Allergens induce upregulated IL-18 and IL-18Rα expression in blood Th2 and Th17 cells of patients with allergic asthma.

Allergic asthma (AA) is closely associated with the polarization of T helper (Th)2 and Th17 cells. Interleukin (IL)-18 acts as an inducer of Th2 and Th17 cell responses. However, expressions of IL-18 and IL-18 receptor alpha (IL-18Rα) in blood Th2 and Th17 cells of patients with AA remain unclear. We therefore investigated their expressions in Th2 and Th17 cells using flow cytometric analysis, quantitative real-time PCR (qPCR), and murine AA model. We observed increased proportions of Th2, Th17, IL-18+, IL-18+ Th2, and IL-18+ Th17 cells in blood CD4+ T cells of patients with AA. Additionally, house dust mite seemed to upregulate further IL-18 expression in Th2 and Th17, and upregulate IL-18Rα expression in CD4+ T, Th2, and Th17 cells of AA patients. It was also found that the plasma levels of IL-4, IL-17A, and IL-18 in AA patients were elevated, and they were correlated between each other. In ovalbumin (OVA)-induced asthma mouse (AM), we observed that the percentages of blood CD4+ T, Th2, and Th17 cells were increased. Moreover, OVA-induced AM expressed higher level of IL-18Rα in blood Th2 cells, which was downregulated by IL-18. Increased IL-18Rα expression was also observed in blood Th2 cells of OVA-induced FcεRIα-/- mice. Collectively, our findings suggest the involvement of Th2 cells in AA by expressing excessive IL-18 and IL-18Rα in response to allergen, and that IL-18 and IL-18Rα expressing Th2 cells are likely to be the potential targets for AA therapy.

Dyslipidemia is associated with sarcopenia of the elderly: a meta-analysis.

PURPOSE: Sarcopenia is a pathological change characterized by muscle loss in older people. According to the reports, there is controversy on the relationship between dyslipidemia and sarcopenia. Therefore, this meta-analysis aimed to explore the association between sarcopenia and dyslipidemia. METHODS: We searched the Cochrane Library, Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), Wan Fang, China Science and Technology Journal Database (VIP Database) for case‒control studies to extract data on the odds ratio (OR) between sarcopenia and dyslipidemia and the MD(mean difference) of TC, LDL-C, HDL-C, TG, and TG/HDL-C between sarcopenia and nonsarcopenia. The JBI(Joanna Briggs) guidelines were used to evaluate the quality. Excel 2021, Review Manager 5.3 and Stata 16.0 were used for the statistical analysis. RESULTS: Twenty studies were included in the meta-analysis, 19 of which were evaluated as good quality. The overall OR of the relationship between sarcopenia and dyslipidemia was 1.47, and the MD values of TC, LDL-C, HDL-C, TG, and TG/HDL-C were 1.10, 1.95, 1.27, 30.13, and 0.16 respectively. In female, compared with the non-sarcopnia, the MD of TC, LDL-C, HDL-C, TG of sarcopenia were - 1.67,2.21,1.02,-3.18 respectively. In male, the MD of TC, LDL-C, HDL-C, TG between sarcopenia and non-sarcopenia were - 0.51, 1.41, 5.77, -0.67. The OR between sarcopenia and dyslipidemia of the non-China region was 4.38, and it was 0.9 in China. In the group(> 60), MD of TC between sarcopenia and non-sarcopenia was 2.63, while it was 1.54 in the group(20-60). CONCLUSION: Dyslipidemia was associated with sarcopenia in the elderly, which was affected by sex, region and age.

Cleaner separation and recovery of valuable metals from spent ternary cathode via carbon dioxide synergetic thermite reduction strategy.

The low-carbon recycling of spent lithium-ion batteries has become crucial due to the increasing need to address resource shortages and environmental concerns. Herein, a low-carbon, facile, and efficient method was developed to separate and recover Li, Al, and transition metals from spent ternary cathodes. Initially, the cathode materials post-discharge and disassembly do not require pre-sorting. Instead of using carbonaceous materials, the Al foil in the cathode serves as the reducing agent during reduction roasting. The impact of different roasting atmospheres (air, N2, CO2) on phase transitions and the extraction of valuable metals was examined. The findings revealed that after synergistic thermite reduction in a carbon dioxide atmosphere, the cathode material is completely dissociated. Li is selectively converted to Li2CO3 rather than LiAlO2, and the reduced reactivity of the Al foil encourages the formation of lower-valence oxides of Ni and Co, rather than their metallic forms. Under optimal roasting conditions at 650 °C for 1.0 h, 91.4% of Li can be preferentially and selectively extracted through carbonation water leaching, with less than 0.1% of Al and transition metals dissolving. Subsequently, ∼98% of Al and ∼99% of Ni, Co, and Mn can be leached using alkaline and acidic solutions, respectively. Compared to the traditional carbon thermal reduction process, this process offers several advantages including the elimination of pre-sorting and additional reducing agents, lower carbon emissions, and higher recovery rates of valuable metals. Thus, this process makes the recovery of metals from spent lithium-ion batteries more environmentally sustainable, simple, cost-effective, and adaptable.

Structural and pharmacological insights into cordycepin for neoplasms and metabolic disorders.

Cytotoxic adenosine analogues were among the earliest chemotherapeutic agents utilised in cancer treatment. Cordycepin, a natural derivative of adenosine discovered in the fungus Ophiocordyceps sinensis, directly inhibits tumours not only by impeding biosynthesis, inducing apoptosis or autophagy, regulating the cell cycle, and curtailing tumour invasion and metastasis but also modulates the immune response within the tumour microenvironment. Furthermore, extensive research highlights cordycepin's significant therapeutic potential in alleviating hyperlipidaemia and regulating glucose metabolism. This review comprehensively analyses the structure-activity relationship of cordycepin and its analogues, outlines its pharmacokinetic properties, and strategies to enhance its bioavailability. Delving into the molecular biology, it explores the pharmacological mechanisms of cordycepin in tumour suppression and metabolic disorder treatment, thereby underscoring its immense potential in drug development within these domains and laying the groundwork for innovative treatment strategies.

Navigating ESKAPE Pathogens: Considerations and Caveats for Animal Infection Models Development.

The misuse of antibiotics has led to the global spread of drug-resistant bacteria, especially multi-drug-resistant (MDR) ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). These opportunistic bacteria pose a significant threat, in particular within hospitals, where they cause nosocomial infections, leading to substantial morbidity and mortality. To comprehensively explore ESKAPE pathogenesis, virulence, host immune response, diagnostics, and therapeutics, researchers increasingly rely on necessitate suitable animal infection models. However, no single model can fully replicate all aspects of infectious diseases. Notably when studying opportunistic pathogens in immunocompetent hosts, rapid clearance by the host immune system can limit the expression of characteristic disease symptoms. In this study, we examine the critical role of animal infection models in understanding ESKAPE pathogens, addressing limitations and research gaps. We discuss applications and highlight key considerations for effective models. Thoughtful decisions on disease replication, parameter monitoring, and data collection are crucial for model reliability. By meticulously replicating human diseases and addressing limitations, researchers maximize the potential of animal infection models. This aids in targeted therapeutic development, bridges knowledge gaps, and helps combat MDR ESKAPE pathogens, safeguarding public health.

Targeted Drug Delivery to ACE2+ Cells Using Engineered Extracellular Vesicles: A Potential Therapeutic Approach for COVID-19.

BACKGROUND: Extracellular vesicles (EVs) are emerging as potential drug carriers in the fight against COVID-19. This study investigates the ability of EVs as drug carriers to target SARS-CoV-2-infected cells. METHODS: EVs were modified using Xstamp technology to carry the virus's RBD, enhancing targeting ability to hACE2+ cells and improving drug delivery efficiency. Characterization confirmed EVs' suitability as drug carriers. For in vitro tests, A549, Caco-2, and 4T1 cells were used to assess the targeting specificity of EVRs (EVs with membrane-surface enriched RBD). Moreover, we utilized an ex vivo lung tissue model overexpressing hACE2 as an ex vivo model to confirm the targeting capability of EVRs toward lung tissue. The study also evaluated drug loading efficiency and assessed the potential of the anti-inflammatory activity on A549 lung cancer cells exposed to lipopolysaccharide. Results demonstrate the successful construction of RBD-fused EVRs on the membrane-surface. In both in vitro and ex vivo models, EVRs significantly enhance their targeting ability towards hACE2+ cells, rendering them a safe and efficient drug carrier. Furthermore, ultrasound loading efficiently incorporates IL-10 into EVRs, establishing an effective drug delivery system that ameliorates the pro-inflammatory response induced by LPS-stimulated A549 cells. CONCLUSION: These findings indicate promising opportunities for engineered EVs as a novel nanomedicine carrier, offering valuable insights for therapeutic strategies against COVID-19 and other diseases.

Efficient phosphate removal by Mg-La binary layered double hydroxides: synthesis optimization, adsorption performance, and inner mechanism.

Layered double hydroxides (LDH) hold great promise as phosphate adsorbents; however, the conventional binary LDH exhibits low adsorption rate and adsorption capacity. In this study, Mg and La were chosen as binary metals in the synthesis of Mg-La LDH to enhance phosphate efficient adsorption. Different molar ratios of Mg to La (2:1, 3:1, and 4:1) were investigated to further enhance P adsorption. The best performing Mg-La LDH, with Mg to La ratio is 4:1 (LDH-4), presented a larger adsorption capacity and faster adsorption rate than other Mg-La LDH. The maximum adsorption capacity (87.23 mg/g) and the rapid adsorption rate in the initial 25 min of LDH-4 (70 mg/(g·h)) were at least 1.6 times and 1.8 times higher than the others. The kinetics, isotherms, the effect of initial pH and co-existing anions, and the adsorption-desorption cycle experiment were studied. The batch experiment results proved that the chemisorption progress occurred on the single-layered LDH surface and the optimized LDH exhibited strong anti-interference capability. Furthermore, the structural characteristics and adsorption mechanism were further investigated by SEM, BET, FTIR, XRD, and XPS. The characterization results showed that the different metal ratios could lead to changes in the metal hydroxide layer and the main ions inside. At lower Mg/La ratios, distortion occurred in the hydroxide layer, resulting in lower crystallinity and lower performance. The characterization results also proved that the main mechanisms of phosphate adsorption are electrostatic adsorption, ion exchange, and inner-sphere complexation. The results emphasized that the Mg-La LDH was efficient in phosphate removal and could be successfully used for this purpose.

Effect of Yogurt Intake Frequency on Blood Pressure: A Cross-Sectional Study.

Yogurt consumption is a significant factor in reducing the risk of hypertension and preventing cardiovascular diseases. Although increasing evidence has emerged regarding the potential benefits of probiotics in hypertension, there is a lack of large, cross-sectional studies assessing the association between yogurt intake and blood pressure parameters. We aimed to evaluate the association between yogurt intake frequency and blood pressure. A cross-sectional study was designed using data from the National Health and Nutrition Examination Survey from 2003 to 2004 and 2005 to 2006. We included 3, 068 adults with blood pressure data and yogurt intake data. Multivariate regression analyses revealed significant inverse associations between yogurt and systolic blood pressure (P < 0.05), diastolic blood pressure (P < 0.05), and mean arterial pressure (P < 0.05) in nonhypertensive participants (n = 1 822) but not in hypertensive participants (n = 1 246). Furthermore, a high frequency of yogurt intake prevented hypertension; however, no additional antihypertensive effects were observed in patients already diagnosed with hypertension.

Insights into the oral microbiota in human systemic cancers.

The oral cavity stands as one of the pivotal interfaces facilitating the intricate interaction between the human body and the external environment. The impact of diverse oral microorganisms on the emergence and progression of various systemic cancers, typified by oral cancer, has garnered increasing attention. The potential pathogenicity of oral bacteria, notably the anaerobic Porphyromonas gingivalis and Fusobacterium nucleatum, has been extensively studied and exhibits obvious correlation with different carcinoma types. Furthermore, oral fungi and viruses are closely linked to oropharyngeal carcinoma. Multiple potential mechanisms of oral microbiota-induced carcinogenesis have been investigated, including heightened inflammatory responses, suppression of the host immune system, influence on the tumor microenvironment, anti-apoptotic activity, and promotion of malignant transformation. The disturbance of microbial equilibrium and the migration of oral microbiota play a pivotal role in facilitating oncogenic functions. This review aims to comprehensively outline the pathogenic mechanisms by which oral microbiota participate in carcinogenesis. Additionally, this review delves into their potential applications in cancer prevention, screening, and treatment. It proves to be a valuable resource for researchers investigating the intricate connection between oral microbiota and systemic cancers.

Rap1GAP exacerbates myocardial infarction by regulating the AMPK/SIRT1/NF-κB signaling pathway.

Rap1 GTPase-activating protein (Rap1GAP) is an important tumor suppressor. The purpose of this study was to investigate the role of Rap1GAP in myocardial infarction (MI) and its potential mechanism. Left anterior descending coronary artery ligation was performed on cardiac-specific Rap1GAP conditional knockout (Rap1GAP-CKO) mice and control mice with MI. Seven days after MI, Rap1GAP expression in the hearts of control mice peaked, the expression of proapoptotic markers (Bax and cleaved caspase-3) increased, the expression of antiapoptotic factors (Bcl-2) decreased, and the expression of the inflammatory factors IL-6 and TNF-α increased; thus, apoptosis occurred, inflammation, infarct size, and left ventricular dysfunction increased, while the heart changes caused by MI were alleviated in Rap1GAP-CKO mice. Mouse heart tissue was obtained for transcriptome sequencing, and gene set enrichment analysis (GSEA) was used to analyze Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We found that Rap1GAP was associated with the AMPK and NF-κB signaling pathways and that Rap1GAP inhibited AMPK/SIRT1 and activated the NF-κB signaling pathway in model animals. Similar results were observed in primary rat myocardial cells subjected to oxygen-glucose deprivation (OGD) to induce ischemia and hypoxia. Activating AMPK with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reversed the damage caused by Rap1GAP overexpression in cardiomyocytes. In addition, the coimmunoprecipitation results showed that exogenous Rap1GAP interacted with AMPK. Rap1GAP was verified to regulate the AMPK SIRT1/NF-κB signaling pathway and exacerbate the damage to myocardial cells caused by ischemia and hypoxia. In conclusion, our results suggest that Rap1GAP promotes MI by modulating the AMPK/SIRT1/NF-κB signaling pathway and that Rap1GAP may be a therapeutic target for MI treatment in the future.

Study on the biodegradation characteristics and mechanism of tetracycline by Serratia entomophila TC-1.

Microbial degradation is an important solution for antibiotic pollution in livestock and poultry farming wastes. This study reports the isolation and identification of the novel bacterial strain Serratia entomophila TC-1, which can degrade 87.8 % of 200 mg/L tetracycline (TC) at 35 °C, pH 6.0, and an inoculation amount of 1 % (v/v). Based on the intermediate products, a possible biological transformation pathway was proposed, including dehydration, oxidation ring opening, decarbonylation, and deamination. Using Escherichia coli and Bacillus subtilis as biological indicators, TC degraded metabolites have shown low toxicity. Whole-genome sequencing showed that the TC-1 strain contained tet (d) and tet (34), which resist TC through multiple mechanisms. In addition, upon TC exposure, TC-1 participated in catalytic and energy supply activities by regulating gene expression, thereby playing a role in TC detoxification. We found that TC-1 showed less interference with changes in the bacterial community in swine wastewater. Thus, TC-1 provided new insights into the mechanisms responsible for TC biodegradation and can be used for TC pollution treatment.

Exosome-specific loading Sox10 for the treatment of Cuprizone-induced demyelinating model.

Demyelination is a pathological feature commonly observed in various central nervous system diseases. It is characterized by the aggregation of oligodendrocyte progenitor cells (OPCs) in the lesion area, which face difficulties in differentiating into mature oligodendrocytes (OLGs). The differentiation of OPCs requires the presence of Sox10, but its expression decreases under pathological conditions. Therefore, we propose a therapeutic strategy to regulate OPCs differentiation and achieve myelin repair by endogenously loading Sox10 into exosomes. To accomplish this, we generated a lentivirus-armed Sox10 that could anchor to the inner surface of the exosome membrane. We then infected HEK293 cells to obtain exosomes with high expression of Sox10 (exosomes-Sox10, ExoSs). In vitro, experiments confirmed that both Exos and ExoSs can be uptaken by OPCs, but only ExoSs exhibit a pro-differentiation effect on OPCs. In vivo, we administered PBS, Exos, and ExoSs to cuprizone-induced demyelinating mice. The results demonstrated that ExoSs can regulate the differentiation of PDGFRα+ OPCs into APC+ OLGs and reduce myelin damage in the corpus callosum region of the mouse brain compared to other groups. Further testing suggests that Sox10 may have a reparative effect on the myelin sheath by enhancing the expression of MBP, possibly facilitated by the exosome delivery of the protein into the lesion. This endogenously loaded technology holds promise as a strategy for protein-based drugs in the treatment of demyelinating diseases.

Based on SIRT1/NF-κB/NLRP3 Signal Pathway to Explore the Effect of Yiqi Huatan Huoxue Recipe on Inflammatory Injury in AIT Mice by Pyroptosis.

OBJECTIVE: Autoimmune thyroiditis (AIT) is the most common autoimmune thyroid disease. In recent decades, its incidence and prevalence have sharply increased. Yiqi Huatan Huoxue recipe is a traditional Chinese medicine formula we use to treat AIT. Its clinical efficacy is clear, but the specific mechanism remains unclear. This study aims to explore whether pyroptosis mediated by the SIRT1/NF-κB/NLRP3 signaling pathway is one of the therapeutic mechanisms of Yiqi Huatan Huoxue recipe. METHODS: Forty 8-week-old female NOD.H-2h4 mice were randomly divided into four groups: the normal group (NG), model group (MG), Yiqi Huatan Huoxue recipe group (YG), and western medicine group (selenium yeast tablet, SeG). The normal group was gavaged with distilled water, while the remaining groups were gavaged with 0.05% sodium iodide (NaI) solution for 8 weeks. After the AIT animal model formed naturally, the mice were euthanized by gavage after 8 weeks. Hematoxylin-eosin staining was used to observe thyroid tissue changes, and enzymelinked immunosorbent assay (ELISA) was used to detect serum anti-thyroglobulin antibodies (TGAb) and mouse anti-thyroid peroxidase antibodies (TPOAb). Real-time quantitative PCR (qRT-PCR), Western blot, and immunohistochemistry were used to detect the expression of sirtuin 1 (SIRT1), nuclear factor κB p65 (NF-κB p65), nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase- 1, gasdermin D (GSDMD), and interleukin (IL)-1ß in thyroid tissue. RESULTS: Compared with the NG group, the thyroid structure of rats in the MG group was severely damaged, with significant lymphocyte infiltration, significantly increased serum TGAb and TPOAb levels, and significantly increased expression levels of SRIT1, NF-κB p65, NLRP3, ASC, Caspase-1, GSDMD, IL-1ß mRNA, and protein. Compared with the MG group, the thyroid structure damage and lymphocyte infiltration in rats of each treatment group were improved, and the serum TGAb, TPOAb, SRIT1, NF-κB p65, NLRP3, ASC, Caspase-1, GSDMD, IL-1ß mRNA, and protein expression levels were significantly reduced. CONCLUSION: Yiqi Huatan Huoxue recipe can alleviate thyroid structural damage in AIT mice, and its mechanism may be related to the upregulation of SIRT1, NF-κB deacetylation, and inhibition of NLRP3-mediated pyroptosis.

A rational designed multi-epitope vaccine elicited robust protective efficacy against Klebsiella pneumoniae lung infection.

BACKGROUND: The emergence of drug-resistant strains of Klebsiella pneumoniae (K. pneumoniae) has become a significant challenge in the field of infectious diseases, posing an urgent need for the development of highly protective vaccines against this pathogen. METHODS AND RESULTS: In this study, we identified three immunogenic extracellular loops based on the structure of five candidate antigens using sera from K. pneumoniae infected mice. The sequences of these loops were linked to the C-terminal of an alpha-hemolysin mutant (mHla) from Staphylococcus aureus to generate a heptamer, termed mHla-EpiVac. In vivo studies confirmed that fusion with mHla significantly augmented the immunogenicity of EpiVac, and it elicited both humoral and cellular immune responses in mice, which could be further enhanced by formulation with aluminum adjuvant. Furthermore, immunization with mHla-EpiVac demonstrated enhanced protective efficacy against K. pneumoniae channeling compared to EpiVac alone, resulting in reduced bacterial burden, secretion of inflammatory factors, histopathology and lung injury. Moreover, mHla fusion facilitated antigen uptake by mouse bone marrow-derived cells (BMDCs) and provided sustained activation of these cells. CONCLUSIONS: These findings suggest that mHla-EpiVac is a promising vaccine candidate against K. pneumoniae, and further validate the potential of mHla as a versatile carrier protein and adjuvant for antigen design.

A highly neutralizing human monoclonal antibody targeting a novel linear epitope on staphylococcal enterotoxin B.

Staphylococcal Enterotoxin B (SEB), produced by Staphylococcus aureus (S. aureus), is a powerful superantigen that induces severe immune disruption and toxic shock syndrome (TSS) upon binding to MHC-II and TCR. Despite its significant impact on the pathogenesis of S. aureus, there are currently no specific therapeutic interventions available to counteract the mechanism of action exerted by this toxin. In this study, we have identified a human monoclonal antibody, named Hm0487, that specifically targets SEB by single-cell sequencing using PBMCs isolated from volunteers enrolled in a phase I clinical trial of the five-antigen S. aureus vaccine. X-ray crystallography studies revealed that Hm0487 exhibits high affinity for a linear B cell epitope in SEB (SEB138-147), which is located distantly from the site involved in the formation of the MHC-SEB-TCR ternary complex. Furthermore, in vitro studies demonstrated that Hm0487 significantly impacts the interaction of SEB with both receptors and the binding to immune cells, probably due to an allosteric effect on SEB rather than competing with receptors for binding sites. Moreover, both in vitro and in vivo studies validated that Hm0487 displayed efficient neutralizing efficacy in models of lethal shock and sepsis induced by either SEB or bacterial challenge. Our findings unveil an alternative mechanism for neutralizing the pathogenesis of SEB by Hm0487, and this antibody provides a novel strategy for mitigating both SEB-induced toxicity and S. aureus infection.

Vaccination with a trivalent Klebsiella pneumoniae vaccine confers protection in a murine model of pneumonia.

Klebsiella pneumoniae (K. pneumoniae) is an opportunistic pathogen and the major cause of healthcare-associated infections, which are increasingly complicated by the prevalence of highly invasive and hyper-virulent K. pneumoniae strains, necessitating the development of alternative strategies for combatting infections caused by this bacterium. In this study, we successfully constructed a fusion antigen called KP-Ag1, comprising three antigens (GlnH, FimA, and KPN_00466) that were previously identified through reverse vaccinology. Immunization with KP-Ag1 formulated with Al(OH)3 adjuvant elicited robust humoral and cellular immune response in mice, and conferred protective immunity in a murine model of K. pneumoniae lung infection. Further analysis of serum IgG subtypes from mice immunized with KP-Ag1 revealed a predominant IgG1 response, indicating that KP-Ag1 predominantly induces a Th2-biased immune response. Additionally, opsonophagocytic killing assay suggested that humoral immune responses play a pivotal role in mediating protection conferred by KP-Ag1. Moreover, KP-Ag1 was found to promote the activation and maturation of BMDCs in vitro, which is essential for subsequent efficient antigen presentation. More importantly, vaccination with KP-Ag1 demonstrated cross-protective efficacy against clinical isolates of K. pneumoniae varying in serotypes, antibiotic resistance, and virulence profiles. Therefore, KP-Ag1 holds promise as a candidate for K. pneumoniae vaccine development.

Interventing mitochondrial PD-L1 suppressed IFN-γ-induced cancer stemness in hepatocellular carcinoma by sensitizing sorafenib-induced ferroptosis.

Evidence recently showed that pleiotropic cytokine interferon-gamma (IFN-γ) in the tumor microenvironment (TME) plays a positive role in hepatocellular carcinoma (HCC) progression through the regulation of liver cancer stem cells (LCSCs) in HCC. The present study explored the role and potential mechanism of mitochondrial programmed cell death-ligand 1 (PD-L1) and its regulation of ferroptosis in modulating the cancer stemness of LCSCs. It was shown that mimicking TME IFN-γ exposure increased the LCSCs ratio and cancer stemness phenotypes in HCC cells. IFN-γ exposure inhibited sorafenib (Sora)-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) expression as well reactive oxygen species (ROS) and lipid peroxidation (LPO) generation in LCSCs. Furthermore, IFN-γ exposure upregulated PD-L1 expression and its mitochondrial translocation, inducing dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and correlating with glycolytic metabolism reprogramming in LCSCs. The genetic intervention of PD-L1 promoted ferroptosis-dependent anti-tumor effects of Sora, reduced glycolytic metabolism reprogramming, and inhibited cancer stemness of HCC in vitro and in vivo. Our results revealed a novel mechanism that IFN-γ exposure-induced mitochondrial translocation of PD-L1 enhanced glycolytic reprogramming to mediate the GPX4-dependent ferroptosis resistance and cancer stemness in LCSCs. This study provided new insights into the role of mitochondrial PD-L1-Drp1-GPX4 signal axis in regulating IFN-γ exposure-associated cancer stemness in LCSCs and verified that PD-L1-targeted intervention in combination with Sora might achieve promising synergistic anti-HCC effects.

Trends in Sexual Harassment Prevalence and Recognition During Intern Year.

This cohort study uses Internal Health Study and Sexual Experiences Questionnaire data to assess changes in sexual harassment prevalence and recognition among training physicians.