Breast cancer remains one of the most serious malignancies threatening women's health. Quercetin, a major active component found in various Chinese herbal medicines, has shown antitumor potential; however, its specific role and underlying mechanisms in breast cancer require systematic investigation. This study demonstrated through MTT, colony formation, wound healing, and Transwell assays that quercetin significantly inhibits the viability, proliferation, and migration capabilities of breast cancer cells. Transcriptome sequencing combined with biochemical assays, qPCR, and Western blot further indicated that quercetin can induce ferroptosis, which is likely the key mechanism underlying its suppression of malignant progression in breast cancer cells. Mechanistically, by promoting the binding between the E3 ubiquitin ligase NEDD4L and SLC7A11, quercetin induces the ubiquitin-proteasome degradation of SLC7A11, ultimately leading to ferroptosis. Notably, quercetin maintained a significant inhibitory effect even during the malignant transformation of breast cancer cells induced by heavy metal lead (Pb) exposure. Collectively, these findings suggest a potential mechanism by which quercetin may inhibits breast cancer progression through ferroptosis activation via the NEDD4L/SLC7A11 axis, offering preliminary evidence that could support its possible therapeutic application in breast cancer.

Exosomes are endogenous vesicles that transport microRNAs (miRNAs), thereby mediating intercellular communication. This study was assigned to expound the regulatory role of exosomal miR-147-3p in asthma progression. The ovalbumin-mediated murine model of asthma was established to obtain bronchoalveolar lavage fluid (BALF), and exosomes were isolated by ultrafiltration centrifugation. Differential expression of exosomal miRNA and mRNA was analyzed by RT-PCR. Dual-luciferase was utilized to validate potential binding between key miRNAs and target genes. Additionally, the impact of miRNA mimics and BALF-exosomes on growth of bronchial epithelial cells (BECs) was assessed, followed by RT-qPCR and Western blot. Ovalbumin exposure induced asthma phenotypes in mice. Notably, miR-147-3p and miR-146b-5p were markedly elevated in BALF exosomes from asthmatic mice, whereas miR-98-5p and RUNX3 were markedly decreased. Luciferase assay confirmed the direct binding of miR-147-3p to RUNX3 mRNA 3' UTR. Furthermore, PKH26-labeled exosomes were internalized by BECs. Asthmatic BALF-exosomes or miR-147-3p mimics reduced cell viability and migration while promoting apoptosis. This phenomenon could be reversed by miR-147-3p inhibition. miR-147-3p overexpression or asthmatic BAF-exosomes suppressed RUNX3 protein and mRNA expression. BALF-derived exosomal miR-147-3p modulated behaviors of BECs via targeting RUNX3, suggesting its potential as a therapeutic target and biomarker for asthma pathogenesis.

Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG1) has been recognized as a biomarker for diabetic nephropathy (DN). This study aimed to elucidate the mechanism by which PAG1 influences DN. The expression and clinical significance of PAG1 in DN were assessed using bioinformatics analysis. PAG1 expression was validated in db/db mice and high glucose (HG)-treated human kidney-2 (HK-2) cells. Subsequently, PAG1 was knocked down in DN models to investigate its effects on DN progression, pyroptosis, and the transforming growth factorbeta 1 (TGF-β1)/Smads pathway. The TGF-β1/Smads pathway activator SRI-011381 was employed to further elucidate the role of PAG1 in DN regulation. Bioinformatics analysis revealed elevated PAG1 expression in DN samples, which correlated with various immune cells and pathways, such as chemokine pathway and cell cycle. This elevated expression was confirmed in animal and cell experiments. In db/db mice, PAG1 knockdown alleviated DN, reduced inflammatory factor levels, inhibited pyroptosis, and suppressed TGF-β1/Smads pathway. In vitro, PAG1 silencing promoted proliferation, inhibited apoptosis and fibrosis, reduced inflammatory and pyroptotic factor levels, and suppressed the TGF-β1/Smads pathway. These effects were reversed by SRI-011381 intervention. PAG1 promotes pyroptosis by upregulating the TGF-β1/Smads pathway, thereby exacerbating DN.

Allergic rhinitis (AR) is characterized by inflammation of the nasal mucosa caused by an allergic reaction. Cornuside has been reported to possess anti-allergic properties. This study aims to investigate whether cornuside can suppress AR. Mice were induced by ovalbumin (OVA) to establish AR models. The AR symptoms including sneezing and nasal rubbing were recorded, and the eosinophils in mouse mucosal tissues were analyzed by hematoxylin and eosin staining. Total leucocytes in nasal lavage fluid (NLF) were quantified under a hemocytometer. Wright's Giemsa staining was utilized to quantify eosinophils, lymphocytes, and neutrophils in NLF. Enzyme-linked immunosorbent assay was conducted to detect histamine, serum cytokines (OVA-specific IgE, OVAspecific IgG1, interleukin-4, and leukotriene C4), and serum inflammation cytokines (tumor necrosis factor-α, interleukin-6, interleukin-13, and interleukin-17). Cornuside administration significantly reduced sneezing and nasal rubbing behaviors in mice with AR. Mice with AR exhibited more inflammatory cells and higher levels of histamine, serum cytokines, and inflammatory cytokines in the blood or NLF than the control group. However, these upregulations were all reversed by the administration of cornuside. In addition, we found that cornuside treatment improved the inflammatory condition of mice with AR dose-dependently Cornuside can attenuate the inflammatory response in mice with AR.

Respiratory syncytial virus (RSV) is a predominant pathogen inducing respiratory tract infections among infants and elderly. Calycosin exhibits antiviral properties, yet its efficacy against RSV has not been elucidated. In this study, cyclophosphamide was administered to induce immune deficiency in adult mice, following which RSV was introduced via the intranasal route to establish an RSV infection model in mice. The viral load in lung tissue, airway resistance, inflammatory cell quantity and pro-inflammatory factor levels within bronchoalveolar lavage fluid (BALF) were quantified. Pathological changes were examined and the NOD-like receptor protein 3 (NLRP3) inflammasome activation status was assessed in lung tissue. The results demonstrated that Calycosin treatment markedly decreased the RSV viral load inside lung tissue, decreased inflammatory factor quantity and pro-inflammatory factor levels within BALF, and alleviated airway resistance, inflammatory injury, as well as goblet cell hyperplasia of mouse lung tissue. Notably, Calycosin significantly suppressed NLRP3 inflammasome activation inside RSV-infected mouse lung tissue. However, co-treatment with Nigericin diminished the protective effects of Calycosin on airway inflammatory injury in RSV-infected mice. These findings indicate that Calycosin alleviates airway injury induced by RSV infection, and the underlying mechanism is associated with the inhibition of the inflammatory response mediated by NLRP3 inflammasome activation.

Atherosclerosis (AS) progression is closely linked to oxidized low-density lipoprotein (Ox-LDL)-induced endothelial cell injury. This study investigates the molecular mechanism by which the PCSK9 inhibitor Evolocumab (EVC) alleviates AS. We used Ox-LDL-induced HUVECs and high-fat diet (HFD)-fed ApoE-/- mice as in vitro and in vivo AS models. AS plaque formation was detected by HE and Oil Red O staining. The levels of lipid indicators and oxidative stress-related factors were measured via ELISA. The expression levels of PCSK9, apoptosis-related proteins, and signaling pathway-related proteins were determined via Western blotting. The result shows that EVC improved blood lipids and alleviated aortic injury in atherosclerotic mice, and concomitantly suppressed Ox-LDL-induced apoptosis and oxidative stress in HUVECs. In terms of the molecular mechanism, EVC attenuated the Ox-LDL-induced phosphorylation of ERK1/2, JNK and p38. Both the ROS inhibitor N-acetylcysteine and the p38 MAPK signaling pathway inhibitor SB203580 can enhance the suppressive effect of the PCSK9 inhibitor EVC on Ox-LDL induced apoptosis and oxidative stress in HUVECs, while the p38 MAPK signaling pathway activator C16-PAF shows the opposite results. In conclusion, the PCSK9 inhibitor EVC inhibits Ox-LDL-induced HUVECs apoptosis and oxidative stress by inhibiting the ROS/MAPK signaling pathway, thereby alleviating the progression of AS.

Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality. Given the reported associations of both SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) with various cancers and ubiquitin-specific protease 7 (USP7) with NSCLC progression, this study aims to elucidate the role of SETDB1 and USP7 in NSCLC progression. mRNA and protein levels were measured by qRT-PCR and Western blot, respectively. Cell biological phenotypes were evaluated using MTT, EdU, flow cytometry, transwell, and sphere formation assays. Ferroptosis was analyzed by measuring Fe2+, MDA GSH, and ROS levels. Relationship between USP7 and SETDB1 was examined through Co-IP, cycloheximide (CHX) chase, and deubiquitination assays. Xenograft tumor models were established to investigate the role of SETDB1 and USP7 in NSCLC in vivo. In NSCLC tissues and cells, SETDB1 levels were elevated. Knockdown of SETDB1 inhibited NSCLC cell viability, proliferation, invasion, and sphere formation ability, while promoting apoptosis and ferroptosis. Mechanistically, USP7 enhanced the stability of SETDB1 protein by its deubiquitination. USP7 knockdown suppressed NSCLC cell biological behavior by downregulating SETDB1. Moreover, USP7 knockdown repressed in vivo tumor growth of NSCLC. Taken together, USP7 suppresses ferroptosis and enhances growth in NSCLC cells by stabilizing SETDB1 protein through deubiquitination.

Pathological cardiac hypertrophy (PaCH) leads to heart failure, whereas exercise-induced physiological cardiac hypertrophy (PhCH) represents a benign adaptive response, and counteracts PaCH. Here, we investigated the association of miR-17-5p and IGFBP5 expressions with PhCH through a PhCH group (five mice with 21-days swimming exercise) and healthy controls (n = 5). The PhCH group showed higher body weight (BW), heart weight (HW), HW/BW ratio, ventricular septal thickness, left-ventricular end-diastolic diameter, and left-ventricular end-systolic diameter than control group (p < 0.05 for all). The IGFBP5 expression was significantly reduced, whereas miR-17-5p expression was significantly elevated in PhCH group (p < 0.05). Dual-luciferase assays validated the direct binding of miR-17-5p with IGFBP5. Wheat germ agglutinin staining revealed enlarged cardiomyocytes of PhCH group, while Masson staining disclosed no increase of fibrosis. The reduction of IGFBP5 and elevation of miR-17-5p are associated with PhCH, suggesting their potentials for further researches in myocardial hypertrophy.

Diabetic nephropathy is a formidable complication arising from diabetes. Compound Danshen Dripping Pills (CDDP) has demonstrated remarkable efficacy in managing diabetic retinopathy. Our study integrates network pharmacology and molecular docking methodologies to explore the therapeutic targets and mechanisms of CDDP in diabetic nephropathy. We systematically retrieved compounds and their corresponding target molecules associated with CDDP from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and UniProt databases. Our exhaustive analysis revealed 76 bioactive compounds and 203 potential targets for CDDP. Through meticulous Protein-Protein Interaction network analysis, we narrowed down on ten pivotal targets central to the therapeutic effects. Functional assessments illuminated the multifaceted impact of CDDP on metabolic homeostasis, inflammatory responses, oxidative stress modulation, and apoptotic regulation, implicating pathways such as lipid metabolism, atherosclerotic processes, and Advanced Glycation End-products receptor for Advanced Glycation End-products (AGE-RAGE) signaling cascade. Molecular docking assays further substantiated these findings by demonstrating a robust binding affinity between the bioactive constituents and their respective molecular targets. In conclusions, this study forecasts the complex interplay of components, therapeutic targets, and modulated pathways involved in CDDP's therapeutic intervention in diabetic nephropathy.

Dysregulation of microRNAs (miRNAs) has been associated with podocyte injury in diabetic nephropathy (DN). This study aimed to investigate the role and underlying mechanism of miR-208a-3p in the development of DN. An in vitro DN model was established by treating podocytes with high glucose (HG). Gene expression was analyzed using reverse transcription quantitative polymerase chain reaction, and protein levels were determined by Western blotting. Immunofluorescence staining was performed to assess microtubule-associated protein 1A/1B-light chain 3 (LC3) intensity as an autophagy marker. Podocyte viability and apoptosis were evaluated via Cell Counting Kit-8 assay and flow cytometry, respectively. Intracellular reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescin diacetate staining. miR-208a-3p was significantly upregulated in HG-stimulated podocytes. HG exposure promoted apoptosis and oxidative stress, while suppressing autophagy and cell viability, effects that were reversed by miR-208a-3p inhibition. Mechanistically, miR-208a-3p directly targeted vav guanine nucleotide exchange factor 3 (VAV3). HG suppressed AKT/mTOR signaling, whereas miR-208a-3p silencing activated it. Conversely, VAV3 knockdown inactivated AKT/mTOR signaling. VAV3 downregulation or treatment with LY294002, an AKT/mTOR inhibitor, abolished the protective effects of miR-208a-3p silencing against HG-induced podocyte injury. These findings indicate that miR-208a-3p silencing attenuates HG-induced podocyte injury by promoting autophagy via targeting the VAV3/AKT/mTOR pathway.