Search Results (4,032)

This experiment was designed to systematically evaluate the immunomodulatory effect of water extract of Artemisia annua L. (WEAA) on sheep, both in vivo and in vitro, and to determine the involvement of the TLR4/NF-κB signaling pathway in mediating these effects. In experiment 1, 32 female sheep (Dorper × Han, 3 months old, 24 ± 0.09 kg each) were designated to 4 groups, with each group receiving a basal diet supplemented with, respectively, 0 (control group), 500, 1000, and 1500 mg/kg WEAA. The serum, liver, and spleen immune indicators and related gene expressions were measured. In experiment 2, the peripheral blood lymphocytes (PBLs) were processed with WEAA (0, 25, 50, 100, 200, and 400 μg/mL), with six replicates assigned to each concentration group, then the cell viability, immune function, and related gene expressions were measured, and the optimal concentration of WEAA was determined. In experiment 3, the experimental groups consisted of PBLs subjected to treatments with or without PDTC (NF-κB inhibitor) and with or without WEAA, forming four distinct treatment groups (six replicates/group): PDTC(−)/WEAA(−) group, PDTC(−)/WEAA(+) group, PDTC(+)/WEAA(−) group and PDTC(+)/WEAA(+) group. The immune indexes and TLR4/NFκB pathway related indexes were determined. The results were as follows: WEAA dose-dependently enhanced the content of immunoglobulins (IgA, IgG, IgM) and cytokines (IL-1β, IL-2, IL-4) in the serum, liver, and spleen tissues, among which IgA, IgG, and IL-4 were the most significantly affected core indicators (p < 0.05). Meanwhile, WEAA dose-dependently upregulated the expression of TLR4/NF-κB pathway-related genes (TLR4, IKKβ, IκBα, NF-κBp65) and their downstream cytokine-related genes (IL-1β, IL-4) in liver and spleen tissues (p < 0.05). Of these genes, liver IL-4, IκBα, and spleen IL-4 were the most prominently regulated core genes (p < 0.05), The optimal supplementary dose of WEAA was determined to be 1000 mg/kg. In addition, adding 100 μg/mL WEAA to the culture medium of PBLs significantly enhanced immune function and cell viability. The underlying mechanism involved the TLR4/NF-κB pathway; that is to say, WEAA enhanced sheep’s immune indicators by upregulating TLR4/NF-κB pathway genes, thereby coordinately regulating humoral and innate immunity, thereby improving the immune indices of sheep. This study provided compelling experimental support for the prospective utilization of WEAA as a functional feed supplement in intensive meat-type sheep production systems. Full article

Background: The senescence of testicular Leydig cells (LCs) is a key cause of age-related testosterone deficiency, in which oxidative stress (OS) and mitochondrial dysfunction are critical driving mechanisms. We explore whether the bioactive peptide C248 of PRDX4, an intracellular antioxidant, exerts mitochondrial protection to ameliorate LCs’ function. Methods: Based on the antioxidant domains of the PRDX4 protein, small molecular peptides were designed, and bioactive peptide C248 stood out from the crowd. An OS-induced senescence model of LCs was constructed by treating the MLTC-1 cell line with hydrogen peroxide (H₂O₂). C248 peptide or nicotinamide mononucleotide (NMN), as the positive control, was administered in the culture medium. The cellular function-related indicators, including DPPH free radical scavenging rate, cell viability, testosterone level, hydrogen peroxide (H₂O₂) content, senescence-associated β-galactosidase (SA-β-gal) activity, 8-hydroxy-2′-deoxyguanosine (8-OHDG) level, and 4-hydroxynonenal (4-HNE) level, were evaluated. The mitochondrial function and structural indicators, such as mitochondrial membrane potential, ATP production, mitochondrial morphology, and mitochondrial DNA (mtDNA) copy number, were subsequently tested. Results: In vitro experiments confirmed that C248 could scavenge DPPH free radicals in a dose-dependent manner, reduce the levels of reactive oxygen species, and increase antioxidant enzyme activity in LCs (p < 0.01). Both C248 and NMN increased testosterone secretion and improved cell viability (p < 0.01). Both C248 and NMN increased mitochondrial morphology and quantity, mitochondrial membrane potential (p < 0.01), ATP production (p < 0.01), and mitochondrial DNA (mtDNA) copy number (p < 0.01). Conclusion: This study reveals that the small molecular C248, a bioactive peptide of PRDX4, is a new candidate molecule for intervening in LC senescence and confirms that mitochondrial protection is a key strategy for improving age-related testicular dysfunction. Full article

Lung cancer (LC) remains the leading cause of cancer-related death in the United States despite advances in therapy. Growth hormone (GH) action has been implicated in tumor progression and therapy resistance across multiple cancers, but its role in LC, particularly non-small cell lung cancer (NSCLC), remains poorly defined. In cancer cells, GH promotes chemoresistance through upregulation of drug-efflux pumps, induction of epithelial-to-mesenchymal transition (EMT), and inhibition of apoptosis. Notably, GH receptor (GHR) expression is significantly elevated in NSCLC compared to normal lung tissue, suggesting a potential therapeutic opportunity. In this study, we investigated the impact of GH action on therapy resistance and tumor progression using integrated transcriptomic analyses and in vitro experiments. Analyses of transcriptomic data from NSCLC patients revealed that high tumoral GHR expression correlates with reduced overall survival, and with upregulation of genes involved in distinct therapy refractory pathways. Our in vitro studies demonstrated that GH promotes chemoresistance in NSCLC cell lines through activation of ABC transporters and EMT pathways, whereas GHR antagonism with the GH receptor antagonist, pegvisomant, effectively counteracts these effects and improves chemotherapy efficacy significantly. Together, our findings identify GHR signaling as a contributor to aggressive and therapy-resistant phenotypes in NSCLC in vitro and suggest that GHR antagonism may enhance chemotherapy sensitivity. These results provide a rationale for further in vivo and mechanistic studies to evaluate the therapeutic potential of targeting GHR in NSCLC. Full article

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse event triggered by antiresorptive and/or anti-angiogenic agents, characterized by bone destruction, sequestrum formation, and refractory mucosal defects. Effective mucosal healing can be a critical factor for MRONJ prevention and treatment. While endoplasmic reticulum stress (ER stress) has been implicated in tissue repair, its role in MRONJ-associated mucosal healing impairment remains undefined. This study investigated the effects of the anti-angiogenic drug sunitinib on oral mucosal healing and its underlying mechanisms. A mouse model of palatal mucosal defects was established, RNA-seq, transmission electron microscopy, and morphological analyses were used to assess how sunitinib affects ER function during mucosal repair. Using human oral keratinocytes (HOKs), we further elucidated the subcellular mechanisms through which sunitinib influences cell proliferation, migration, cell cycle progression, tight junctions, and apoptosis via techniques such as qPCR, Western blotting, immunofluorescence, and flow cytometry. Our findings demonstrated that sunitinib might induce significant alterations in the morphology of the ER and mitochondria. Both in vivo and in vitro experiments revealed that sunitinib persistently activates the GRP78 (BIP)/PERK/ATF4/CHOP axis in HOKs. This sustained ER stress can inhibit keratinocytes migration and proliferation, disrupt tight junctions, and trigger the intrinsic mitochondrial apoptotic pathway, ultimately leading to impaired oral mucosal healing and barrier dysfunction. Critically, pharmacological inhibition of ER stress was shown to restore keratinocytes’ function and promote effective mucosal healing. These results indicated that targeting sunitinib-induced persistent ER stress might represent a promising therapeutic strategy to prevent and treat oral mucosal toxicity associated with this drug. Full article

Gallium-based liquid metals have been extensively studied in the field of biomedical engineering, including applications in tumor and inflammatory disease therapy, as well as targeted drug delivery. Among these, leveraging the photothermal effect of gallium liquid metals enables effective treatment of heat-sensitive cells in tumor regions and enhances the diffusion capability of liquid metal microdroplets. However, research on the active treatment of ulcerative colitis (UC) using photothermal therapy with liquid metals remains unexplored. This study focuses on constructing an active composite colloidal motor based on gallium indium liquid metal alloy, using liquid metal microdroplets as the core. Through layer-by-layer assembly of polyelectrolytes, a liquid metal active droplet loaded with the drug mesalazine (5-aminosalicylic acid), named as LMAD-A was developed. Under asymmetric light fields generated by NIR-II light source irradiation, LMAD-A exhibits autonomous locomotion, achieving an effective diffusion coefficient more than 800 times greater than that of Brownian motion in liquid metal microdroplets of similar size. Furthermore, LMAD-A demonstrates phototactic behavior, moving toward the NIR light source autonomously. Through in vitro and in vivo experiments in mice, it was verified that LMAD-A can aggregate, deform, and fuse in the mouse colon under photothermal effects, leading to enhanced release of the loaded drug. In simulated treatments, LMAD-A significantly alleviated DSS-induced colitis in mice, confirming the targeted therapeutic capability of active liquid metal microdroplets as an active therapeutic agent in UC-affected regions. Full article

Background: Peripheral artery disease (PAD) represents a major global cause of mortality and disability. A primary therapeutic strategy involves promoting angiogenesis in ischemic limbs. The Xuefu Zhuyu Capsule (XFZYC) is widely used in China for treating PAD and demonstrates therapeutic potential; however, the mechanism underlying its pro-angiogenic effect remains unclear. Methods: The components of XFZYC were identified via TCMSP and HERB databases, with network pharmacology and molecular docking predicting its potential targets and pathways. For in vitro validation, drug-containing serum and blank control serum were prepared. Human Microvascular Endothelial Cells (HMEC-1) cells were treated with 1.25%, 2.5%, or 5% serum to determine the optimal concentration using tube formation assays and Western blot (WB) analysis of HIF-1α, HK2, and PFKFB3. The efficacy of XFZYC was further assessed through CCK-8, scratch wound healing, cell adhesion, and tube formation assays. Glycolytic metabolite levels and enzyme activities were measured by colorimetric assays and WB. Results: Network pharmacology screening identified 167 active components in XFZYC and 2967 potential targets. GO functional and KEGG pathway enrichment analyses suggested that XFZYC likely promotes the glycolytic pathway via the HIF-1 signaling pathway, specifically mediated by HK2 and PFKFB3. In vitro experiments confirmed that XFZYC enhanced HMEC-1 cell viability, migration, adhesion, and tube formation. Concurrently, it augmented the glycolytic capacity of HMEC-1 cells, manifested by increased glucose consumption, lactate production, enhanced activity of key glycolytic enzymes (HK, PFK, and PK), and upregulated protein expression of PFKFB3. Treatment with 3PO, a glycolytic inhibitor, significantly suppressed these drug-induced effects. Conclusions: XFZYC promotes angiogenesis in endothelial cells by modulating the glycolytic pathway, an effect primarily mediated through the upregulation of PFKFB3 expression. This study offers a preliminary exploration of the underlying mechanisms by which XFZYC may act in the treatment of PAD, thereby providing a new scientific perspective for further understanding its therapeutic effects. Full article

Hepatoblastoma (HB), the most common pediatric liver malignancy, tends to be highly curable although advanced or recurrent disease has less favorable outcomes. Because patients are invariably <3–4 years of age, chemotherapies can cause significant long-term morbidities. Immortalized HB cell lines could be of great utility for drug screening, for the identification of novel therapeutic susceptibilities, and for studies requiring highly regulated and/or rapidly changing in vitro environments. However, HB research is hampered by a paucity of these lines that could be used for such purposes, with only two human cell lines being readily available, neither of which represents the most common HB molecular subtypes. Recently, immortalized cell lines have been derived from murine HBs that are driven by the most common oncogenes and tumor suppressors associated with human tumors. These comprise five distinct groups associated with the deregulation of each of the four possible combinations of oncogenic forms of the β-catenin, YAP and NRF2 transcription factors or the over-expression of MYC. All five groups share many of the attributes and molecular signatures of actual human HBs. In addition, they have been used for purposes as diverse as identifying novel molecular targets through the use of Crispr-based screens and the demonstration that some HB cells can trans-differentiate into endothelial cells that facilitate tumor growth. The experience gained from these models and advances in the propagation of human hepatocytes in mice suggests that it may soon be possible to generate bespoke human immortalized human cell lines. Full article

Hypertrophic cardiomyopathy (HCM) is a common and deadly cardiac disease characterized by enlarged myocytes, increased myocardial wall thickening, and fibrosis. A majority of HCM cases are associated with mutations in the β-myosin heavy chain (MYH7) converter domain locus, which leads to varied pathophysiological and clinical manifestations. Using base-editing technology, we generated mutant human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harboring HCM-causing myosin converter domain mutations (MYH7 c.2167C>T [R723C]; MYH6 c.2173C>T [R725C]) to define HCM pathogenesis in vitro. In this study, we integrated transcriptomic analysis with phenotypic and molecular analyses to dissect the HCM disease mechanisms using MYH6/7 myosin mutants. Our KEGG analysis of bulk RNA-sequencing data revealed significant upregulation of transcripts associated with HCM in the mutant hiPSC-CMs. Further, in-depth transcriptomic analysis using Gene-Ontology (GO-term) analysis for biological process showed upregulation of several transcripts associated with heart development and disease. Notably, our analysis showed robust upregulation of cytoskeletal transcripts, including actin-cytoskeleton networks, sarcomere components, and other structural proteins in the mutant CMs. Furthermore, cellular and nuclear morphological analysis showed that the MYH6/7 mutation induced cellular hypertrophy and increased aspect ratio compared to the isogenic control. Immunostaining experiments showed marked sarcomere disorganization with lower sarcomeric order and higher dispersion in the mutant hiPSC-CMs, highlighting the remodeling of the myofibril arrangement. Notably, the MYH6/7 mutant showed reduced cortical F-actin expression and increased central F-actin expression compared to the isogenic control, confirming the cytoskeletal remodeling and sarcomeric organization during HCM pathogenesis. These pathological changes accumulated progressively over time, underscoring the chronic and evolving nature of HCM driven by the MYH6/7 mutations. Together, our findings provide critical insights into the cellular and molecular underpinnings of MYH6/7-mutation-associated disease. These findings offer valuable insights into HCM pathogenesis, aiding in future therapies. Full article

Objective: Ongoing debates focus on the role of human leukocyte antigen (HLA) class II expression in shaping clinical phenotypes of chronic inflammatory airway diseases. This study seeks to clarify the impact of class II HLA on chronic obstructive pulmonary disease (COPD) and asthma–COPD overlap (ACO). Method: The expression levels of HLA-DQ/DR in blood immune cells were analyzed in 116 participants: 41 with COPD, 37 with ACO, 20 with pure asthma, and 18 healthy subjects (HS). Results: In the COPD group, HLA-DR protein expression levels were significantly elevated on blood M2a monocytes (7695 ± 3743 vs. 5391 ± 3153 MFI, p = 0.026), helper T cells (2551 ± 956 vs. 1836 ± 531 MFI, adjusted p = 0.018), cytotoxic T cells (1591 ± 531 vs. 1360 ± 477 MFI, adjusted p = 0.036), and B cells (20,667 ± 7985 vs. 15,694 ± 2003 MFI, adjusted p = 0.031) compared to the HS group. Conversely, no significant changes were observed in the asthma group. In ACO patients, helper T cells showed increased HLA-DR protein expression (2416 ± 914 MFI; adjusted p = 0.016) compared with the HS group. Higher levels of HLA-DR expression correlated with reduced pulmonary function, frequent exacerbations, and more severe symptoms. Following one year of treatment in 14 COPD and 16 ACO patients, HLA-DR protein expression on blood helper T cells, cytotoxic T cells, M2a monocytes, and neutrophils significantly declined (all p < 0.05). In vitro experiments demonstrated that exposure of M2- or M1-polarized THP-1 cells to a stimulus mix containing cigarette smoke extract, house dust mite antigens, and lipopolysaccharide led to up-regulation of HLA-DR expression. This response was linked to increased apoptosis and reduced production of reactive oxygen species. Conclusions: Up-regulation of HLA-DR in COPD and ACO patients may represent a novel biomarker for assessing disease severity and treatment response. Additionally, it could serve as a useful tool to distinguish COPD and ACO from asthma. Full article

Background: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by limited therapeutic options and poor prognosis. Temozolomide (TMZ) remains the standard chemotherapy; however, its effectiveness is often hindered by the development of acquired resistance. Cuproptosis, a recently identified copper-dependent form of regulated cell death, has emerged as a potential therapeutic target. The synergistic effects of TMZ and copper, as well as the molecular mechanisms underlying their combined action, remain unclear. This study aimed to investigate the role of tripartite motif-containing protein 14 (TRIM14) and its downstream effector ATP7A in mediating TMZ- and copper-induced cuproptosis in glioma. Methods: We employed in vitro cellular assays, in vivo xenograft models, bioinformatic analysis, immunofluorescence staining, Western blotting, and co-immunoprecipitation experiments to examine the functional involvement of TRIM14 and ATP7A during combined TMZ and copper chloride (CuCl₂) treatment. Intracellular copper levels and cuproptosis markers, including Dihydrolipoamide S-acetyltransferase (DLAT), were assessed to evaluate copper-dependent cytotoxicity. Results: TMZ combined with CuCl₂ markedly enhanced cuproptosis in glioma cells, as evidenced by increased DLAT expression and elevated intracellular copper accumulation. This combination treatment significantly suppressed TRIM14 expression, downregulated the TRIM14–ATP7A axis, and inhibited non-canonical NF-κB signaling. Co-immunoprecipitation assays further revealed a potential interaction between TRIM14 and ATP7A, suggesting that TRIM14 may modulate ATP7A stability or activity. Conclusions: Our findings indicate that TMZ and copper synergistically induce cuproptosis in GBM by disrupting the TRIM14–ATP7A regulatory axis and promoting intracellular copper accumulation. Targeting TRIM14 or ATP7A to enhance cuproptosis may represent a promising therapeutic strategy to overcome TMZ resistance and improve clinical outcomes in GBM patients. Full article

This study aims to identify optimal parameters for the clinical implementation of magnetic fields in therapeutic contexts, with a particular focus on in vitro magneto-mechanical actuation in biological systems. This approach relies on the transduction of magnetic energy into mechanical stress at low frequencies (<<100 Hz). Accordingly, the investigation centers on evaluating the magnetic field gradients responsible for initiating the motion of intracellular magnetic nanoparticles and the resulting mechanical forces acting upon them. To achieve this, a novel, custom-built, and highly adaptable three-dimensional turntable system was designed, calibrated, and implemented. This apparatus allows the generation of magnetic fields with precisely tunable amplitude and frequency, enabling controlled activation of magneto-mechanical mechanisms. In vitro experiments using this device facilitated the exposure of cancer cells to well-characterized magnetic fields, thereby inducing mechanical stimulation in the presence of nanoparticles distributed within intracellular or extracellular environments. Quantitative measurements of magnetic field intensities were performed, providing estimations of the forces exerted by magnetic nanoparticles with diverse physical characteristics (phase, size, and shape) under varying magnetic field gradients. Full article

Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with limited treatment options, commonly managed with mitotane, which can cause serious side effects, including central hypothyroidism and dyslipidemia. This study aimed to evaluate the incidence, clinical features, and relationship between mitotane-induced central hypothyroidism and dyslipidemia in ACC patients, as well as to investigate mitotane’s direct toxic effects on thyroid cells. Thirty-eight ACC patients treated with mitotane for at least six months were monitored for thyroid function and lipid profiles. Central hypothyroidism developed in 50% of patients with normal baseline thyroid function, mostly women, who were at higher risk. Dyslipidemia occurred in 40% of patients, more frequently in men, and appeared earlier than hypothyroidism. In vitro experiments on rat thyroid cells demonstrated a dose-dependent toxic effect of mitotane on cell viability. No significant link was found between hypothyroidism and dyslipidemia risk. These findings reveal sex-specific susceptibilities to mitotane toxicity and provide novel evidence of direct mitotane-induced thyroid cell damage. This insight supports the need for careful thyroid and lipid profile monitoring during mitotane treatment and may inform the development of safer therapies for ACC. Full article

Lipid peroxide (LPO) accumulation and a depletion of intracellular antioxidants are hallmarks of ferroptosis, a controlled iron-dependent form of cell death. Iron chelators and radical scavengers can stop it, while erastin or iron overload can cause it. The main catechin in green tea extract (GTE), epigallocatechin-3-gallate (EGCG), has iron-chelating and antioxidant activities. Herein, we investigated the effects of EGCG-rich GTE on ferroptosis in iron-loaded hepatocytes. The contents of EGCG, total phenolics (TPC), and flavonoids (TFC), as well as ABTS^•+-scavenging activity and cytotoxicity, were determined. Human hepatoma (Huh7) cells were treated with ferric ammonium citrate (FAC) to induce ferroptosis and were co-treated with various concentrations of GTE. Labile iron pool (LIP), reactive oxygen species (ROS), LPO, glutathione (GSH), and glutathione peroxidase 4 (GPX-4) activity were then measured in the cells. One gram of GTE contained 26 mg of EGCG, with a TPC of 172.2 mg gallic acid equivalents and a TFC of 32.9 mg quercetin equivalents. GTE displayed concentration-dependent ABTS^•+-scavenging activity (IC₅₀ = 1.03 mg) that was equivalent to 0.29 mg of Trolox, reporting a Trolox-equivalent antioxidant capacity (TEAC) value of 0.29 mg. High-dose GTE (>100 µM EGCG equivalent) reduced cell viability below 80% (p < 0.05). Intracellular LIP, ROS, and LPO levels were markedly elevated, whereas GSH and GPX-4 activity levels were decreased (p < 0.05) in iron-loaded Huh7 cells. GTE treatment mitigated these alterations in a dose-dependent manner (p < 0.05). These cell-based in vitro findings indicate that EGCG-rich GTE can attenuate ferroptosis-associated oxidative stress in hepatocytes under iron-loading conditions. GTE may serve as a potential dietary antioxidant candidate; further mechanistic studies and in vivo experiments are required to determine its physiological relevance and translational applicability. Full article

Background: This study explores the therapeutic potential of radiodynamic therapy (RDT), a combination of the photosensitizer 5-aminolevulinic acid (5-ALA) administration and X-ray irradiation, for high-grade glioma (HGG). The research aims to verify the RDT efficacy in both normoxic and hypoxic environments, examine its mechanisms, and assess its impact on the tumor micro-immune environment to address resistance to RDT. Methods: Glioma cell lines U87MG and U251MG were used in experiments in vitro. The cells were divided into four groups with or without 5-ALA and X-ray exposure. Results: Results demonstrated that RDT was effective under normoxia (20% O₂), increasing reactive oxygen species (ROS) production and significantly decreasing U87MG cell viability in a 5-ALA concentration-dependent manner at 2 Gy and 6 Gy. However, under hypoxic conditions (3% O₂) or long-term 3% O₂ exposure, the RDT effect was not significant compared to controls. The study also found that RDT under normoxia influenced immune reaction-related gene expression, while under hypoxia, it primarily affects genes related to epithelial–mesenchymal transition (EMT). Further analysis revealed that RDT reduces the secretion of soluble PD-L1, a marker of immune checkpoint inhibition, in a 20% O₂ environment. Additionally, RDT suppressed the vascular endothelial growth factor (VEGF), an angiogenesis marker, under 3% O₂ conditions. RDT also reduced the secretion of colony-stimulating factor -1 (CSF-1), a differentiation inhibitory marker for macrophages, in a 20% O₂ environment. Conclusion: In conclusion, this study provides evidence that RDT, combining 5-ALA and X-ray irradiation, has potential as a therapeutic strategy for HGG, especially under normoxic conditions. It may also offer benefits under hypoxia, particularly in inhibiting angiogenesis. The study also highlights the importance of understanding the role of oxygen levels in the efficacy of RDT and its potential impact on immune responses, angiogenesis, and macrophage differentiation in the tumor microenvironment. Further research is needed to fully elucidate the underlying mechanisms and optimize RDT for clinical application. Full article

In animal husbandry and livestock farming, with the spread of the plasmid-mediated MCR-1 gene, polymyxin E, as the last line of defense against drug-resistant Gram-negative bacteria, is facing severe challenges. This study investigated the in vitro and in vivo synergistic effects and mechanisms of QUE combined with polymyxin E against MCR-1-positive chicken E. coli JD37. In vitro experiments showed that QUE could restore the sensitivity of E. coli JD37 to polymyxin E (FIC = 0.34375) and enhance the bactericidal effect of polymyxin E by increasing cell membrane permeability, fluidity, and membrane potential, downregulating the expression of the AcrAB-TolC efflux pump and LPS-related genes. Molecular docking further identified the key residues for QUE binding to the MCR-1 protein. The in vivo chick infection model confirmed that combination therapy increased survival rates, reduced bacterial load in tissues, alleviated pathological damage, and decreased levels of intestinal inflammatory factors. Our results demonstrate the synergistic bactericidal effect of the QUE-polymyxin E combination against MCR-1-positive E. coli and elucidate its underlying mechanism. Full article