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This study aimed to investigate the toxic effects of ellipticine on liver cancer cells and predict its anti-liver cancer mechanism through network pharmacology, especially by targeting FGFR3 to regulate the RAS/MAPK-P38 signaling pathway, thereby inducing apoptosis of liver cancer cells. The inhibitory effect of ellipticine on the proliferation of HepG2, Huh-7, SMMC7721, BEL-7402, SK-HEP-1, LX-2, and MHCC97H cells was detected by CCK-8 assay, and the IC 50 value was calculated. The potential targets of ellipticine were predicted by the database, and the intersection analysis with liver cancer-related targets was performed to construct a protein interaction network (PPI), (KEGG) pathway enrichment analysis, and molecular docking verification. FGFR3 in HepG2 cells was knocked down by siRNA, and the effects on cell proliferation, apoptosis, and ROS levels were observed. The expression changes of FGFR3, RAS, P38, and their phosphorylated forms after ellipticine treatment, as well as the effects of RAS agonist ML-908 and P38 inhibitor PD169316 on cell proliferation, apoptosis, and migration, were detected by Western blotting. Ellipticine has an inhibitory effect on all tested liver cancer cell lines, among which HepG2 has the strongest inhibitory effect, with an IC50 of 5.15 ± 0.25 μM. Ellipticine is predicted to have 32 potential targets, and 5 common targets among the 225 targets related to liver cancer, including PDGFRA, KIT, FGFR3, ERBB2, and STAT3. KEGG analysis showed that these targets are mainly involved in cancer pathways. Molecular docking showed that Ellipticine can bind strongly to FGFR3. FGFR3 expression is highest in HepG2 cells. After knocking down FGFR3, the proliferation ability of HepG2 cells is further weakened, and the addition of apoptosis inhibitor ZVAD can partially restore the proliferation ability. ROS levels increase after Ellipticine treatment, and ROS levels further increase after knocking down FGFR3, and ZVAD treatment can reduce ROS levels. After Ellipticine treatment, the expression levels of FGFR3, RAS, and p-P38 decrease. Ellipticine-induced cell proliferation inhibition and apoptosis were reversed by RAS agonist ML-908, whereas P38 inhibitor PD169316 exacerbated cell apoptosis and migration inhibition. Ellipticine induces apoptosis of liver cancer cells by targeting FGFR3 and inhibiting the RAS/MAPK-P38 signaling pathway. This discovery provides new mechanistic insights into Ellipticine as a liver cancer treatment and may lay the foundation for the development of targeted therapeutic strategies.

Radon exposure is significantly associated with lung cancer. Radon concentration is currently reduced mainly by physical methods, but there is a lack of protective drugs or biochemical reagents for radon damage. This study aimed to explore the protective effect of polydatin (PD) on the radon-exposed injury. The results showed that PD can significantly reduce ROS level, raise SOD activity, weaken the migration ability, increase E-cad, and decrease mesenchymal cell surface markers (FN1, Vimentin, N-cad, α-SMA, and Snail) in radon-exposed epithelial cells. In vivo, PD increased the mice weight, promoted SOD activity, and decreased MDA content, the number of bullae, pulmonary septum thickness, lung collagenous fibers, and mesenchymal cell surface markers. Furthermore, PD inhibited p-PI3K, p-AKT, and p-mTOR expression. Compared with directly adding PD on radon-exposed cells, adding PD before and after radon exposure could more obviously improve the adhesion of radon-exposed cells, significantly alleviate the migration ability, and more significantly reduce mesenchyme markers and p-AKT and p-mTOR. These results indicate that PD can reduce oxidative stress, weaken epithelial-mesenchymal transition (EMT) and lung fibrosis in radon-exposed cells/mice, and have good radiation protection against radon injury. The mechanism is related to the inhibition of the PI3K/AKT/mTOR pathway.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. In the present study, we revealed that the expression of miR-30a was significantly decreased in TNBC, and TNBC patients with low expression of miR-30a were associated with high histological grade and more lymph node metastasis. Moreover, we found that miR-30a suppressed TNBC cell epithelial-mesenchymal transition (EMT), as demonstrated by the overexpression of miR-30a which increased the expression of epithelial marker E-cadherin but decreased the expression of mesenchymal markers N-cadherin and vimentin. Furthermore, we demonstrated that overexpression of miR-30a significantly suppressed TNBC cell invasion and migration, as well as inhibited tumor growth and metastasis in vivo. More importantly, RTK-like orphan receptor 1 (ROR1) was predicted as the direct target of miR-30a, which was subsequently confirmed by luciferase assays. Forced expression of miR-30a in TNBC cells decreased ROR1 expression, whereas the overexpression of ROR1 reversed the suppressive effects of miR-30a in TNBC cell migration and invasion. Collectively, this study indicated that miR-30a functions as a tumor-metastasis suppressor miRNA in TNBC by directly targeting ROR1 and that miR-30a may serve as a novel therapeutic target for TNBC.

Brain metastasis is thought to be related to the high mortality and poor prognosis of lung cancer. Despite significant advances in the treatment of primary lung cancer, the unique microenvironment of the brain renders current therapeutic strategies largely ineffective against brain metastasis. The lack of effective drugs for brain metastasis treatment is primarily due to the incomplete understanding of the mechanisms underlying its initiation and progression. Currently, our understanding of brain metastasis remains limited, primarily due to the absence of appropriate models that can realistically simulate the entire process of tumor cell detachment from the primary site, circulation through the bloodstream, and eventual colonization of the brain. Therefore, there is a pressing need to develop more suitable lung cancer brain metastasis models that can effectively replicate these critical stages of metastasis. Here, based on the traditional carotid artery injection model, we established a novel orthotopic mouse model by using a light-controlled hydrogel to repair the puncture site on the carotid artery, with sustained cerebral blood circulation and the capability of multiple delivery cancer cell to mimic lung cancer brain metastasis. The optimized orthotopic mouse model significantly reduced cerebral ischemia and improved cerebral oxygenation by 60% compared to the traditional orthotopic mouse model, enhancing post-operative survival rates. It also showed a reduction in pro-inflammatory cytokines and featured less inflammatory and more resting states of microglial and astrocyte cells. Furthermore, the optimized orthotopic mouse model markedly increased the success rate and absolute number of the metastatic clones in the brain. Additionally, the multiple delivery model based on the optimized orthotopic mouse model substantially augmented the tumor clone number and formation rates compared to single injection in the optimized orthotopic mouse model. This model overcomes previous limitations by maintaining cerebral circulation, providing a more accurate simulation of the continuous entry of tumor cells into cerebral circulation. It offers a robust platform for studying the interactions of cancer cells with the brain microenvironment and testing new therapeutic approaches. Graphical abstract

Analyzing the driving factors and mechanisms of urban carbon emission correlation networks can provide effective carbon reduction decision-making support for Shandong Province and other regions with similar industrial characteristics. Based on industrial carbon emission data from various cities in Shandong Province from 2013 to 2021, the spatial correlation network of carbon emission was established by using a modified gravity model. The characteristics of the network were explored by using the Social Network Analysis (SNA) method, and significant factors affecting the network were identified through Quadratic Assignment Procedure (QAP) correlation analysis and motif analysis. The driving mechanism of the carbon emission correlation network was analyzed by using Temporal Exponential Random Graph Models (TERGMs). The results show that: (1) The spatial correlation network of urban carbon emission in Shandong Province exhibits multi-threaded complex network correlations with a relatively stable structure, overcoming geographical distance limitations. (2) Qingdao, Jinan, and Rizhao have high degree centrality, betweenness centrality, and closeness centrality in the network, with Qingdao and Jinan being relatively central. (3) Shandong Province can be spatially clustered into four regions, each with distinct roles, displaying a certain “neighboring clustering” phenomenon. (4) Endogenous network structures such as Mutual, Ctriple, and Gwesp significantly impact the formation and evolution of the network, while Twopath does not show the expected impact; FDI can promote the generation of carbon emission reception relationships in the spatial correlation network; IR can promote the generation of carbon emission spillover relationships in the spatial correlation network; GS, differences in GDP, differences in EI, and similarities of IR can promote the generation of organic correlations within the network; on the temporal level, the spatial correlation network of urban carbon emission in Shandong Province has shown significant stability during the study period.

Human activities affect the Earth’s climate through modifying the composition of the atmosphere, which then creates radiative forcing that drives climate change. The warming effect of anthropogenic greenhouse gases has been partially balanced by the cooling effect of anthropogenic aerosols. In 2020, fuel regulations abruptly reduced the emission of sulfur dioxide from international shipping by about 80% and created an inadvertent geoengineering termination shock with global impact. Here we estimate the regulation leads to a radiative forcing of +0.2±0.11Wm-2 averaged over the global ocean.The amount of radiative forcing could lead to a doubling (or more) of the warming rate in the 2020s compared with the rate since 1980 with strong spatiotemporal heterogeneity.The warming effect is consistent with the recent observed strong warming in 2023 and expected to make the 2020s anomalously warm. The forcing represents 80% to the measured increase in planetary heat uptake since 2020. The radiative forcing also has strong hemispheric contrast, which has important implications for precipitation pattern changes. Our result suggests marine cloud brightening may be a viable geoengineering method in temporarily cooling the climate that has its unique challenges due to inherent spatiotemporal heterogeneity.

How to explore the allocation and green utilization level of urban construction land resources has an important role in the sustainable development of the city. Taking 47 counties and cities in Jilin Province as an example, this paper evaluates the green utilization efficiency of urban construction land (GUEUCL) in 2011 and 2015 by using the unexpected output super-SBM model and explores the spatial-temporal differentiation characteristics and influencing factors of GUEUCL by using GIS and machine learning methods. The results show that (1) the GUEUCL in Jilin Province is low, mainly distributed in small- and medium-sized areas, with significant positive spatial correlation. The L-L concentration area is mainly distributed in the eastern region, but the degree of spatial concentration is small, the spatial structure characteristics of the two periods are different, and the spatial heterogeneity is large; (2) the internal factor decomposition shows the impact of pure technical efficiency on the comprehensive efficiency and the restriction ability is stronger than the scale efficiency, that is to say, the factors such as management and technology have a greater impact on the comprehensive efficiency; (3) the relative importance of external factors has always been ranked as socioeconomic factors, urban development factors, and natural science and technology factors. This paper focuses on the temporal and spatial characteristics of each county and city and the influencing factors, which provides a certain value reference for the pilot of ecological construction and the development of ecoenvironmental benefit economic system in Jilin Province.

Darolutamide is the next-generation androgen receptor inhibitor approved for the treatment of advanced prostate cancer, including non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). However, the efficacy and safety of darolutamide are nonetheless worthy of further clinical studies. The objective of this meta-analysis was to evaluate the overall survival, metastasis-free survival and various specific adverse events of darolutamide combination therapy in patients with mHSPC or nmCRPC. This meta-analysis was performed on PubMed, EMBASE, Web of Science, ClinicalTrials.gov, and the Cochrane Library for English-language articles to collect randomized clinical trials of darolutamide combination therapy in mHSPC and nmCRPC from the start of the database to 15 January 2026. The primary efficacy outcomes were overall survival and metastasis-free survival. Key safety outcomes included the total number of overall adverse events, the total number of grade ≥3 adverse events and serious adverse events, and the occurrence of specific adverse events of interest. The risk of bias was assessed by the Cochrane risk-of-bias tool for randomized trials (RoB 2). Publication bias was assessed by funnel plots. There were 8 research articles from 3 randomized clinical trials with 3,483 patients involved in this meta-analysis, including 1,509 nmCRPC patients from the ARAMIS trial, 1974 mHSPC patients from the ARASENS and ARANOTE trials. Combining darolutamide with ADT significantly prolonged overall survival (OS) and metastasis-free survival (MFS) in nmCRPC patients compared with placebo plus ADT. And darolutamide plus ADT with or without docetaxel also showed favorable overall survival in mHSPC patients. Subgroup meta-analyses of OS among mHSPC patients for baseline total PSA (tPSA) values and Gleason scores showed the beneficial efficacy of darolutamide in mHSPC. The addition of darolutamide in ADT and/or docetaxel did not lead to serious adverse events, like heart failure, bone fracture and hypertension, in both nmCRPC and mHSPC patients. Darolutamide combination therapy was beneficial to the prognosis and demonstrated a favorable safety profile in patients with advanced prostate cancer. Identifier CRD420251145736.

Objective. To investigate the effects and corresponding mechanisms of total flavonoids (TFL) from Lycium barbarum leaves on photoaged human dermal fibroblasts (HDFs). Methods. Crude TFL was extracted with 70% ethanol, and a Rutin standard curve was drawn using the sodium nitrite-aluminum nitrate-sodium hydroxide colorimetry method to calculate its yield and mass concentration. After that, the photoaging HDFs model was established by UVA combined with 8-MOP. CCK-8 was performed to assess the influence of TFL on the proliferation of HDFs and photoaging HDFs. β-galactosidase (SA-β-gal) staining and activity assays were performed to evaluate the activity of SA-β-gal and the rate of SA-β-gal-positive cells in HDFs cells. The level of skin ECM proteins and oxidative stress-related substances in HDFs cells of each group was determined by ELISA and biochemical detection, respectively. Apoptosis of HDFs in each group was assessed by flow cytometry. The expressions of MAPK signaling pathway-related proteins in HDFs were detected by western blot. Results. The yield rate of TFL extracted by 70% ethanol was 41.9%, and its purity rate was 34.6%. TFL at 25, 50, and 100 μg/mL was able to greatly promote the proliferation of HDFs. A photoaged HDFs model was successfully constructed by combining UVA irradiation at 9 J/cm2 and 8-MOP at 50 mg/L. TFL treatment could significantly inhibit apoptosis, SA-β-gal-positive cell staining rate, SA-β-gal activity, lactate dehydrogenase (LDH) leakage, and malondialdehyde (MDA) content in photoaged HDFs. Further, TFL increased the proliferative activity, superoxide dismutase (SOD) activity, catalase (CAT) activity, type I collagen (Col I), hydroxyproline (HYP), and hyaluronic acid (HA) level of photoaged HDFs in a dose-dependent manner. Additional experiments suggested that TFL played a protective role by downregulating MAPK signaling pathway activity in photoaged HDFs cells. Conclusion. TFL could inhibit oxidative stress and apoptosis, promote cell proliferation and the level of ECM-related component proteins, and participate in antiphotoaging in a concentration-dependent manner. The protective role of TFL in photoaged HDFs might be related to its inhibition of MAPK signaling pathways.

Fertilization is an effective measure to rapidly improve soil quality in reclaimed mining areas. However, the combined effects of fertilization regimes and reclamation age on phosphorus (P) fraction transformation and the pqqC-harboring microbial community in reclaimed soils remain unclear. In this study, we investigated the dynamics of inorganic P fractions and the pqqC-harboring bacterial community under different fertilization treatments (no fertilizer: CK; chemical fertilizer: CF; organic manure: M) and reclamation ages (1, 5, and 10 years) in a coal mining reclamation area of Shanxi Province, using long-term field experiments combined with high-throughput sequencing. Results showed that compared with the CF and CK treatments, the M treatment significantly increased soil organic matter (SOM), available P (AP), and total nitrogen (TN) content, and promoted the conversion of moderately labile P (NaOH-Pi) to labile P fractions (H2O-Pi, NaHCO3-Pi). Meanwhile, the pqqC gene abundance increased with reclamation age, with the M treatment maintaining the highest levels in all fertilization regimes. Co-occurrence network analysis of core species revealed that the number of connections gradually decreased and the network structure simplified with increasing reclamation age. Correspondingly, the microbial community transitioned from an initial stage characterized by rapid response and intense competition to a stable phase. Specifically, Pseudomonas spp. played a key role in P mobilization. Structural equation modeling (SEM) further demonstrated that reclamation age directly promoted the pqqC gene abundance and AP content, whereas fertilization indirectly influenced P transformation by regulating microbial diversity. Our findings reveal that reclamation age and fertilization synergistically shape the inorganic P profile and the associated bacterial community, providing insights for developing targeted P management strategies in reclaimed lands.