, inadequate tumor penetration, drug resistance, and immunosuppression tumor microenvironment (TME). To address these challenges, a "three-in-one" thermosensitive gel system (PM/LOS@FLP/P1@G) was developed. Here, platinum prodrug (Pt-2CLB), TME modulator losartan (LOS), and immune checkpoint inhibitor (ICI) anti-PD-1 (P1) are integrated into a hierarchical micelle-liposome-thermosensitive gel structure, resulting in enhanced chemo-immunotherapy. Specifically, the enhancement of antitumor efficacy primarily involves five mechanisms: (i) prolonged IP retention and tumor tissue contact-dependent active targeting mediated by thermosensitive gel and folate-targeting; (ii) matrix metalloproteinase (MMP) and reduced glutathione (GSH)-triggered spatiotemporally sequential delivery of LOS to cancer-associated fibroblasts (CAFs), Pt-2CLB to tumor cells, and P1 to the PD-1/PD-L1 axis; (iii) the DNA damage, GSH depletion, and ROS accumulation induced by Pt-2CLB not only amplify chemotherapeutic efficacy while suppressing drug resistance but also activate the cGAS-STING signaling pathway, thereby enhancing immune responses; (iv) the blockade of transforming growth factor-β (TGF-β)/Smad signaling pathway by LOS inhibits CAFs activation and tumor extracellular matrix (ECM) production, thereby promoting the penetration of drugs and immune cells, boosting chemoimmunotherapy; (v) chemoimmunotherapy synergy exerts potent antitumor effects. In summary, PM/LOS@FLP/P1@G exhibited excellent antitumor efficacy and safety, demonstrating a significant tumor inhibition rate (93.28 %) and survival extension, while fostering immune memory to prevent recurrence, representing a promising IP chemoimmunotherapy strategy for peritoneal metastatic OC.

Abstract Targeted inhibition of intestinal human carboxylesterase 2A (hCES2A) represents a promising strategy to mitigate irinotecan-induced intestinal toxicity (IIT). Herein, a rational molecular engineering strategy was adopted for a high-performance near-infrared (NIR) fluorogenic probe of hCES2A. First, HDCI was identified as an ideal fluorophore scaffold (λex/λem = 510 nm/720 nm), exhibiting a large Stokes shift (210 nm), high metabolic stability, and excellent endoplasmic reticulum (ER)-targeting capability. Further investigations established PA-HDCI as a robust ER-localized probe for monitoring hCES2A activity across diverse biological systems. The PA-HDCI-based high-throughput screening assay identified A4 as an extremely potent covalent hCES2A inhibitor (IC50 = 0.052 nM). In vivo studies showed that A4 exhibited favorable safety profiles and robust therapeutic efficacy to ameliorate IIT in tumor-bearing mice. Collectively, this work devises a novel NIR fluorogenic probe for in situ monitoring of hCES2A in living systems, and establishes a high-throughput platform for discovering hCES2A inhibitors to combat IIT.

Human catechol-O-methyltransferase (COMT) is a key target for neuropsychiatric disorders. Inhibiting COMT to prevent levodopa (L-DOPA) metabolism is a crucial strategy for Parkinson's disease (PD) treatment. While clinically used COMT inhibitors are primarily nitrocatechol-based, they often cause adverse effects, prompting efforts to develop safer non-nitrocatechol alternatives. In this study, baicalein (BA) was identified as a potent lead compound for COMT inhibition after screening a series of natural flavonoids using a fluorescence-based visualization inhibitor screening method. Subsequent multi-dimensional structural optimizations addressed the druggable deficiencies of BA, resulting in compound BA24, which demonstrated a 26-fold increase in cellular COMT inhibition and approximately 10-fold improvements in metabolic stability, membrane permeability and oral bioavailability, respectively, compared to BA. Mechanistically, BA24 competitively inhibited COMT by binding to the catechol pocket with a Ki of 89.28 nM. Furthermore, BA24 exhibited favorable safety profiles and significantly modulated L-DOPA metabolism in rats. Additionally, the relationships between the structural properties, inhibitory activity and metabolic stability of flavonoids as COMT inhibitors were comprehensively investigated. Collectively, this work not only presents a novel non-nitrocatechol COMT inhibitor with favorable safety profiles and potent anti-COMT effects both in vitro and in vivo, but also provides valuable insights into optimizing the druggability of flavonoids as lead compounds.

To explore and expand the chemical space of natural products, there is an urgent need for efficient and functional modification of natural products. Here, a photoinduced strategy is reported to access flavanone-based pseudonatural products via late-stage functionalization. This mild procedure enables the chemical evolution of diverse flavanones via introduction of 1,1-diarylalkane scaffolds. The method features mild reaction conditions, operational simplicity, high functional group tolerance, and scalability. Moreover, the cheminformatics results indicate that the pseudonatural products possess excellent drug-like properties and shape diversity. Finally, the catechol-O-methyltransferase (COMT) inhibitory activity analysis demonstrated that compounds 26d and 28d exhibit potent COMT inhibition, with IC50 values of 85.2 and 99.7 nM, respectively, providing valuable insights for the development of novel flavanone-based non-nitrocatechol COMT inhibitors for Parkinson's disease treatment.

Food allergy (FA) poses a growing global food safety concern, yet no effective cure exists in clinics. Previously, we discovered a potent antifood allergy compound, butyrolactone I (BTL-I, 1), from the deep sea. Unfortunately, it has a very low exposure and poor pharmacokinetic (PK) profile in rats. Therefore, a series of structural optimizations toward the metabolic pathways of BTL-I were conducted to provide 18 derives (2-19). Among them, BTL-MK (19) showed superior antiallergic activity and favorable pharmacokinetics compared to BTL-I, being twice as potent with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, C-max and area under the concentration-time curve (AUC(0-infinity)) were 565 and 204 times higher than those of BTL-I, respectively. These findings suggest that butyrolactone methyl ketone (BTL-BK) could serve as a drug candidate for the treatment of FAs and offer valuable insights into optimizing the druggability of lead compounds.

Hypoxia-inducible factors (HIFs) play a key role in regulating cellular responses to low-oxygen conditions, particularly in promoting angiogenesis in tumor microenvironments. Aberrant HIF signaling enhances tumor growth and contributes to resistance against chemotherapy and radiotherapy. Targeting the HIF pathway has emerged as a promising strategy for cancer therapy. This study aimed to identify novel inhibitors of HIF signaling and evaluate their potential against the HIF-vascular endothelial growth factor (VEGF) axis for antiangiogenic therapy. In screening our in-house drug library using hypoxia response element dual-luciferase assay, HST3782, a novel 3-hydroxy-8-azabicyclo[3.2.1]octane-bridged compound, was identified as a promising HIF inhibitor, with IC50 of 1.028 mu mol/L. In this work, the inhibitory effect of HST3782 on HIF signaling was confirmed in triple-negative breast cancer cells (SUM159) under hypoxic conditions (1% O-2). Quantitative real-time polymerase chain reaction suggested the inhibitory effect of HST3782 on the expression of angiogenic genes, including VEGFa, VEGFR-1, BNIP3, and SERPINE1 in 786-O cells. Zebrafish model testing revealed that HST3782 inhibited intersegmental and subintestinal vessel development by up to 56% without marked toxicity. HST3782 was synthesized through a two-step 1,2,4 triazole cyclization reaction, followed by amide formation and ketone reduction steps. The last step of hydrogenation with sodium borohydride yielded a pair of endo-exo isomers. 2D-NOESY (Nuclear Overhauser effect spectroscopy) analysis confirmed that the compound's endo isomer (HST3782) had superior inhibitory effects relative to its exo form (8b). Given the above, HST3782 is a novel HIF inhibitor, with strong antiangiogenic effects and presents a valuable scaffold for future development of antiangiogenic drugs targeting the HIF-VEGF axis. Further studies are warranted to optimize HST3782's pharmacokinetics and therapeutic efficacy for antiangiogenic therapy in hypoxia-related malignancies.

As the only Food and Drug Administration (FDA)-approved dual-encapsulation liposome injection for treating Acute myeloid leukemia (AML), CPX-351 outperforms the standard chemotherapy treatment "DA 7 + 3 '' in terms of clinical effectiveness. Although research on dual-loaded liposomes has increased in recent years, little attention has been paid to their preparation, which can affect their quality, efficacy, and safety. This study explored various preparation processes to create the cytarabine/daunorubicin co-loaded liposome (the Cyt/Daun liposome) and eventually settled on two methods: the sequential loading approach, thin film hydrationextrusion-copper ion gradient, and the simultaneous encapsulation technique, copper ion gradientconcentration gradient. Different preparation methods resulted in different particle sizes and encapsulation efficiencies; the two aforementioned preparation processes generated dual-loaded liposomes with comparable physicochemical properties. The sequential encapsulation technique was selected for the subsequent research owing to its higher encapsulation efficiency prior to purification; the prepared Cyt/Daun liposomes had small and uniform particle size (108.6 +/- 1.02 nm, Polydispersity index (PDI) 0.139 +/- 0.01), negative charge (-(60.2 +/- 1.15) mV), high drug encapsulation efficiency (Cyt 88.2 +/- 0.24 %, Duan 94.2 +/- 0.45 %) and good plasma stability. To improve its storage stability, the Cyt/Daun liposome was lyophilized (-40 degrees C for 4 h, maintained for 130 min, and dried for 1200 min) using sucrose-raffinose (mass ratio 7:3; glycolipid ratio 4:1, w/w) as a lyoprotectant. The lyophilized liposomes were purple cakes, redissolved rapidly with insignificant alterations in particle size and encapsulation efficiency, and possessed well storage stability. The pharmacokinetic and tissue distribution studies demonstrated that the Cyt/Daun liposome could achieve long circulation and maintain synergic proportions of drugs within 24 h, increasing the accumulation of drugs at tumor sites. Furthermore, the in vitro/in vivo pharmacodynamic studies confirmed its good anti-tumor activity and safety.

Breast cancer metastasis and recurrence accounts for vast majority of breast cancer-induced mortality. Tumor microenvironment (TME) plays an important role at each step of metastasis, evasion of immunosurveillance, and therapeutic resistance. Consequently, TME-targeting alternatives to traditional therapies focused on breast cancer cells are gaining increasing attention. These new therapies involve the use of tumor cells, and key TME components or secreted bioactive molecules as therapeutic targets, alone or in combination. Recently, TME-related nanoparticles have been developed to deliver various agents, such as bioactive ingredients extracted from natural sources or chemotherapeutic agents, genes, proteins, small interfering RNAs, and vaccines; they have shown great therapeutic potential against breast cancer metastasis. Among various types of nanoparticles, biomimetic nanovesicles are a promising means of addressing the limitations of conventional nanocarriers. This review highlights various nanoparticles related to or mediated by TME according to the key TME components responsible for metastasis. Furthermore, TME-related biomimetic nanoparticles against breast cancer metastasis have garnered attention owing to their promising efficiency, especially in payload delivery and therapeutic action. Here, we summarize recent representative studies on nanoparticles related to cancer-associated fibroblasts, extracellular matrix, endothelial cells, angiogenesis, and immune cells, as well as advanced biomimetic nanoparticles. Future challenges and opportunities in the field are also discussed.

Oral delivery of therapeutic agents is complicated by issues associated with nanocarrier transfer in the gastrointestinal tract, such as physical stability, mucus penetration, and cellular uptake and transport. Various functional nanocarriers have been devised but more research is required to assure the desirable physical stability in the intestinal lumen and biology-responsive diffusion in the mucus. Here, we developed nanoparticles coated with microbial-derived sophorolipid assemblies for oral delivery of therapeutic agents, focusing on improved bioavailability and inhibition of breast cancer metastasis. Upon exposure to the intestinal lumen, the nanoparticles resisted changes in the pH and ion content, and retained their size and composition. They exhibited intestinal biologically responsive diffusion in the mucus because of a charge change from negative to nearly neutral, accompanied by a detachment of sophorolipid assemblies. The latter was possibly caused by the high sophorolipid affinity for mucin, which protected the nanoparticles during mucus penetration. The increased stability and enhanced mucus diffusion improved the intracellular uptake of nanoparticles, thus improving the oral bioavailability of the payload. Administration of silibinin and curcumin co-loaded nanoparticles resulted in an improved therapeutic effect of inhibiting breast cancer metastasis, by regulating tumor microenvironment, in 4T1 tumor bearing mice. The nanoparticles modulated epithelial-mesenchymal transition and inhibited angiogenesis. They also increased the infiltration of CD4(+) and CD8(+) T cells, and downregulated the immunosuppressive regulatory T cells and myeloid-derived suppressor cells in tumors. In conclusion, the novel nanocarriers are a promising oral drug delivery system.