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Ruscogenin, an important steroid sapogenin derived from Ophiopogon japonicus, has been shown to inhibit cerebral ischemic injury. However, its potential molecular action on blood-brain barrier (BBB) dysfunction after stroke remains unclear. This study aimed to investigate the effects of ruscogenin on BBB dysfunction and the underlying mechanisms in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice and oxygen–glucose deprivation/reoxygenation (OGD/R)-injured mouse brain microvascular endothelial cells (bEnd.3). The results demonstrated that administration of ruscogenin (10 mg/kg) decreased the brain infarction and edema, improved neurological deficits, increased cerebral brain flow (CBF), ameliorated histopathological damage, reduced evans blue (EB) leakage and upregulated the expression of tight junctions (TJs) in MCAO/R-injured mice. Meanwhile, ruscogenin (0.1–10 µM) treatment increased cell viability and trans-endothelial electrical resistance (TEER) value, decreased sodium fluorescein leakage, and modulated the TJs expression in OGD/R-induced bEnd.3 cells. Moreover, ruscogenin also inhibited the expression of interleukin-1β (IL-1β) and caspase-1, and markedly suppressed the expression of Nucleotide-binding domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) and thiredoxin-interactive protein (TXNIP) in vivo and in vitro. Furthermore, ruscogenin decreased reactive oxygen species (ROS) generation and inhibited the mitogen-activated protein kinase (MAPK) pathway in OGD/R-induced bEnd.3 cells. Our findings provide some new insights into its potential application for the prevention and treatment of ischemic stroke.

Metastasis is the main cause of cancer patients' death despite tremendous efforts invested in developing the related molecular mechanisms. During cancer cell migration, cells undergo dynamic regulation of filopodia, focal adhesion, and endosome trafficking. Cdc42 is imperative for maintaining cell morphology and filopodia, regulating cell movement. Integrin beta1 activates on the endosome, the majority of which distributes itself on the plasma membrane, indicating that endocytic trafficking is essential for this activity. In cancers, high expression of lysosome‐associated protein transmembrane 4B (LAPTM4B) is associated with poor prognosis. LAPTM4B‐35 has been reported as displaying plasma membrane distribution and being associated with cancer cell migration. However, the detailed mechanism of its isoform‐specific distribution and whether it relates to cell migration remain unknown. Here, we first report and quantify the filopodia localization of LAPTM4B‐35: mechanically, that specific interaction with Cdc42 promoted its localization to the filopodia. Furthermore, our data show that LAPTM4B‐35 stabilized filopodia and regulated integrin beta1 recycling via interaction and cotrafficking on the endosome. In our zebrafish xenograft model, LAPTM4B‐35 stimulated the formation and dynamics of focal adhesion, further promoting cancer cell dissemination, whereas in skin cancer patients, LAPTM4B level correlated with poor prognosis. In short, this study establishes an insight into the mechanism of LAPTM4B‐35 filopodia distribution, as well as into its biological effects and its clinical significance, providing a novel target for cancer therapeutics development. This study establishes an insight into the mechanism of LAPTM4B‐35 filopodia distribution, as well as into its biological effects and its clinical significance, providing a novel target for cancer therapeutics development.

Clear cell renal cell carcinoma (ccRCC) represents a highly heterogeneous kidney malignancy associated with the poorest prognosis. The metastatic potential of advanced ccRCC tumors is notably high, posing significant clinical challenges. There is an urgent imperative to develop novel therapeutic approaches to address ccRCC metastasis. Recent investigations indicated a potential association between GBP2 and tumor immunity. However, the precise functional role of GBP2 in the progression of ccRCC remains poorly understood. The present study revealed a strong correlation between GBP2 and M2 macrophages. Specifically, our findings demonstrated that the inhibition of GBP2 significantly impedes the migratory and invasive capabilities of ccRCC cells. We observed that the presence of M2 macrophages can reverse the effects of GBP2 knockdown on tumor cell migration and invasion. Mechanistically, we demonstrated that M2 macrophages promote the expression of the GBP2/p‐STAT3 and p‐ERK axis in tumor cells through the secretion of interleukin‐10 (IL‐10) and transforming growth factor‐β (TGF‐β), thereby substantially enhancing the migratory and invasive capacities of the tumor cells. Simultaneously, we have identified that GBP2 promotes the polarization of macrophages to the M2 phenotype by stimulating the secretion of interleukin‐18 (IL‐18). In summary, our investigation anticipates that the GBP2/IL‐18/M2 macrophages/IL‐10 and the TGF‐β/GBP2, p‐STAT3, p‐ERK loop plays a crucial role in ccRCC metastasis. The collective findings from our research underscore the significant role of GBP2 in tumor immunity and emphasize the potential for modulating GBP2 as a promising therapeutic strategy for targeting ccRCC metastasis. A positive promoter loop of GBP2/IL‐18/M2 macrophage/IL‐10 TGF‐β/GBP2, p‐ERK, p‐STAT3 is formed, and the metastasis of ccRCC was stimulated.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.

Purpose: DNA primase subunit 2 (PRIM2) is a component of the DNA polymerase α ‐primase complex involved in DNA replication. Previous studies have implicated PRIM2 in cancer progression, but a comprehensive pan‐cancer analysis is lacking. Here, we systematically analyzed PRIM2 across various cancer types to elucidate its potential role in cancer biology. Methods: The expression data of PRIM2 was obtained from The Cancer Genome Atlas (TCGA) and Genotype‐Tissue Expression Project (GTEx) databases. A range of bioinformatics tools were employed to analyze the expression of PRIM2 with the correlation of clinical data, diagnosis, prognosis, subtypes, immunomodulatory, and drug sensitivity. Further validation experiments were performed in HT‐29 and HepG2 cell lines. Results: PRIM2 expression was elevated in most tumor tissues, indicating its potential diagnostic value. Elevated PRIM2 levels affected prognosis and survival and varied with clinical status. Mutations and methylation events drove the aberrant expression of PRIM2 in various cancers. Furthermore, PRIM2 was linked to key immunoregulatory genes such as PD‐L1 and infiltration of Th2 cells in tumor tissues. Our findings suggested that PRIM2 is correlated to immunotherapy and may be sensitive to specific small molecule PLK1 inhibitors. Knocking down PRIM2 in HT‐29 and HepG2 cell lines reduced their proliferation, migration, invasion, and epithelial‐mesenchymal transition. Conclusion: This research highlights the potential of PRIM2 as a biomarker for cancer diagnosis and prognosis, and as a target for immunomodulatory therapy, offering valuable insights for clinical applications.

Background Stroke can induce cardiac dysfunction in the absence of primary cardiac disease; however, the mechanisms underlying the interaction between the neurological deficits and the heart are poorly understood. The objective of this study was to investigate the effects of stroke on cardiac function and to identify the transcriptome characteristics of the heart. Results Stroke significantly decreased heart weight/tibia length ratio and cardiomyocyte cross-sectional areas and increased atrogin-1 and the E3 ubiquitin ligase MuRF-1 , indicating myocardial atrophy in MCAO-induced mouse hearts. RNA sequencing of mRNA revealed 383 differentially expressed genes (DEGs) in MCAO myocardium, of which 221 were downregulated and 162 upregulated. Grouping of DEGs based on biological function and quantitative PCR validation indicated that suppressed immune response and collagen synthesis and altered activity of oxidoreductase, peptidase, and endopeptidase may be involved in MCAO-induced cardiomyopathy. The DEGs were mainly distributed in the membrane or extracellular region of cardiomyocytes and acted as potential mediators of stroke-induced cardiac dysregulation involved in cardiac atrophy. Conclusion Stroke induced a unique transcriptome response in the myocardium and resulted in immediate cardiac atrophy and dysfunction.

Timely, reliable and comprehensive global observation information is essential for space weather research. However, limited observation technology hinders the consecutive global coverage of observation data. For the integrity and continuity of the global observation data, deep learning can obtain a global Ionospheric total electron content (TEC) map by fusing multi‐source TEC maps. Different from the previous methods, in the study, a deep learning hybrid model (RFGAN) based on Dual‐Discriminator Conditional Generative Adversarial Network (DDcGAN) and Free‐Form Image Inpainting with Gated Convolution (Deepfill v2) is proposed to fuse the Massachusetts Institute of Technology (MIT)—TEC, International Global Navigation Satellite System TEC (IGS‐TEC) and altimetry satellite TEC. Throughout the RFGAN structure, we use an autoencoder model with gated convolution to inpaint the missing parts of MIT‐TEC and altimetry satellite TEC. Meanwhile, DDcGAN fuses the inpainted MIT‐TEC (MIT'‐TEC) and IGS‐TEC to get a global TEC map with high accuracy. To a certain extent, we inpainted the ocean area of MIT‐TEC through RFGAN. At the same time, RFGAN keeps the consistency of RFGAN‐TEC and MIT‐TEC in the continent area. Our proposed deep learning hybrid model can be easily extended and widely applied to other fields of space science, especially in addressing observational data loss and multi‐source data fusion.

There is a growing trend to integrate scientific research training into undergraduate medical education, and mentoring styles are believed to help develop students' research capabilities. Critical thinking, attitude toward communication skills, and academic passion are important factors in enhancing students' research capabilities. This study aimed to explore the impact of exposure to scientific research and mentoring styles on medical undergraduates' critical thinking, attitude toward communication skills, and academic passion. This study surveyed 366 medical students from Central South China, assessing students' research involvement, mentoring style, self-perceived items of critical thinking, attitude toward communication skills, harmonious academic passion, and obsessive academic passion. Structural equation modeling (SEM) was used to model the structural relationships between the exposure to research and the self-perceived latent factors. SEM results showed that the model fit was acceptable (CFI = 0.903, RMSEA = 0.070, and SRMR = 0.060) based on the cutoff criteria used in empirical research. SEM analysis revealed that exposure to research significantly influenced critical thinking (β = 0.139,  < .01) and communication attitude (β = 0.258,  < .001) but did not affect academic passion. An inclusive mentoring style significantly enhanced critical thinking (β = 0.472,  < .001), communication attitude (β = 0.423,  < .001), and harmonious academic passion (β = 0.377,  < .001). Inclusive mentoring plays a crucial role in enhancing medical students' critical thinking, communication skills, and harmonious academic passion. Medical institutions should focus on strengthening mentoring programs to better support these outcomes.

Conventional thrombolytic agents demonstrated limited efficacy in treating thrombotic disorders characterized by narrow therapeutic windows and progressive vascular injury, lacking the required precision, timeliness, and treatment durability. Here an engineered probiotic powered micro‐rod robot for targeted and penetrative treatment for thrombus is developed. This micro‐rod robot (SrEcNPL) using natural probiotics as bio‐carriers, functionalized with thrombolytic carbon nanotubes and platelet membrane‐coated nanoparticles loaded with targeted vasodilators. The robot exploits the rapid movement of probiotics, combined with the active targeting ability of the platelet membrane, to achieve rapid and precise drug delivery to thrombus tissue. Based on the natural rod‐shaped structure of probiotics, SrEcNPL can deeply penetrate thrombus tissue, achieving faster thrombolysis efficiency. The thrombolytic micro‐robot combines thrombus‐targeting capability with prolonged circulation time and controlled vasodilation, maintaining vascular patency and inhibiting secondary thrombus. Results indicate that this micro‐robot can quickly and accurately target and penetrate thrombus tissue, extending the biological half‐life of thrombolytic drugs by ≈332 times and enabling sustained thrombolysis. This novel dual‐pronged combined thrombolytic therapy has significant scientific implications for treating thrombotic diseases with narrow therapeutic windows caused by vascular injury. For thrombotic diseases with narrow therapeutic windows and persistent vascular damage; existing thrombolytic drugs are difficult to achieve precise; timely; and sustained thrombolytic effects. Here an engineered probiotic driven micro‐rod robot for targeted and penetrative treatment for thrombus is developed. This micro‐robot can rapidly and accurately target and penetrate thrombus tissue; significantly prolonging the biological half‐life of thrombolytic drugs (≈332 times) and achieving sustained thrombolysis. This novel dual pronged thrombolytic therapy holds great scientific promise for the treatment of thrombotic diseases with shorter treatment time windows caused by vascular injury.

Background Acupoint application therapy (AAT) has been widely used to treat allergic inflammation induced by allergic rhinitis (AR). The therapeutic effect of acupoint application is obvious. But the underlying therapeutic mechanism is still indistinct. Nerve growth factor (NGF) expression showed a dramatic rise in nasal mucosa tissue after AR, and allergic inflammation also increased significantly. To demonstrate how AAT can improve allergic inflammation by down-regulating the expression of NGF, AR rat models were established by intraperitoneal injection of ovalbumin (OVA) and nasal drops in SD rats. The number of nasal rubbing, sneezing and the degree of runny nose were observed and the symptoms were scored by behavioral symptom scoring method within 3 min. The expression levels of NGF and its downstream key proteins, such as IL-4, IL-5, IL-13, IgE and IFN-γ were determined by q-PCR, Western blot analysis, ELISA and immunofluorescence staining. Furthermore, H&E staining and toluidine blue staining were used to observe the pathological structure of nasal mucosa and mast cells in nasal mucosa, and the ultrastructure of nasal mucosa was observed by electron microscopy. Results Our data demonstrated that acupoint application significantly reduced the score of behavioral symptoms, and decreased the expression levels of NGF and its downstream key proteins, including IL-4, IL-5, IL-13, IgE, as well as promoting the expression level of IFN-γ in nasal mucosa tissue in AR rats. Thus, the activation of IgE and viability of mast cells was inhibited. Conclusion Our findings suggest that AAT can attenuate allergic inflammation by inhibiting the expression of NGF and its downstream pathway.