The Novel Application of EUK-134 in Retinal Degeneration: Preventing Mitochondrial Oxidative Stress-Triggered Retinal Pigment Epithelial Cell Apoptosis by Suppressing MAPK/p53 Signaling Pathway.

Age-related macular degeneration (AMD), a leading cause of blindness, is characterized by mitochondrial dysfunction of retinal pigment epithelium (RPE) cells. EUK-134 is a mimetic of SOD2 and catalase, widely used for its antioxidant properties in models of light-induced damage or oxidative stress. However, its effects on the retina are not yet clear. Here, we investigated the capability of EUK-134 in averting AMD using sodium iodate (NaIO3)-induced Balb/c mouse and ARPE-19 cells (adult RPE cell line). In vivo, EUK-134 effectively antagonized NaIO3-induced retinal deformation and prevented outer and inner nuclear layer thinning. In addition, it was found that the EUK-134-treated group significantly down-regulated the expression of cleaved caspase-3 compared with the group treated with NaIO3 alone. Our results found that EUK-134 notably improved cell viability by preventing mitochondrial ROS accumulation-induced membrane potential depolarization-mediated apoptosis in NaIO3-inducted ARPE-19 cells. Furthermore, we found that EUK-134 could inhibit p-ERK, p-p38, p-JNK, p-p53, Bax, cleaved caspase-9, cleaved caspase-3, and cleaved PARP by increasing Bcl-2 protein expression. Additionally, we employed MAPK pathway inhibitors by SB203580 (a p38 inhibitor), U0126 (an ERK inhibitor), and SP600125 (a JNK inhibitor) to corroborate the aforementioned observation. The results support that EUK-134 may effectively prevent mitochondrial oxidative stress-mediated retinal apoptosis in NaIO3-induced retinopathy.

MiR-125a-5p regulates the radiosensitivity of laryngeal squamous cell carcinoma via HK2 targeting through the DDR pathway.

Objective: To determine the function of miR-125a-5p in laryngeal squamous cell carcinoma (LSCC), its correlation with radiation sensitivity, and the underlying regulatory mechanism. Materials and methods: We conducted the analysis on the correlation between miR-125a-5p and head and neck squamous cell carcinoma (HNSCC) using data obtained from The Cancer Genome Atlas (TCGA). The putative gene targeted by miR-125a-5p has been identified as HK2, while the expression levels of miR-125a-5p and HK2 were measured in laryngeal cancer tissues and cells using RT-PCR. MiR-125a-5p and HK2 were introduced into the lentiviral vector and the vector was used to transfect AMC-HN-8 cells. The roles of miR-125a-5p and HK2 in LSCC and on radiosensitivity were determined by evaluating cell growth, examining colony formation, analyzing flow cytometry, and utilizing the single hit multi-target model. Western blotting was used to measure H2AX and rH2AX levels in the DNA damage response (DDR) pathway. The validation of the interaction between miR-125a-5p and HK2 was conducted through the dual-luciferase assay. To further confirm the association between miR-125a-5p and HK2, as well as its influence on radiosensitivity, rescue experiments were performed. Results: The expression of miR-125a-5p is downregulated in LSCC, while upregulating its expression could suppress cell growth, induce apoptosis, and enhance radiosensitivity. Additionally, HK2 exhibited high expression in LSCC and the biological function was opposite to miR-125a-5p. Western blotting analysis revealed that miR-125a-5p increased rH2AX levels and decreased H2AX levels, conversely, HK2 had the opposite effect on miR-125a-5p. These findings suggested that HK2 may serve as the target gene of miR-125a-5p. The double luciferase assay confirmed the binding of HK2 to miR-125a-5p, and rescue trials confirmed the role of miR-125a-5p in regulating the effects and radiation sensitivity of LSCC by targeting HK2 via the DDR pathway. Conclusion: By targeting HK2 and impacting the DDR pathway, miR-125a-5p has been found to inhibit cellular proliferation, enhance apoptosis, and heighten radiosensitivity in LSCC.

Glucosamine inhibits myoblast proliferation and differentiation, and stimulates myotube atrophy through distinct signal pathways.

Glucosamine (GlcN) is one of the dietary supplements used in the treatment of osteoarthritis. Endogenously, GlcN is synthesized from glucose through the hexosamine pathway. In addition to ameliorating arthritis, several biological functions of GlcN have been reported, including insulin resistance in skeletal muscle. However, the regulatory role of GlcN in skeletal muscle development is not clear. We therefore investigated the effect of GlcN on myoblast proliferation, differentiation, and myotube development and their underlying mechanisms in C2C12 cells. Myoblast proliferation was measured by MTT assay. The expressions of MyoD, myogenin (MyoG), and myosin heavy chain (MyHC) were identified as determinants of myoblast differentiation. Expressions of atrogin-1 and muscle RING-finger protein-1 (MuRF-1) were identified as markers of myotube atrophy. The results show that treatment with GlcN significantly reduced myoblast proliferation and phosphorylation of Stat3 and S6K. These findings suggest that GlcN can inhibit growth of myoblasts through inhibiting phosphorylation of Stat3 and S6K. In addition, GlcN significantly suppressed the expression of MyoD, MyoG, and MyHC, as well as myotube formation. Pretreatment of C2C12 myoblast cells with ER stress inhibitors significantly blocked GlcN-inhibited MyHC expression and myotube formation. It can be concluded that GlcN suppressed myogenic differentiation via a pathway that involved ER stress. Moreover, GlcN decreased myotube diameter and expression of MyHC, as well as increased MuRF-1 in C2C12 myotubes. Meanwhile, GlcN also reduced the expressions of phosphorylated Akt and mTOR were stimulated after GlcN treatment in C2C12 myotubes. Thus, GlcN induced skeletal muscle atrophy by inhibiting the protein synthesis pathway. Chronic GlcN infusion also caused skeletal muscle atrophy in mice. In conclusion, GlcN regulated important stages of skeletal muscle development through different signaling pathways.

Abnormal circadian rhythms exacerbate dilated cardiomyopathy by reducing the ventricular mechanical strength.

AIMS: Dilated cardiomyopathy (DCM) has etiological and pathophysiological heterogeneity. Abnormal circadian rhythm (ACR) is related to the development of DCM in animal models, but exploration based on clinical samples is lacking. Sleep apnea (SA) is the most common disease related to ACR, and we chose SA as the study object to explore ACR-DCM. METHODS AND RESULTS: We included a derivation cohort (n =105) and a validation cohort (n = 65). DCM patients were divided into SA and without SA group. RT-qPCR was used to determine the change of rhythm gene expression pattern of heart samples from different timepoints. We used single-nucleus RNA sequencing (snRNA-seq) to explore the abnormal transcriptional patterns in the ACR group, and we verified the findings by pathological staining, atomic force microscopy (AFM), and Rev-erbα/ß knockout (KO) mice analysis. DCM patients with SA showed decreased amplitude of rhythm gene expression. SA group showed more severe dilation of left heart chambers. From snRNA-seq, ACR-DCM lost the morning transcriptional patterns, detailly, actin cytoskeleton organization of cardiomyocytes (CMs) disrupted and hypertrophy aggravated, and the proportion of activated fibroblasts (Fibs) decreased with the reduction of fibrotic area ratio. The results of pathological staining, mechanical experiments, and transcriptional feature of Rev-erbα/ß KO mice supported the above findings. CONCLUSION: Compared with the non-SA group, left ventricular (LV) wall dilation was more severe and the structural strength was lower in DCM patients with SA, and phenotypic changes in CM and Fib were involved in this process. ACR-DCM was histopathologically characterized by a structurally weak ventricular wall.

Electrochemical sensor based on Cu2-xS/graphene heterostructures for sub-picomolar dopamine detection.

Detecting dopamine (DA) in biological samples is vital to understand its crucial role in numerous physiological processes, such as motion, cognition, and reward stimulus. In this work, p-type graphene on sapphire, synthesized via chemical vapor deposition, serves as substrate for the preparation of p-type Cu2-xS films through solid-phase sulfurization. The optimized Cu2-xS/graphene heterostructure, prepared at 250 °C using a 15-nm copper film sulfurized for 2 h, exhibits superior electron transfer performance, ideal for electrochemical sensing. It is confirmed that the spontaneous charge transfer from graphene to Cu2-xS, higher Cu(II)/Cu(I) ratio (~ 0.8), and the presence of well-defined nanocrystalline structures with an average size of ~ 35 nm in Cu2-xS significantly contribute to the improved electron transfer of the heterostructure. The electrochemical sensor based on Cu2-xS/graphene heterostructure demonstrates remarkable sensitivity towards DA, with a detection limit as low as 100 fM and a dynamic range greater than 109 from 100 fM to 100 µM. Additionally, it exhibits excellent selectivity even in the presence of uric acid and ascorbic acid 100 times higher, alongside notable storage and measurement stability and repeatability. Impressively, the sensor also proves capable of detecting DA concentrations as low as 100 pM in rat serum, showcasing its potential for clinically relevant analytes and promising applications in sensitive, selective, reliable, and efficient point-of-care diagnostics.

Causal Association Between Atopic Dermatitis and Keratoconus: A Mendelian Randomization Study.

Purpose: Although many studies have indicated that atopic dermatitis (AD) could contribute to the risk of keratoconus (KC), the causality between AD and KC remains controversial. This study aimed to explore the potential causal associations between AD and KC. Methods: Instrumental variables for both exposures and outcomes were obtained from large-scale genome-wide association study summary statistics from previous meta-analyses. Mendelian randomization (MR) was applied to infer causal associations between AD and KC. Our main analyses were conducted by inverse-variance weighted (IVW) method multiplicative random effect model, complemented with additional five models and sensitivity analyses. Reverse MR analysis was applied to determine the direction of the causal association between AD and KC. Results: Both IVW and weighted median methods revealed a causal effect of AD on KC (IVW odds ratio [OR], 1.475; P = 4.16 × 10-4; weighted median OR, 1.351; P = 7.65 × 10-3). The weighted mode, simple mode, and MR Egger methods demonstrated consistent direction of causality. Evidence from all sensitivity analyses further supported these associations. Reverse MR analyses did not suggest causal effects of KC on AD. Conclusions: This study supported a significant causal effect of AD on KC, and reverse MR analysis proved that the causal association was unilateral. Translational Relevance: This study provides valid evidence that regular ophthalmic examinations are recommended for patients with AD to detect and prevent KC at an early stage.

Multi-adductomics: Advancing mass spectrometry techniques for comprehensive exposome characterization.

Adductomics, an emerging field within the 'omics sciences, focuses on the formation and prevalence of DNA, RNA, and protein adducts induced by endogenous and exogenous agents in biological systems. These modifications often result from exposure to environmental pollutants, dietary components, and xenobiotics, impacting cellular functions and potentially leading to diseases such as cancer. This review highlights advances in mass spectrometry (MS) that enhance the detection of these critical modifications and discusses current and emerging trends in adductomics, including developments in MS instrument use, screening techniques, and the study of various biomolecular modifications from mono-adducts to complex hybrid crosslinks between different types of biomolecules. The review also considers challenges, including the need for specialized MS spectra databases and multi-omics integration, while emphasizing techniques to distinguish between exogenous and endogenous modifications. The future of adductomics possesses significant potential for enhancing our understanding of health in relation to environmental exposures and precision medicine.

Binding Behavior of Human Hepatoma-Derived Growth Factor on SMYD1.

The protein-induced fluorescence change technique was employed to investigate the interactions between proteins and their DNA substrates modified with the Cy3 fluorophore. It has been reported that the human hepatoma-derived growth factor (HDGF), containing the chromatin-associated N-terminal proline-tryptophan-tryptophan-proline (PWWP) domain (the N-terminal 100 amino acids of HDGF) capable of binding the SMYD1 promoter, participates in various cellular processes and is involved in human cancer. This project investigated the specific binding behavior of HDGF, the PWWP domain, and the C140 domain (the C-terminal 140 amino acids of HDGF) sequentially using protein-induced fluorescence change. We found that the binding of HDGF and its related proteins on Cy3-labeled 15 bp SMYD1 dsDNA will cause a significant decrease in the recorded Cy3 fluorophore intensity, indicating the occurrence of protein-induced fluorescence quenching. The dissociation equilibrium constant was determined by fitting the bound fraction curve to a binding model. An approximate 10-time weaker SMYD1 binding affinity of the PWWP domain was found in comparison to HDGF. Moreover, the PWWP domain is required for DNA binding, and the C140 domain can enhance the DNA binding affinity. Furthermore, we found that the C140 domain can regulate the sequence-specific binding capability of HDGF on SMYD1.

Development and validation of an artificial intelligence model for predicting de novo distant bone metastasis in breast cancer: a dual-center study.

OBJECTIVE: Breast cancer has become the most prevalent malignant tumor in women, and the occurrence of distant metastasis signifies a poor prognosis. Utilizing predictive models to forecast distant metastasis in breast cancer presents a novel approach. This study aims to utilize readily available clinical data and advanced machine learning algorithms to establish an accurate clinical prediction model. The overall objective is to provide effective decision support for clinicians. METHODS: Data from 239 patients from two centers were analyzed, focusing on clinical blood biomarkers (tumor markers, liver and kidney function, lipid profile, cardiovascular markers). Spearman correlation and the least absolute shrinkage and selection operator regression were employed for feature dimension reduction. A predictive model was built using LightGBM and validated in training, testing, and external validation cohorts. Feature importance correlation analysis was conducted on the clinical model and the comprehensive model, followed by univariate and multivariate regression analysis of these features. RESULTS: Through internal and external validation, we constructed a LightGBM model to predict de novo bone metastasis in newly diagnosed breast cancer patients. The area under the receiver operating characteristic curve values of this model in the training, internal validation test, and external validation test1 cohorts were 0.945, 0.892, and 0.908, respectively. Our validation results indicate that the model exhibits high sensitivity, specificity, and accuracy, making it the most accurate model for predicting bone metastasis in breast cancer patients. Carcinoembryonic Antigen, creatine kinase, albumin-globulin ratio, Apolipoprotein B, and Cancer Antigen 153 (CA153) play crucial roles in the model's predictions. Lipoprotein a, CA153, gamma-glutamyl transferase, α-Hydroxybutyrate dehydrogenase, alkaline phosphatase, and creatine kinase are positively correlated with breast cancer bone metastasis, while white blood cell ratio and total cholesterol are negatively correlated. CONCLUSION: This study successfully utilized clinical blood biomarkers to construct an artificial intelligence model for predicting distant metastasis in breast cancer, demonstrating high accuracy. This suggests potential clinical utility in predicting and identifying distant metastasis in breast cancer. These findings underscore the potential prospect of developing economically efficient and readily accessible predictive tools in clinical oncology.

Advancing immunomodulatory functions in mesenchymal stem/stromal cells through targeting the GATA6-mediated pathway.

BACKGROUND AIMS: The immunomodulatory capacity of mesenchymal stem/stromal cells (MSCs) is a key feature that makes them particularly valuable for regenerative medicine. However, this potential is affected by the chronological aging of the donors and the cell expansion procedures in culture. We have demonstrated that GATA binding protein 6 (GATA6) plays a pivotal role in the aging of MSCs and inhibiting GATA6 rejuvenates the characteristics of MSCs. METHODS: In this study, we compared the immunomodulatory capabilities of young and old MSC models, using induced pluripotent stem cells-derived rejuvenated MSCs (rMSCs) and their parental MSCs (pMSCs), respectively, to identify a key mechanism involved in the differential regulation of these capabilities. Additionally, we explored the role of GATA6 in mediating the mechanism. RESULTS: Our results demonstrated that rMSCs exhibited downregulated aging-associated regulators, including p53, p21 and GATA6, and showed enhanced suppression of T cell proliferation compared to pMSCs. Through analyzing our previous RNA-seq data and employing target gene knockdown, we determined both suppressors of cytokine signaling 3 (SOCS3) and interleukin 6 were involved in GATA6-induced regulation, collectively affecting the expression of programmed death ligand 1 (PDL1) in both pMSCs and rMSCs. CONCLUSIONS: Our findings underline the significance of the GATA6/SOCS3/PDL1 pathway in regulating aging-associated changes in MSC immunomodulatory activity, providing valuable insights into the potential use of rMSCs in the treatment of immune diseases and regenerative medicine.

Efficacy of antihypertensive treatment for target organ protection in patients with masked hypertension (ANTI-MASK): a multicentre, double-blind, placebo-controlled trial.

Background: Masked hypertension is associated with target organ damage (TOD) and adverse health outcomes, but whether antihypertensive treatment improves TOD in patients with masked hypertension is unproven. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial at 15 Chinese hospitals, untreated outpatients aged 30-70 years with an office blood pressure (BP) of <140/<90 mm Hg and 24-h, daytime or nighttime ambulatory BP of ≥130/≥80, ≥135/≥85, or ≥120/≥70 mm Hg were enrolled. Patients had ≥1 sign of TOD: electrocardiographic left ventricular hypertrophy (LVH), brachial-ankle pulse wave velocity (baPWV) ≥1400 cm/s, or urinary albumin-to-creatinine ratio (ACR) ≥3.5 mg/mmol in women and ≥2.5 mg/mmol in men. Exclusion criteria included secondary hypertension, diabetic nephropathy, serum creatinine ≥176.8 µmol/L, and cardiovascular disease within 6 months of screening. After stratification for centre, sex and the presence of nighttime hypertension, eligible patients were randomly assigned (1:1) to receive antihypertensive treatment or placebo. Patients and investigators were masked to group assignment. Active treatment consisted of allisartan starting at 80 mg/day, to be increased to 160 mg/day at month 2, and to be combined with amlodipine 2.5 mg/day at month 4, if the ambulatory BP remained uncontrolled. Matching placebos were used likewise in the control group. The primary endpoint was the improvement of TOD, defined as normalisation of baPWV, ACR or LVH or a ≥20% reduction in baPWV or ACR over the 48-week follow-up. The intention-to-treat analysis included all randomised patients, the per-protocol analysis patients who fully adhered to the protocol, and the safety analysis all patients who received at least one dose of the study medication. This study is registered with ClinicalTrials.gov, NCT02893358. Findings: Between February 14, 2017, and October 31, 2020, 320 patients (43.1% women; mean age ± SD 53.7 ± 9.7 years) were enrolled. Baseline office and 24-h BP averaged 130 ± 6.0/81 ± 5.9 mm Hg and 136 ± 8.6/84 ± 6.1 mm Hg, and the prevalence of elevated baPWV, ACR and LVH were 97.5%, 12.5%, and 7.8%, respectively. The 24-h BP decreased on average (±SE) by 10.1 ± 0.9/6.4 ± 0.5 mm Hg in 153 patients on active treatment and by 1.3 ± 0.9/1.0 ± 0.5 mm Hg in 167 patients on placebo. Improvement of TOD occurred in 79 patients randomised to active treatment and in 49 patients on placebo: 51.6% (95% CI 43.7%, 59.5%) versus 29.3% (22.1, 36.5%; p < 0.0001). Per-protocol and subgroup analyses were confirmatory. Adverse events were generally mild and occurred in 38 (25.3%) and 43 (26.4%) patients randomised to active treatment and placebo, respectively (p = 0.83). Interpretation: Our results suggest that antihypertensive treatment improves TOD in patients with masked hypertension, highlighting the need of treatment. However, the long-term benefit in preventing cardiovascular complications still needs to be established. Funding: Salubris China.

Benzaldehyde stimulates autophagy via the sonic hedgehog signaling pathway in mouse brain astrocytes after treatment with Angiostrongylus cantonensis excretory-secretory products.

Autophagy is a vital cellular process responsible for digesting various cytoplasmic organelles. This process plays a crucial role in maintaining cell survival and homeostasis, especially under conditions that cause nutrient deficiency, cellular damage, and oxidative stress. Neuroangiostrongyliasis is an infection caused by the parasitic nematode Angiostrongylus cantonensis and is considered as an emerging disease in many parts of the world. However, effective therapeutic strategies for neuroangiostrongyliasis still need to be further developed. In this study, we investigated the effects of benzaldehyde treatment on autophagy and sonic hedgehog (Shh) signaling in A. cantonensis-infected mice and its mechanisms. First, we found autophagosome generation in the central nervous system after A. cantonensis infection. Next, benzaldehyde combined with albendazole treatment reduced eosinophilic meningitis and upregulated the expression of Shh signaling- and autophagy-related molecules in A. cantonensis-infected mouse brains. In vitro experiments demonstrated that benzaldehyde could induce autophagy via the Shh signaling pathway in A. cantonensis excretory-secretory products (ESPs)-treated mouse astrocytes. Finally, benzaldehyde treatment also decreased lipid droplet accumulation and increased cholesterol production by activating the Shh pathway after ESPs treatment. In conclusion, these findings suggested that benzaldehyde treatment could alleviate brain damage by stimulating autophagy generation through the Shh signaling pathway.

Strategies for arterial graft optimization at the single-cell level.

Common arterial grafts used in coronary artery bypass grafting include internal thoracic artery (ITA), radial artery (RA) and right gastroepiploic artery (RGA) grafts; of these, the ITA has the best clinical outcome. Here, by analyzing the single-cell transcriptome of different arterial grafts, we suggest optimization strategies for the RA and RGA based on the ITA as a reference. Compared with the ITA, the RA had more lipid-handling-related CD36+ endothelial cells. Vascular smooth muscle cells from the RGA were more susceptible to spasm, followed by those from the RA; comparison with the ITA suggested that potassium channel openers may counteract vasospasm. Fibroblasts from the RA and RGA highly expressed GDF10 and CREB5, respectively; both GDF10 and CREB5 are associated with extracellular matrix deposition. Cell-cell communication analysis revealed high levels of macrophage migration inhibitory factor signaling in the RA. Administration of macrophage migration inhibitory factor inhibitor to mice with partial carotid artery ligation blocked neointimal hyperplasia induced by disturbed flow. Modulation of identified targets may have protective effects on arterial grafts.

3D/2D-Bismuth Oxybromide Spheres with Selenium-Doped Graphitic Carbon Nitride Sheets: An Efficient Electrocatalyst for the Detection of Arsenic Drug Roxarsone.

Heavy metals are crucial carcinogenic agents threatening the environment and living habituates. Among them, arsenic (As) is an important metalloid that is categorized as a group I toxic carcinogen. Roxarsone (RX) is an organoarsenic antibiotic compound primarily used as a veterinarian drug and growth promoter for poultry animals. The extensive usage of RX increased the accumulation of As in living beings and the ecosystem. Therefore, we have prepared an electrochemical sensor based on 3D bismuth oxybromide with 2D selenium-doped graphitic carbon nitride (BOB/SCN) electrocatalyst for the rapid detection of RX. The elemental and structural details were thoroughly investigated with several spectroscopic techniques. The electrochemical properties were measured by impedance and voltammetric measurements. The electrocatalytic behavior toward the RX was estimated with different voltammetric methods. Therefore, our BOB/SCN-based electrochemical sensor demonstrated a low detection limit (2.3 nM), low quantification value (7.7 nM), optimal sensitivity (0.675 µA µM-1 cm-2), and good linear ranges (0.01-77 and 77-857 µM). Additionally, this sensor showed good electrochemical performance and was applied to monitor the RX in various real samples with remarkable recoveries. Based on these results, our BOB/SCN sensor is a promising electrochemical platform for determining RX.

Andrographolide suppresses the malignancy of pancreatic cancer via alleviating DNMT3B-dependent repression of tumor suppressor gene ZNF382.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type that urgently requires effective therapeutic strategies. Andrographolide, a labdane diterpenoid compound abundant in Andrographis paniculata, has anticancer effects against various cancer types, but its anticancer activity and mechanism against PDAC remain largely uncharacterized. PURPOSE: This study explores novel drug target(s) and underlying molecular mechanism of andrographolide against PDAC. STUDY DESIGN AND METHODS: The malignant phenotypes of PDAC cells, PANC-1 and MIA PaCa-2 cells, were measured using MTT, clonogenic assays, and Transwell migration assays. A PDAC xenograft animal model was used to evaluate tumor growth in vivo. Western blot, immunofluorescence and immunohistochemistry were used for measuring protein expression. The TCGA database was analyzed to evaluate promoter methylation status, gene expression, and their relationship with patient survival rates. RT-qPCR was used for detecting mRNA expression. Reporter assays were used for detecting signal transduction pathways. Promoter DNA methylation was determined by sodium bisulfite treatment and methylation-specific PCR (MSP). The biological function and role of specific genes involved in drug effects were measured through gene overexpression. RESULTS: Andrographolide treatment suppressed the proliferation and migration of PDAC cells and impaired tumor growth in vivo. Furthermore, andrographolide induced the mRNA and protein expression of zinc finger protein 382 (ZNF382) in PDAC cells. Overexpression of ZNF382 inhibited malignant phenotypes and cancer-associated signaling pathways (AP-1, NF-κB and ß-catenin) and oncogenes (ZEB-1, STAT-3, STAT-5, and HIF-1α). Overexpression of ZNF382 delayed growth of PANC-1 cells in vivo. ZNF382 mRNA and protein expression was lower in tumor tissues than in adjacent normal tissues of pancreatic cancer patients. Analysis of the TCGA database found the ZNF382 promoter is hypermethylated in primary pancreatic tumors which correlates with its low expression. Furthermore, andrographolide inhibited the expression of DNA methyltransferase 3 beta (DNMT3B) and increased the demethylation of the ZNF382 promoter in PDAC cells. Overexpression of DNMT3B attenuated the andrographolide-suppressed proliferation and migration of PDAC cells. CONCLUSION: Our finding revealed that ZNF382 acts as a tumor suppressor gene in pancreatic cancer and andrographolide restores ZNF382 expression to suppress pancreatic cancer, providing a novel molecular target and a promising therapeutic approach for treating pancreatic cancer.

Molecular Engineering of Hydrogen-Bonded Organic Framework for Enhanced Nitrate Electroreduction to Ammonia.

Electrocatalytic nitrate reduction is an efficient way to produce ammonia sustainably. Herein, we rationally designed a copper metalloporphyrin-based hydrogen-bonded organic framework (HOF-Cu) through molecular engineering strategies for electrochemical nitrate reduction. As a result, the state-of-the-art HOF-Cu catalyst exhibits high NH3 Faradaic efficiency of 93.8%, and the NH3 production rate achieves a superior activity of 0.65 mmol h-1 cm-2. The in situ electrochemical spectroscopic combined with density functional theory calculations reveals that the dispersed Cu promotes the adsorption of NO3- and the mechanism is followed by deoxidation of NO3- to *NO and accompanied by deep hydrogenation. The generated *H participates in the deep hydrogenation of intermediate with fast kinetics as revealed by operando electrochemical impedance spectroscopy, and the competing hydrogen evolution reaction is suppressed. This research provides a promising approach to the conversion of nitrate to ammonia, maintaining the nitrogen balance in the atmosphere.

Development and validation of AI models using LR and LightGBM for predicting distant metastasis in breast cancer: a dual-center study.

Objective: This study aims to develop an artificial intelligence model utilizing clinical blood markers, ultrasound data, and breast biopsy pathological information to predict the distant metastasis in breast cancer patients. Methods: Data from two medical centers were utilized, Clinical blood markers, ultrasound data, and breast biopsy pathological information were separately extracted and selected. Feature dimensionality reduction was performed using Spearman correlation and LASSO regression. Predictive models were constructed using LR and LightGBM machine learning algorithms and validated on internal and external validation sets. Feature correlation analysis was conducted for both models. Results: The LR model achieved AUC values of 0.892, 0.816, and 0.817 for the training, internal validation, and external validation cohorts, respectively. The LightGBM model achieved AUC values of 0.971, 0.861, and 0.890 for the same cohorts, respectively. Clinical decision curve analysis showed a superior net benefit of the LightGBM model over the LR model in predicting distant metastasis in breast cancer. Key features identified included creatine kinase isoenzyme (CK-MB) and alpha-hydroxybutyrate dehydrogenase. Conclusion: This study developed an artificial intelligence model using clinical blood markers, ultrasound data, and pathological information to identify distant metastasis in breast cancer patients. The LightGBM model demonstrated superior predictive accuracy and clinical applicability, suggesting it as a promising tool for early diagnosis of distant metastasis in breast cancer.

Microfluidic Continuous Synthesis of Size- and Facet-Controlled Porous Bi2O3 Nanospheres for Efficient CO2 to Formate Catalysis.

Bismuth-based catalysts are effective in converting carbon dioxide into formate via electrocatalysis. Precise control of the morphology, size, and facets of bismuth-based catalysts is crucial for achieving high selectivity and activity. In this work, an efficient, large-scale continuous production strategy is developed for achieving a porous nanospheres Bi2O3-FDCA material. First-principles simulations conducted in advance indicate that the Bi2O3 (111)/(200) facets help reduce the overpotential for formate production in electrocatalytic carbon dioxide reduction reaction (ECO2RR). Subsequently, using microfluidic technology and molecular control to precisely adjust the amount of 2, 5-furandicarboxylic acid, nanomaterials rich in (111)/(200) facets are successfully synthesized. Additionally, the morphology of the porous nanospheres significantly increases the adsorption capacity and active sites for carbon dioxide. These synergistic effects allow the porous Bi2O3-FDCA nanospheres to stably operate for 90 h in a flow cell at a current density of ≈250 mA cm- 2, with an average Faradaic efficiency for formate exceeding 90%. The approach of theoretically guided microfluidic technology for the large-scale synthesis of finely structured, efficient bismuth-based materials for ECO2RR may provide valuable references for the chemical engineering of intelligent nanocatalysts.

AI models predicting breast cancer distant metastasis using LightGBM with clinical blood markers and ultrasound maximum diameter.

Breast cancer metastasis significantly impacts women's health globally. This study aimed to construct predictive models using clinical blood markers and ultrasound data to predict distant metastasis in breast cancer patients, ensuring clinical applicability, cost-effectiveness, relative non-invasiveness, and accessibility of these models. Analysis was conducted on data from 416 patients across two centers, focusing on clinical blood markers (tumor markers, liver and kidney function indicators, blood lipid markers, cardiovascular biomarkers) and maximum lesion diameter from ultrasound. Feature reduction was performed using Spearman correlation and LASSO regression. Two models were built using LightGBM: a clinical model (using clinical blood markers) and a combined model (incorporating clinical blood markers and ultrasound features), validated in training, internal test, and external validation (test1) cohorts. Feature importance analysis was conducted for both models, followed by univariate and multivariate regression analyses of these features. The AUC values of the clinical model in the training, internal test, and external validation (test1) cohorts were 0.950, 0.795, and 0.883, respectively. The combined model showed AUC values of 0.955, 0.835, and 0.918 in the training, internal test, and external validation (test1) cohorts, respectively. Clinical utility curve analysis indicated the combined model's superior net benefit in identifying breast cancer with distant metastasis across all cohorts. This suggests the combined model's superior discriminatory ability and strong generalization performance. Creatine kinase isoenzyme (CK-MB), CEA, CA153, albumin, creatine kinase, and maximum lesion diameter from ultrasound played significant roles in model prediction. CA153, CK-MB, lipoprotein (a), and maximum lesion diameter from ultrasound positively correlated with breast cancer distant metastasis, while indirect bilirubin and magnesium ions showed negative correlations. This study successfully utilized clinical blood markers and ultrasound data to develop AI models for predicting distant metastasis in breast cancer. The combined model, incorporating clinical blood markers and ultrasound features, exhibited higher accuracy, suggesting its potential clinical utility in predicting and identifying breast cancer distant metastasis. These findings highlight the potential prospects of developing cost-effective and accessible predictive tools in clinical oncology.

Progress of organoid platform in cardiovascular research.

Cardiovascular disease is a significant cause of death in humans. Various models are necessary for the study of cardiovascular diseases, but once cellular and animal models have some defects, such as insufficient fidelity. As a new technology, organoid has certain advantages and has been used in many applications in the study of cardiovascular diseases. This article aims to summarize the application of organoid platforms in cardiovascular diseases, including organoid construction schemes, modeling, and application of cardiovascular organoids. Advances in cardiovascular organoid research have provided many models for different cardiovascular diseases in a variety of areas, including myocardium, blood vessels, and valves. Physiological and pathological models of different diseases, drug research models, and methods for evaluating and promoting the maturation of different kinds of organ tissues are provided for various cardiovascular diseases, including cardiomyopathy, myocardial infarction, and atherosclerosis. This article provides a comprehensive overview of the latest research progress in cardiovascular organ tissues, including construction protocols for cardiovascular organoid tissues and their evaluation system, different types of disease models, and applications of cardiovascular organoid models in various studies. The problems and possible solutions in organoid development are summarized.