Tissue & cell最新文献

Background: Breast cancer (BRCA) ranks among the most frequently diagnosed malignancies worldwide. Immune infiltration plays a critical role in tumor progression and therapeutic response. However, the precise mechanisms underlying immune infiltration in BRCA remain incompletely understood.

Methods: Machine learning (support vector machine-recursive feature elimination and least absolute shrinkage and selection operator regression) and weighted gene co-expression network were utilized to screen hub genes. An immune infiltration assessment was carried out via TIMER and CIBERSORT. The prognostic and survival of risk model and immune infiltration-associated hub genes were analyzed through Kaplan-Meier survival analysis, Cox regression, and ROC curve evaluation. Cell functional assays and xenograft models in vivo were utilized to examine lipoprotein lipase (LPL) function. The impact of LPL on macrophage polarization was evaluated using THP-1-derived macrophages and immunohistochemistry analysis of immune infiltration (CD4, CD8, and F4/80) in vivo.

Results: 10 hub immune regulators were identified in BRCA, which were associated with lipid metabolism. Hub genes and a prognostic risk model exhibited high predictive accuracy for BRCA patient survival and prognosis. Overexpression of LPL inhibited BRCA cell proliferation, migration, and invasion while promoting M1-like macrophage polarization. In vivo, LPL overexpression significantly suppressed tumor growth and enhanced immune cell infiltration, as indicated by the elevation of CD4 + and F4/80 + cells along with a decline in CD8 + macrophage abundance.

Conclusion: This study identifies a novel lipid metabolism-related gene signature and demonstrates that LPL overexpression modulates macrophage polarization and inhibits BRCA progression.

Aluminum oxide nanoparticles (Al₂O₃NPs) are used across industrial and consumer sectors, raising concerns about their potential neurotoxic effects. Despite growing application, the mechanisms underlying Al₂O₃NP-induced neurodegeneration remain poorly understood. This study investigated the mechanistic pathways of Al₂O₃NP neurotoxicity in adult male Sprague-Dawley rats exposed intraperitoneally to 15, 30, or 60 mg/kg Al₂O₃NPs for 60 days. Comprehensive analyses included hematological profiling, serum biochemistry, oxidative stress markers (MDA, Nrf2/Keap1), neurotransmitter assays (dopamine, acetylcholine, AChE), quantitative PCR of APP, BACE1, and BDNF, inductively coupled plasma spectroscopy for brain aluminum levels, histopathology, immunohistochemistry (caspase-3, BCL2), and ultrastructural examination by transmission electron microscopy. Al₂O₃NP exposure induced dose-dependent anemia, disrupted iron and calcium homeostasis, and triggered oxidative stress, evidenced by elevated MDA and suppressed Nrf2/Keap1 signaling. Neurochemical analyses revealed marked dopamine and acetylcholine depletion alongside diminished AChE activity. Molecular assays showed significant upregulation of amyloidogenic markers (APP, BACE1) and severe BDNF suppression, indicating impaired neurotrophic support. Brain histopathology revealed progressive neuronal shrinkage, Purkinje cell loss, astrogliosis, and perivascular edema, while immunohistochemistry demonstrated heightened caspase-3 activation and reduced BCL2 expression. TEM confirmed ultrastructural axonal degeneration, demyelination, and necrotic neuronal profiles. Notably, aluminum bioaccumulation increased 116-fold at the highest dose, tightly correlating with neurodegeneration severity. These findings demonstrate that subchronic Al₂O₃NP exposure promotes neurodegeneration via a multifaceted oxidative stress mechanism, activating the amyloidogenic pathway, synaptic dysfunction, neurotrophic impairment, and apoptosis. This work underscores the urgent need for rigorous safety assessments of nanoparticle exposure in biomedical and environmental settings.

‎Head trauma is one of the main reasons for morbidity and mortality in motor vehicle and work accidents. This study aimed to evaluate the effect of hydrogen on head trauma injury. The study groups were divided into four groups, with six rats in each group as follows: Control or no treatment (group C), Head Trauma Injury (group HI), Hydrogen-rich Saline (group H2), and Head Trauma Injury + hydrogen-rich saline (group HI+H2). Blood and brain tissues, serum, interleukin (IL-6), and tumor necrosis factor (TNF-α) parameters were analyzed. Histopathologically, hematoxylin-eosin and TUNEL staining were performed on the tissue samples. A significant increase in TNF-α and IL-6 levels in the HI group that decreased when hydrogen-rich saline was applied, i.e., the HI+H2 group. Histopathologically, a decrease in degenerative cells was observed in the treatment group (i.e., HI+H2). TUNEL staining also showed a decrease in the number of stained cells in the HI+H2 group compared to the HI group. It is thought that hydrogen-rich saline treatment may be suggested to alleviate the damage caused by head trauma injury.

Objective: Trophoblasts, a unique placental cell type, are sensitive to ferroptosis. Targeting trophoblast ferroptosis may be protective against trophoblast damage in patients with pre-eclampsia (PE). Herein, this study probed the role of the deubiquitinating enzyme ubiquitin-specific protease 7 (USP7) in trophoblast ferroptosis during PE.

Methods: Trophoblasts (HTR-8/SVneo) were subjected to hypoxia treatment to simulate the placental status in PE. USP7 expression in hypoxia-treated HTR-8/SVneo cells was measured. After gain- and loss-of-function assays in hypoxia-treated HTR-8/SVneo cells, biological activities, such as viability, invasion, migration, and ferroptosis, were detected. NRF2, x-CT, and GPX4 expression levels were examined. The binding between NRF2 and USP7 was analyzed.

Results: USP7 expression was reduced in hypoxia-treated HTR-8/SVneo cells. Cell viability, invasion, and migration were notably decreased, but ferroptosis was markedly enhanced in hypoxia-treated HTR-8/SVneo cells. Erastin treatment stimulated ferroptosis, which was blocked by USP7 overexpression or ferroptosis inhibitor. Mechanistically, NRF2 bound to USP7, and USP7 induced NRF2 deubiquitination and repressed its degradation. Overexpression of USP7 upregulated x-CT and GPX4 in hypoxia-treated HTR-8/SVneo cells. NRF2 knockdown counteracted changes in biological properties and ferroptosis of hypoxia-treated HTR-8/SVneo cells caused by USP7 overexpression.

Conclusion: USP7-mediated NRF2 deubiquitination stabilizes NRF2 and activates the xCT/GPX4 pathway, suppressing trophoblast ferroptosis in the setting of PE. This study highlights a promising strategy against trophoblast ferroptosis and supports the development of new therapies for PE.

Glioblastoma multiforme (GBM) remains a lethal malignancy with limited therapeutic options due to its aggressive progression and resistance to apoptosis. SPARC (secreted protein acidic and rich in cysteine), a multifunctional glycoprotein implicated in glioma survival and chemoresistance, is stabilized by deubiquitinating enzymes (DUBs), yet the regulatory mechanisms driving its turnover are poorly defined. Lupeol, a natural triterpenoid, exhibits anticancer potential, but its effects on glioma and underlying molecular mechanisms remain elusive. Here, we demonstrate that lupeol induces apoptosis in glioma cells by targeting ubiquitination-mediated SPARC degradation. Mechanistically, lupeol enhanced SPARC polyubiquitination by disrupting its interaction with ubiquitin-specific protease 14 (USP14), a DUB that antagonizes proteasomal degradation of SPARC. These findings unveil a novel mechanism by which lupeol triggers apoptosis through USP14-dependent SPARC ubiquitination and degradation, highlighting the therapeutic potential of targeting the USP14-SPARC axis in glioma treatment. This study provides the first evidence linking lupeol's anticancer activity to ubiquitination-regulated protein turnover, offering insights for developing SPARC-directed therapies against gliomas.

Extracellular vesicles (EVs), particularly exosomes (EXOs), are essential in cellular communication and play significant roles in various physiological and pathological processes. Ranging in size from 30 to 150 nm, EXOs are lipid vesicles derived from the endosomal system and characterized by their distinctive cup-shaped morphology. These vesicles are produced by hematopoietic and non-hematopoietic cells and are found in all body fluids, including blood plasma, cerebrospinal fluid, urine, saliva, and breast milk. EXOs are equipped to transfer a myriad of bioactive materials-proteins, lipids, nucleic acids, and microRNAs-to recipient cells locally and distantly, potentially altering cellular function and influencing the microenvironment. Given their significant roles, this review comprehensively examines the various aspects of EXOs, from their biogenesis and preparation to their isolation and detailed characterization. We discuss the necessity of understanding these fundamental aspects to harness EXOs' potential in clinical applications, particularly in regenerative medicine. The review highlights the latest advances in using EXOs as carriers for therapeutic molecules, ranging from small molecules and genes to large therapeutic proteins and nanoparticles, emphasizing their application in drug delivery for cancer treatment and immunotherapy. Moreover, the paper delves into the promising applications of EXOs in tissue repair and regeneration, detailing specific cases in skin, bone, cartilage, heart, lung, and neurological diseases, among others. Each section explores not only the therapeutic potential but also the underlying mechanisms by which EXOs facilitate these regenerative processes. By discussing the clinical applications and inherent challenges of utilizing EXOs, this review underscores the critical need for continued research to fully exploit EXOs' therapeutic capabilities, offering insights into their future implications in medicine.

Endometrial regeneration is a cornerstone of reproductive health, with the extracellular matrix (ECM) playing a pivotal role in tissue repair, regeneration, and fertility restoration. Dysregulated ECM remodeling is at the heart of many debilitating conditions, including infertility, endometriosis, Asherman's syndrome, and uterine fibroids, all of which disrupt the delicate balance necessary for effective endometrial regeneration. This review presents a cutting-edge analysis of ECM dynamics, emphasizing its central role in the endometrial regeneration process and highlighting novel ECM-targeted therapies that hold transformative potential for addressing these complex disorders. We focus on emerging strategies such as stem cell-based therapies, growth factor modulation, matrix metalloproteinase inhibition, and peptide-based interventions that precisely regulate ECM composition to promote healing and restore functionality to the endometrium. Revolutionary technological advancements, including 3D bioprinting, biocompatible ECM scaffolds, and organoid models, are providing new avenues for personalized therapeutic approaches aimed at optimizing ECM interaction and enhancing regenerative outcomes for individual patients. Despite these promising developments, significant challenges remain in evaluating the long-term safety and efficacy of ECM-targeted treatments. This review also identifies critical knowledge gaps, particularly in understanding the molecular mechanisms governing ECM remodeling in the endometrial context, urging further exploration to unlock the full therapeutic potential of ECM-based regeneration strategies. Through precise modulation of ECM dynamics, this research sets the stage for innovative treatments that could revolutionize the management of uterine dysfunction and significantly enhance fertility restoration.