Cisplatin (DDP)-based chemotherapy remains the main therapeutic strategy for human gastric cancer (GC). Combination therapy with Chinese medicine monomers and DDP has been investigated as a means to enhance the anti-tumor effect of DDP while reducing toxicity. Previous studies have shown that crocin combined with DDP can inhibit the apoptosis of BG-823 GC cells. However, the mechanism of this combination therapy in inhibiting GC is not fully unclear. In this study, we measured the IC50 values of crocin combined with DDP in AGS cells and assessed its effect on cell proliferation using an MTT assay. Furthermore, we assessed apoptosis, cell migration, and EMT-related protein levels by using flow cytometry, scratch assay, and Western blotting, respectively. Our results showed that crocin combined with DDP inhibited the proliferation, induced apoptosis, and inhibited invasion and EMT. Next, we performed RNA sequence and KEGG enrichment analysis on GC cells treated with Crocin+DDP. The results showed that the most significant factor down-regulated by this combination therapy was Fibroblast growth factor receptor 3 (FGFR3) expression and that a differential gene was enriched in the MAPK/ERK pathway. We further constructed an FGFR3 OE transfection plasmid to overexpress FGFR3 and evaluate its effects on proliferation, apoptosis, migration, EMT, and MAPK/ERK pathway proteins in GC cells. We also conducted subcutaneous tumorigenesis experiments in nude mice to evaluate the effects of crocin and DDP on the progression of GC xenografts in vivo. Finally, we performed a rescue experiment using the MAPK/ERK pathway inhibitor PD184352. Our results showed that up-regulation of FGFR3 reversed the inhibitory effect of crocin+DDP on the MAPK/ERK signaling pathway. Still, this effect could be counteracted by PD184352, which simultaneously regulated the proliferation, apoptosis, and EMT of AGS cells. In conclusion, crocin, combined with DDP, inhibits proliferation, apoptosis, and EMT of GC through the FRFR3/MAPK/ERK pathway.

Gentiana veitchiorum Hemsl. (GV) has a long history in Tibetan medicine for treating hepatobiliary disease cholestasis. However, the mechanisms mediating its efficacy in treating cholestasis have yet to be determined. To elucidate the mechanisms of action of GV in the treatment of cholestasis, an integrated approach combining ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis with network pharmacology was established. A comprehensive analysis of the chemical composition of GV was achieved by UPLC-MS/MS. Subsequently, a network pharmacology method that integrated target prediction, a protein-protein interaction (PPI) network, gene set enrichment analysis, and a component- target-pathway network was established, and finally, molecular docking and experiments in vitro were conducted to verify the predicted results. Twenty compounds that were extracted from GV were identified by UPLC-MS/MS analysis. Core proteins such as AKT1, TNF, and IL6 were obtained through screening in the Network pharmacology PPI network. The Kyoto Encyclopedia of the Genome (KEGG) pathway predicted that GV could treat cholestasis by acting on signaling pathways such as TNF/IL-17 / PI3K-Akt. Network pharmacology suggested that GV might exert a therapeutic effect on cholestasis by regulating the expression levels of inflammatory mediators, and the results were further confirmed by the subsequent construction of an LPS-induced RAW 264.7 cell model. In this study, UPLC-MS/MS analysis, network pharmacology, and experiment validation were used to explore potential mechanisms of action of GV in the treatment of cholestasis.

Inspired by the recently observed resonance states PψsΛ(4338)0 and Pcs(4459)0 by LHCb Collaboration in J/ψΛ decay channel, we perform a systematical study of all possible hidden-heavy pentaquarks with strangeness S=0,−1,−2,−3, in unified framework of MIT bag model. The color-spin wave functions in terms of Young-Yamanouchi bases and transformed into baryon-meson couplings are utilized to calculate masses, magnetic moments, and relative partial widths of the hidden-heavy pentaquarks, suggesting that the observed PψsΛ(4338)0 is likely to be a 1/2− compact Pcs pentaquark, and the Pcs(4459)0 favors two-peak structure of 3/2− and 1/2− Pcs states. Our computation indicates that hidden-heavy pentaquarks have the masses around 4.35–4.90 GeV for the Pcs, 11.21–11.67 GeV for the Pbs, 4.73–5.02 GeV for the Pcss, and 11.54–11.77 GeV for the Pbss. Published by the American Physical Society 2024

Field investigation revealed that soil liquefaction occurred in seasonal freezing regions, which was frequently associated with earthquakes. Most previous studies focused on the effects of freeze-thaw cycles on the cyclic response of seasonal freezing soil, little attention has been given to the influence of pre-seismic history on soil liquefaction resistance. Therefore, a series of element tests were conducted on sand to explore the combined impact of freeze-thaw cycles and pre-seismic history. The test results showed that both the frost heaving ratio and thaw settlement coefficient initially increased and then stabilized after the 4th freeze-thaw cycle. The sand’s liquefaction resistance was found to improve with a small pre-seismic history (upre≤0.2), but gradually decreased with upre≥0.4. Notably, the sand exhibited the highest strength at approximately 1.3 times that of the original sample, while showing the weakest resistance at only 0.33 times that of the original. Furthermore, when sand underwent both freeze-thaw cycles and pre-seismic history, only 15% of samples showed increased resistance. These findings suggest that the influence of freeze-thaw cycles on sand liquefaction was more pronounced than the impact of pre-seismic history.

The construction of green infrastructure networks is an effective measure to guide orderly city expansion and ensure ecological security. However, limited research has been conducted to explore practical strategies for enhancing ecosystem services threatened by urban development, particularly in plateau cities with constrained natural resources. Xining, the largest and most densely urbanized city on the Tibetan Plateau in China, faces a significant conflict between urban expansion and ecosystem service conservation that is limited by an uninhabitable climate and mountainous topography. It is the only central city on the Tibetan Plateau, with a population of 2.47 million (2020). From 2000 to 2020, the urban area expanded by 37.42%; thus, reconciling the escalating demand for natural resources driven by urban development and promoting synergistic development between ecosystem services and urbanization remains a challenge. Here, we propose a modeling framework to reconstruct ecosystem service values using improved temporal (pi) and spatial (di) difference indices, highlighting the temporal sensibility and spatial aggregation of multiple ecosystem services. The material quantities (di) and monetary values (pi) of seven ecosystem services were estimated using experimentally verified local parameters as a case study in Xining from 2000 to 2020. The green infrastructure network and its interactions were identified based on the reconstructed ecosystem service value using the gravity modeling toolbox proposed in our previous study. The results illustrated that the identified green infrastructure network comprised 48 ecological sources and 96 corridors, covering an area of 162318.3 hm2; while this includes approximately one-fifth of the total study area, but it contributes to one-third of the overall ecosystem service value. The conservation priority and planning construction areas in the Xining City Master Planning (2021–2035) outlines were then optimized based on the identified green infrastructure network. Overall, these optimized urban planning scenarios would reserve 59.3 million CNY of the reconstructed ecosystem service value encroached on by urban sprawl. The opportunity cost is transferring 14.7% of the planned construction area overlapping with the green infrastructure network. This study provides a distinctive example for establishing a green infrastructure network based on the spatiotemporal dynamic sensitivity of ecosystem services and provides a strong reference for sustainable development and ecosystem service conservation, particularly in plateau cities.

Myeloid-derived suppressor cells (MDSCs) are a subset of immature myeloid cells that inhibit anti-tumor immunity and contribute to poor cancer outcomes. In this study, the authors used multi-color flow cytometry to detect changes in MDSCs in patients with cancer and tumor-bearing mice. Then the authors studied changes in MDSCs ratio and mouse tumors after administration of hypoxia-inducible factor 1α (HIF-1α) inhibitor. The results showed that the ratio of MDSCs, specifically polymorphonuclear MDSCs (PMN-MDSCs), was higher in patients with cancer, and both PMN-MDSCs and monocytic MDSCs (M-MDSCs) ratio were higher in tumor-bearing mice. When provided with the HIF-1α inhibitor LW-6, the ratio of MDSCs decreased in tumor-bearing mice, particularly PMN-MDSCs, and the volume of liver metastases also decreased. The authors' findings suggest that reducing MDSCs by inhibiting hypoxia-inducible factor 1α may slow tumor progression.

BackgroundPrimary sheep fetal fibroblasts (SFFCs) have emerged as a valuable resource for investigating the molecular and pathogenic mechanisms of orf viruses (ORFV). However, their utilization is considerably restricted due to the exorbitant expenses associated with their isolation and culture, their abbreviated lifespan, and the laborious procedure.ResultsIn our investigation, the primary SFFCs were obtained and immortalized by introducing a lentiviral recombinant plasmid containing the large T antigen from simian virus 40 (SV40). The expression of fibronectin and vimentin proteins, activity of SV40 large T antigen, cell proliferation assays, and analysis of programmed cell death revealed that the immortalized large T antigen SFFCs (TSFFCs) maintained the same physiological characteristics and biological functions as the primary SFFCs. Moreover, TSFFCs demonstrated robust resistance to apoptosis, extended lifespan, and enhanced proliferative activity compared to primary SFFCs. Notably, the primary SFFCs did not undergo in vitro transformation or exhibit any indications of malignancy in nude mice. Furthermore, the immortalized TSFFCs displayed live ORFV vaccine susceptibility.ConclusionsImmortalized TSFFCs present valuable in vitro models for exploring the characteristics of ORFV using various techniques. This indicates their potential for secure utilization in future studies involving virus isolation, vaccine development, and drug screening.

Abstract Invasion and migration are the key hallmarks of cancer, and aggressive growth is a major factor contributing to treatment failure and poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed to promote the malignant proliferation of GBM cells in previous studies. However, the effects of PRMT6 on GBM cell invasion and migration and its underlying mechanisms remain elusive. Here, we report that PRMT6 functions as a driver element for tumor cell invasion and migration in glioblastoma. Bioinformatics analysis and glioma sample detection results demonstrated that PRMT6 is highly expressed in mesenchymal subtype or invasive gliomas, and is significantly negatively correlated with their prognosis. Inhibition of PRMT6 (using PRMT6 shRNA or inhibitor EPZ020411) reduces GBM cell invasion and migration in vitro, whereas overexpression of PRMT6 produces opposite effects. Then, we identified that PRMT6 maintains the protein stability of EZH2 by inhibiting the degradation of EZH2 protein, thereby mediating the invasion and migration of GBM cells. Further mechanistic investigations found that PRMT6 inhibits the transcription of TRAF6 by activating the histone methylation mark (H3R2me2a), and reducing the interaction between TRAF6 and EZH2 to enhance the protein stability of EZH2 in GBM cells. Xenograft tumor assay and HE staining results showed that the expression of PRMT6 could promote the invasion of GBM cells in vivo, the immunohistochemical staining results of mouse brain tissue tumor sections also confirmed the regulatory relationship between PRMT6, TRAF6, and EZH2. Our findings illustrate that PRMT6 suppresses TRAF6 transcription via H3R2me2a to enhance the protein stability of EZH2 to facilitate GBM cell invasion and migration. Blocking the PRMT6-TRAF6-EZH2 axis is a promising strategy for inhibiting GBM cell invasion and migration.

The smart grid, as a crucial part of modern energy systems, handles extensive and diverse data, including inputs from various sensors, metering devices, and user interactions. Outsourcing data storage to remote cloud servers presents an economical solution for enhancing data management within the smart grid ecosystem. However, ensuring data privacy before transmitting it to the cloud is a critical consideration. Therefore, it is common practice to encrypt the data before uploading them to the cloud. While encryption provides data confidentiality, it may also introduce potential issues such as limiting data owners’ ability to query their data. The searchable attribute-based encryption (SABE) not only enables fine-grained access control in a dynamic large-scale environment but also allows for data searches on the ciphertext domain, making it an effective tool for cloud data sharing. Although SABE has become a research hotspot, existing schemes often have limitations in terms of computing efficiency on the client side, weak security of the ciphertext and the trapdoor. To address these issues, we propose an efficient server-aided ciphertext-policy searchable attribute-based encryption scheme (SA-CP-SABE). In SA-CP-SABE, the user’s data access authority is consistent with the search authority. During the search process, calculations are performed not only to determine whether the ciphertext matches the keyword in the trapdoor, but also to assist subsequent user ciphertext decryption by reducing computational complexity. Our scheme has been proven under the random oracle model to achieve the indistinguishability of the ciphertext and the trapdoor and to resist keyword-guessing attacks. Finally, the performance analysis and simulation of the proposed scheme are provided, and the results show that it performs with high efficiency.