Revealing the potential of solute carrier family 31 (copper transporters), member 1: Insights into its role in bladder cancer progression and therapeutic implications.

Introduction: Bladder cancer represents a significant public health concern with diverse genetic alterations influencing disease onset, progression, and therapy response. In this study, we explore the multifaceted role of Solute Carrier Family 31 Member 1 (SLC31A1) in bladder cancer, a pivotal gene involved in copper homeostasis. Methods: Our research involved analyzing the SLC31A1 gene expression via RT-qPCR, promoter methylation via targeted bisulfite sequencing, and mutational status via Next Generation Sequencing (NGS) using the clinical samples sourced by the local bladder cancer patients. Later on, The Cancer Genome Atlas (TCGA) datasets were utilized for validation purposes. Moreover, prognostic significance, gene enrichment terms, and therapeutic drugs of SLC31A1 were also explored using KM Plotter, DAVID, and DrugBank databases. Results: We observed that SLC31A1 was significantly up-regulated at both the mRNA and protein levels in bladder cancer tissue samples, suggesting its potential involvement in bladder cancer development and progression. Furthermore, our investigation into the methylation status revealed that SLC31A1 was significantly hypomethylated in bladder cancer tissues, which may contribute to its overexpression. The ROC analysis of the SLC31A1 gene indicated promising diagnostic potential, emphasizing its relevance in distinguishing bladder cancer patients from normal individuals. However, it is crucial to consider other factors such as cancer stage, metastasis, and recurrence for a more accurate evaluation in the clinical context. Interestingly, mutational analysis of SLC31A1 demonstrated only benign mutations, indicating their unknown role in the SLC31A1 disruption. In addition to its diagnostic value, high SLC31A1 expression was associated with poorer overall survival (OS) in bladder cancer patients, shedding light on its prognostic relevance. Gene enrichment analysis indicated that SLC31A1 could influence metabolic and copper-related processes, further underscoring its role in bladder cancer. Lastly, we explored the DrugBank database to identify potential therapeutic agents capable of reducing SLC31A1 expression. Our findings unveiled six important drugs with the potential to target SLC31A1 as a treatment strategy. Conclusion: Our comprehensive investigation highlights SLC31A1 as a promising biomarker for bladder cancer development, progression, and therapy.

A Re-Examination of Neoadjuvant Therapy for Thymic Tumors: A Long and Winding Road.

For most patients with advanced thymic epithelial tumors (TETs), a complete resection is a strong indicator of a better prognosis. But sometimes, primary surgery is unsatisfactory, and preoperative therapy is needed to facilitate complete resection. Neoadjuvant chemotherapy is the most used form of preoperative therapy. But studies on neoadjuvant chemotherapy have included mainly patients with thymoma; its efficacy in patients with thymic carcinoma is less known. Neoadjuvant chemoradiation has also been explored in a few studies. Novel therapies such as immunotherapy and targeted therapy have shown efficacy in patients with recurrent/metastatic TETs as a second-line option; their role as preoperative therapy is still under investigation. In this review, we discuss the existing evidence on preoperative therapy and the insight it provides for current clinical practice and future studies.

Identification of seven variants in the col4a1 gene that alter RNA splicing by minigene assay.

Type IV collagen is an integral component of basement membranes. Mutations in COL4A1, one of the key genes encoding Type IV collagen, can result in a variety of diseases. It is clear that a significant proportion of mutations that affect splicing can cause disease directly or contribute to the susceptibility or severity of disease. Here, we analyzed exonic mutations and intronic mutations described in the COL4A1 gene using bioinformatics programs and identified candidate mutations that may alter the normal splicing pattern through a minigene system. We identified seven variants that induce splicing alterations by disrupting normal splice sites, creating new ones, or altering splice regulatory elements. These mutations are predicted to impact protein function. Our results help in the correct molecular characterization of variants in COL4A1 and may help develop more personalized treatment options.

Cogeneration of Clean Water and Valuable Energy/Resources via Interfacial Solar Evaporation.

Water, covering over two-thirds of the Earth's surface, holds immense potential for generating clean water, sustainable energy, and metal resources, which are the cornerstones of modern society and future development. It is highly desired to produce these crucial elements through eco-friendly processes with minimal carbon footprints. Interfacial solar evaporation, which utilizes solar energy at the air-liquid interface to facilitate water vaporization and solute separation, offers a promising solution. In this review, we systematically report the recent progress of the cogeneration of clean water and energy/resources including electricity, hydrogen, and metal resources via interfacial solar evaporation. We first gain insight into the energy and mass transport for a typical interfacial solar evaporation system and reveal the residual energy and resources for achieving the cogeneration goal. Then, we summarize the recent advances in materials/device designs for efficient cogeneration. Finally, we discuss the existing challenges and potential opportunities for the further development of this field.

Unraveling the formation of oxygen vacancies on the surface of transition metal-doped ceria utilizing artificial intelligence.

Ceria has been extensively utilized in different fields, with surface oxygen vacancies playing a central role. However, versatile oxygen vacancy regulation is still in its infancy. In this work, we propose an effective strategy to manipulate the oxygen vacancy formation energy via transition metal doping by combining first-principles calculations and analytical learning. We elucidate the underlying mechanism driving the formation of oxygen vacancies using combined symbolic regression and data analytics techniques. The results show that the Fermi level of the system and the electronegativity of the dopants are the paramount parameters (features) influencing the formation of oxygen vacancies. These insights not only enhance our understanding of the oxygen vacancy formation mechanism in ceria-based materials to improve their functionality but also potentially lay the groundwork for future strategies in the rational design of other transition metal oxide-based catalysts.

Diagnostic Performance of [18F]AlF-Thretide PET/CT in Patients with Newly Diagnosed Prostate Cancer Using Histopathology as Reference Standard.

This study aimed to assess the diagnostic value of [18F]AlF-thretide PET/CT in patients with newly diagnosed prostate cancer (PCa). Methods: In total, 49 patients with biopsy-proven PCa were enrolled in this prospective study. All patients underwent [18F]AlF-thretide PET/CT, and the scoring system of the PRIMARY trial was used for PET image analysis. The dosimetry evaluation of [18F]AlF-thretide was performed on 3 patients. Pathologic examination was used as the reference standard to evaluate the location, number, size, and Gleason score of tumors, for comparison with the [18F]AlF-thretide PET/CT results. PSMA expression was evaluated by immunohistochemical staining. Results: All patients tolerated the [18F]AlF-thretide PET/CT well. The total effective dose of [18F]AlF-thretide was 1.16E-02 mSv/MBq. For patient-based analysis of intraprostatic tumors, 46 of 49 (93.9%) patients showed pathologic uptake on [18F]AlF-thretide PET/CT. For lesion-based analysis of intraprostatic tumors, the sensitivity and positive predictive value for [18F]AlF-thretide PET/CT were 58.2% and 90.5%, respectively. Delayed images can detect more lesions than standard images (n = 57 vs. 49, P = 0.005), and the SUVmax and tumor-to-background ratio of the former were higher than those of the latter (SUVmax: 14.5 ± 16.7 vs. 11.4 ± 13.6, P < 0.001; tumor-to-background ratio: 37.1 ± 42.3 vs. 23.1 ± 27.4, P < 0.001). The receiver-operating-characteristic curve analysis showed that the areas under the curve for PRIMARY score-predicted true-positive and false-positive lesions were significantly higher than those for the SUVmax of standard images (P = 0.015) and seemed higher than those for the SUVmax of delayed images (P = 0.257). [18F]AlF-thretide PET/CT showed a higher detection rate than multiparametric MRI for all intraprostatic foci (53.5% vs. 40.8%, P = 0.012) and clinically significant PCa (75.0% vs. 61.4%, P = 0.031). Conclusion: [18F]AlF-thretide PET/CT showed high diagnostic value for patients with primary PCa and can be used as an excellent imaging modality for preoperative evaluation of PCa patients.

Reconstructive strategies following surgical resection of malignant sublingual gland tumors: A single institution experience.

OBJECTIVE: To investigate the characteristics and treatment modalities of malignant tumors originating from the sublingual gland, as well as evaluate the therapeutic outcomes following free flap reconstruction. METHODS: A retrospective statistical analysis was conducted on the clinical data of nine patients diagnosed with malignant neoplasms tumor of the sublingual gland. RESULTS: Nine case of malignant tumors originated from the sublingual glandular tissue, encompassing eight adenoid cystic carcinoma (ACC) and a single case of bipartite differentiated carcinoma-a hybrid of epithelial-myoepithelial carcinoma and adenoid cystic carcinoma. Among the nine patients, four anterolateral thigh flaps were used (three of which were thin flaps), and five forearm flaps were also empoyed. The size of flaps varied, with the lengths ranging from 4 cm to 9 cm, and the widths ranging from 2.5 cm to 6 cm. The vessels chosen for anastomosis were the superior thyroid artery in seven cases, the facial artery in one case, and the lingual artery in one case. Among the eight patients who underwent dissection of cervical lymph nodes, metastasis were found in one case. Two patients underwent adjuvant radiotherapy. Upon postoperative follow-up, there was no recurrence in any of the nine patients . CONCLUSION: The anterolateral thigh perforator flap thinning technique can be employed for postoperative reconstruction of malignant sublingual gland tumors.

Risk factors and metabolomics of mild cognitive impairment in type 2 diabetes mellitus.

Objective: This study aimed to explore the risk factors, metabolic characteristics, and potential biomarkers of mild cognitive impairment in type 2 diabetes mellitus (T2DM-MCI) and to provide potential evidence for the diagnosis, prevention, and treatment of mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 103 patients with T2DM were recruited from the Endocrinology Department of The Second Affiliated Hospital of Dalian Medical University for inclusion in the study. The Montreal Cognitive Assessment (MoCA) was utilized to evaluate the cognitive functioning of all patients. Among them, 50 patients were categorized into the T2DM-MCI group (MoCA score < 26 points), while 53 subjects were classified into the T2DM without cognitive impairment (T2DM-NCI) group (MoCA score ≥ 26 points). Serum samples were collected from the subjects, and metabolomics profiling data were generated by Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS). These groups were analyzed to investigate the differences in expression of small molecule metabolites, metabolic pathways, and potential specific biomarkers. Results: Comparison between the T2DM-MCI group and T2DM-NCI group revealed significant differences in years of education, history of insulin application, insulin resistance index, insulin-like growth factor-binding protein-3 (IGFBP-3), and creatinine levels. Further binary logistic regression analysis of the variables indicated that low educational level and low serum IGFBP-3 were independent risk factor for T2DM-MCI. Metabolomics analysis revealed that differential expression of 10 metabolites between the T2DM-MCI group and T2DM-NCI group (p < 0.05 and FDR<0.05, VIP>1.5). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis revealed that fatty acid degradation was the most significant pathway. Receiver operating characteristic (ROC) analysis shows that lysophosphatidylcholine (LPC) 18:0 exhibited greater diagnostic efficiency. Conclusion: This study revealed that a shorter duration of education and lower serum IGFBP-3 levels are independent risk factors for T2DM-MCI. Serum metabolites were found to be altered in both T2DM-MCI and T2DM-NCI groups. T2DM patients with or without MCI can be distinguished by LPC 18:0. Abnormal lipid metabolism plays a significant role in the development of MCI in T2DM patients.

Disulfidptosis-related lncRNA signature reveals immune microenvironment and novel molecular subtyping of stomach adenocarcinoma.

The main challenge in treating stomach adenocarcinoma (STAD) is chemotherapy resistance, which is characterized by changes in the immune microenvironment. Disulfidptosis, a novel form of programmed cell death, is involved in STAD but its mechanism is not fully understood. Long non-coding RNAs (LncRNAs) may play a role in regulating disulfidptosis and influencing the immune microenvironment and chemotherapy resistance in STAD. This study aims to establish disulfidptosis-related lncRNA (DRL) features and explore their significance in the immune microenvironment and chemotherapy resistance in STAD patients. By analyzing RNA sequencing and clinical data from STAD patients and extracting disulfidptosis-related genes, we identified DRLs through co-expression, single-factor and multi-factor Cox regression, and Lasso regression analyses. We also investigated differences in the immune microenvironment, immune function, immune checkpoint gene expression, and chemotherapy resistance between different risk groups using various algorithms. A prognostic risk model consisting of 2 DRLs was constructed, with a strong predictive value for patient survival, outperforming other clinical-pathological factors in predicting 3-year and 5-year survival. Immune-related analysis revealed a strong positive correlation between T cell CD4+ cells and risk score across all algorithms, and higher expression of immune checkpoint genes in the high-risk group. In addition, high-risk patients showed better sensitivity to Erlotinib, Oxaliplatin, and Gefitinib. Furthermore, three novel molecular subtypes of STAD were identified based on the 2-DRLs features, with evaluation of the immune microenvironment and chemotherapy drug sensitivity for each subgroup, which holds significant implications for achieving precise treatment in STAD. Overall, our 2-DRLs prognostic model demonstrates high predictive value for patient survival in STAD, potentially providing new targets for individualized immune and chemical therapy.

Integrated micro/nano drug delivery system based on magnetically responsive phase-change droplets for ultrasound theranostics.

Phase-change droplets (PCDs) are intelligent responsive micro and nanomaterials developed based on micro/nano bubbles. Subject to external energy inputs such as temperature and ultrasound, the core substance, perfluorocarbon (PFC), undergoes a phase transition from liquid to gas. This transformation precipitates alterations in the PCDs' structure, size, ultrasound imaging capabilities, drug delivery efficiency, and other pertinent characteristics. This gives them the ability to exhibit "intelligent responses". This study utilized lipids as the membrane shell material and perfluorohexane (PFH) as the core to prepare lipid phase-change droplets. Superparamagnetic nanoparticles (PEG-functionalized Fe3O4 nanoparticles) and the anti-tumor drug curcumin (Cur) were loaded into the membrane shell, forming magnetic drug-loaded phase-change droplets (Fe-Cur-NDs). These nanoscale phase-change droplets exhibited excellent magnetic resonance/ultrasound imaging capabilities and thermal/ultrasound-mediated drug release. The Fe-Cur-NDs showed excellent anti-tumor efficacy for the MCF-7 cells under low-intensity focused ultrasound (LIFU) guidance in vitro. Therefore, Fe-Cur-NDs represent a promising smart responsive theranostic integrated micro/nano drug delivery system.

Casein hydrolysate in naturally-fermented buckwheat sourdough: Effects on fermented and physicochemical characteristics, texture, and bacterial microbial composition.

The effect of a casein hydrolysate (CH) on the fermentation and quality of a naturally-fermented buckwheat sourdough (NFBS) were investigated, through assessing the fermentation characteristics, carbohydrate and protein degradation, texture, and bacterial composition of NFBS. According to the assaying data, CH might both increase the amount of lactic acid bacteria by 2.62 % and shorten the fermentation period by at least 3 h, subsequently leading to enhanced degradation of carbohydrate and protein, accompanied by a softer texture. More importantly, CH increased the relative abundance of lactobacillus in NFBS, making it the dominant bacterial genus and inhibited the growth of spoilage bacteria. In addition, Spearman correlation analysis indicated that the pH value, lactic and acetic acid contents, carbohydrates, protease activity, and these textural indices like hardness, elasticity, and adhesion had a positive/negative correlation with the bacterial composition of NFBS (Spearman correlation coefficient: -0.93-0.95). CH was thus regarded to be helpful to NFBS processing and production mainly by shortening its fermentation time, improving its fermentation performance, causing a finer texture and microstructure, and changing bacterial composition.

Leveraging Bilateral Correlations for Multi-Label Few-Shot Learning.

Multi-label few-shot learning (ML-FSL) refers to the task of tagging previously unseen images with a set of relevant labels, giving a small number of training examples. Modeling the correlations between instances and labels, formulated in the existing methods, allows us to extract more available knowledge from limited examples. However, they simply explore the instance and label correlations with a uniform importance assumption without considering the discrepancy of importance in different instances or labels, making the utilization of instance and label correlations a bottleneck for ML-FSL. To tackle the issue, we propose a unified framework named bilateral correlation reconstruction (BCR) to enable the network to effectively mine underlying instance and label correlations with varying importance information from both instance-to-label and label-to-instance perspectives. Specifically, from the instance-to-label perspective, we refine prototypes per category by reweighting each image with its specific instance-importance degree extracted from the similarity between the instance and the corresponding category. From the label-to-instance perspective, we smooth labels for each image by recovering latent label-importance with considering the integrated topology of all samples in a task. Experimental results on multiple benchmarks validate that BCR could outperform existing ML-FSL methods by large margins.

A novel self-inflatable balloon for treating refractory benign esophageal strictures: a prospective, single-arm, multicenter study.

BACKGROUND AND AIM: Current treatments for refractory benign esophageal strictures (BESs) often take several years and have poor effects. The authors propose a novel method of self-help inflatable balloon (SHIB) and evaluate its efficacy and safety. METHODS: A prospective, multicenter study was conducted from January 2019 to March 2022. All enrolled patients were diagnosed with refractory BESs and received SHIB. The primary endpoint was the clinical success rate at 12 months after removing SHIB. The secondary endpoints were the number of days of placing SHIB, and changes from baseline in BMI and health-related quality of life at 1, 3, 6, and 12 months. RESULTS: The clinical success rate was 51.2% (21/41) with the median days of placing SHIB being 104.0 days (range: 62.0-134.5 days), which was higher in the endoscopic group compared to the caustic and surgery groups (63.3 vs. 28.6% vs. 0, P=0.025). All patients (100%) showed significant improvement in dysphagia scores during placing SHIB. Although 20 patients (48.8%) experienced recurrent stricture, the median stricture length was decreased (P<0.001) and the median intervention-free interval was prolonged (P<0.001). In all patients, the mean BMI at and health-related quality of life at 1, 3, 6, and 12 months were significantly increased compared with baseline (P<0.05). On multivariate analysis, stricture etiology and wearing time were independent predictors of recurrent stricture. CONCLUSIONS: The SHIB has high efficacy and safety in treating refractory BESs of different origins, especially for endoscopic resection. Stricture etiology and wearing time were independent predictors of recurrent stricture.

Comparative genomics of macaques and integrated insights into genetic variation and population history.

The crab-eating macaques ( Macaca fascicularis ) and rhesus macaques ( M. mulatta ) are widely studied nonhuman primates in biomedical and evolutionary research. Despite their significance, the current understanding of the complex genomic structure in macaques and the differences between species requires substantial improvement. Here, we present a complete genome assembly of a crab-eating macaque and 20 haplotype-resolved macaque assemblies to investigate the complex regions and major genomic differences between species. Segmental duplication in macaques is ∼42% lower, while centromeres are ∼3.7 times longer than those in humans. The characterization of ∼2 Mbp fixed genetic variants and ∼240 Mbp complex loci highlights potential associations with metabolic differences between the two macaque species (e.g., CYP2C76 and EHBP1L1 ). Additionally, hundreds of alternative splicing differences show post-transcriptional regulation divergence between these two species (e.g., PNPO ). We also characterize 91 large-scale genomic differences between macaques and humans at a single-base-pair resolution and highlight their impact on gene regulation in primate evolution (e.g., FOLH1 and PIEZO2 ). Finally, population genetics recapitulates macaque speciation and selective sweeps, highlighting potential genetic basis of reproduction and tail phenotype differences (e.g., STAB1 , SEMA3F , and HOXD13 ). In summary, the integrated analysis of genetic variation and population genetics in macaques greatly enhances our comprehension of lineage-specific phenotypes, adaptation, and primate evolution, thereby improving their biomedical applications in human diseases.

Identification of survival related key genes and long-term survival specific differentially expressed genes related key miRNA network of primary glioblastoma.

Primary glioblastoma(pGBM) is the most malignant tumor of the central nervous system. Radiotherapy, chemotherapy and surgical treatment have little effect on the survival of pGBM patients. The prognosis is often poorly once the tumor recurs. It is urgent to develop new therapies for patients. In recent years, studies have been clarified that miRNA have a powerful regulating effect on the genes. However, the main group of miRNAs in regulating long-term survival specific related genes of pGBM is still unclear. Given that the survival period of most glioma patients is relatively short, studying long-term survival patients with pGBM is of great value for this disease. Our study aim to identify key miRNAs with long-term survival related genes present in pGBM and uncover their potential mechanisms. The gene expression profiles of GSE53733, GSE15824, GSE30563, GSE50161 were obtained from the Gene Expression Omnibus database. Firstly, samples were divided into 3 groups according to its survival time and each group compare to the normal control group. Then we obtained differential expression genes (DEGs) with a long-term survival specific (LTSDEGs) and a short-term survival specific DEGs (STSDEGs). Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted with LTSDEGs and STSDEGs together. Moreover, we used the UALCAN database to verify LTSDEGs and STSDEGs, and obtained long-term verified survival specific DEGs(LTVSDEGs) and short-term verified survival specific DEGs(STVSDEGs). Finally, we established the predicted key miRNAs-LTVSDEGs interaction network. The protein expressions of the top 4 LTVSDEGs were verified in the HPA database with immunohistochemical staining. In total, we found 260 genes changed in LTSDEGs and 822 genes changed in STSDEGs. GO and KEGG results shown that the major changes are focused on tumor metabolism. 9 LTVSDEGs and 18 STVSDEGs were verified in UALCAN database. As for protein expression verification in top 4 LTVSDEGs, ZNF630, BLVRB and RPA3 were verified, while TPBG was not detected. We obtained 59 key miRNA from the predicted key miRNAs-LTVSDEGs interaction network. 25 key miRNAs were verified using GSE90603. Finally, we constructed the key miRNAs-LTVSDEGs network using a Sankey diagram, including 25 miRNAs and 7 LTVSDEGs. In conclusion, our study shows that there is a close relationship between metabolic changes and survival in pGBM. Besides, we established a key miRNAs-LTVSDEGs network for pGBM, which could be the key path in prolonging the life of pGBM patients.

Is postmastectomy radiotherapy necessary for breast cancer patients with clinically node-positive downstaging to ypN0 after neoadjuvant chemotherapy?

PURPOSE: The significance of postmastectomy radiotherapy (PMRT) in breast cancer patients who initially have clinically node-positive (cN +) status but achieve downstaging to ypN0 following neoadjuvant chemotherapy (NAC) remains uncertain. This study aims to assess the impact of PMRT in this patient subset. METHODS: Patients were enrolled from West China Hospital, Sichuan University from 2008 to 2019. Overall survival (OS), Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and assessed with the log-rank test. The impact of PMRT was further analyzed by the Cox proportional hazards model. Propensity score matching (PSM) was performed to reduce the selection bias. RESULTS: Of the 333 eligible patients, 189 (56.8%) received PMRT, and 144 (43.2%) did not. At a median follow-up period of 71 months, the five-year LRFS, DMFS, BCSS, and OS rates were 99.1%, 93.4%, 96.4%, and 94.3% for the entire cohort, respectively. Additionally, the 5-year LRFS, DMFS, BCSS, and OS rates were 98.9%, 93.8%, 96.7%, and 94.5% with PMRT and 99.2%, 91.3%, 94.9%, and 92.0% without PMRT, respectively (all p-values not statistically significant). After multivariate analysis, PMRT was not a significant risk factor for any of the endpoints. When further stratified by stage, PMRT did not show any survival benefit for patients with stage II-III diseases. CONCLUSION: In the context of comprehensive treatments, PMRT might be exempted in ypN0 breast cancer patients. Further large-scale, randomized controlled studies are required to investigate the significance of PMRT in this patient subset.

The Bach1/HO-1 pathway regulates oxidative stress and contributes to ferroptosis in doxorubicin-induced cardiomyopathy in H9c2 cells and mice.

Doxorubicin (DOX) is one of the most frequently used chemotherapeutic drugs belonging to the class of anthracyclines. However, the cardiotoxic effects of anthracyclines limit their clinical use. Recent studies have suggested that ferroptosis is the main underlying pathogenetic mechanism of DOX-induced cardiomyopathy (DIC). BTB-and-CNC homology 1 (Bach1) acts as a key role in the regulation of ferroptosis. However, the mechanistic role of Bach1 in DIC remains unclear. Therefore, this study aimed to investigate the underlying mechanistic role of Bach1 in DOX-induced cardiotoxicity using the DIC mice in vivo (DOX at cumulative dose of 20 mg/kg) and the DOX-treated H9c2 cardiomyocytes in vitro (1 µM). Our results show a marked upregulation in the expression of Bach1 in the cardiac tissues of the DOX-treated mice and the DOX-treated cardiomyocytes. However, Bach1-/- mice exhibited reduced lipid peroxidation and less severe cardiomyopathy after DOX treatment. Bach1 knockdown protected against DOX-induced ferroptosis in both in vivo and in vitro models. Ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, significantly alleviated DOX-induced cardiac damage. However, the cardioprotective effects of Bach1 knockdown were reversed by pre-treatment with Zinc Protoporphyrin (ZnPP), a selective inhibitor of heme oxygenase-1(HO-1). Taken together, these findings demonstrated that Bach1 promoted oxidative stress and ferroptosis through suppressing the expression of HO-1. Therefore, Bach1 may present as a promising new therapeutic target for the prevention and early intervention of DOX-induced cardiotoxicity.

Mitochondrial (mt)DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis.

BACKGROUND: Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown. METHODS: Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS -/- and sting -/- mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro. RESULTS: SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis. CONCLUSIONS: Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.