The activation of asparagine synthetase by the transcription factor FOXM1 plays a pivotal role in the initiation and progression of ESCC.

This study explores the role of the transcription factor FOXM1 in the initiation and progression of oesophageal squamous cell carcinoma (ESCC). Our findings reveal that FOXM1 is highly expressed in ESCC and correlates with the prognosis of the disease. The relationship between FOXM1 and asparagine synthetase (ASNS) is investigated, and the study demonstrates that FOXM1 activates ASNS, impacting the tumour stemness of ESCC. In this study, we reveal the association between FOXM1 and ESCC development, as well as FOXM1's promotion of migration and proliferation in ESCC cells. The study also highlights FOXM1's regulation of ASNS transcription and the functional role of ASNS in ESCC metastasis and growth. Furthermore, the study explores the impact of FOXM1 and ASNS on ESCC stemness and their potential implications for chemotherapy resistance.

Prevalence and impact of metabolic associated fatty liver disease in non-metastatic breast cancer women at initial diagnosis: a cross-sectional study in China.

PURPOSE: The epidemiologic data of metabolic associated fatty liver disease (MAFLD) in breast cancer (BC) patients remains limited. We aimed to investigate the prevalence and clinicopathological characteristics of hepatic steatosis (HS) and MAFLD in Chinese BC women at initial diagnosis. METHODS: 3217 non-metastatic primary BC women with MAFLD evaluation indexes at initial diagnosis and 32,170 age-matched (in a 1:10 ratio) contemporaneous health check-up women were enrolled. RESULTS: The prevalence of HS (21.5% vs. 19.7%, p = 0.013) and MAFLD (20.8% vs. 18.6%, p = 0.002) were significantly higher in BC women than in health check-ups, respectively. Meanwhile, the prevalence of HS/MAFLD among elderly BC women (≥ 60 years) was significantly higher than the health check-ups (38.7%/37.6% vs 31.9%/30.8%), respectively. In BC women with HS/MAFLD, the prevalence of overweight/obesity was up to 85.7%/88.6%, dyslipidemia and elevated blood pressure were 63.2%/63.7% and 59.7%/61.7%, respectively. No statistical significance of the expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER-2) and Ki67 were found between BC women with HS/MAFLD and BC women without HS/MAFLD. After adjustment, BC women with HS showed significantly higher risk of lymph node metastasis than BC women without HS. Subjects with HS/MAFLD had higher risks of overweight/obesity, dyslipidemia, elevated blood pressure, hyperuricemia, and elevated enzymes than those without HS/MAFLD. CONCLUSIONS: Compared with health check-ups, BC patients have higher prevalence of HS/MAFLD. HS/MAFLD coexist with high prevalence of metabolic complications, and the risk of lymph node metastasis was significantly higher in BC women with HS than in BC women without HS.

Hsp90α promotes chemoresistance in pancreatic cancer by regulating Keap1-Nrf2 axis and inhibiting ferroptosis.

Chemoresistance is the primary reason for poor prognosis in patients with pancreatic cancer (PC). Recent studies have indicated that ferroptosis may improve chemoresistance, but the underlying mechanisms remain unclear. In this study, significant upregulation of heat shock protein 90α (Hsp90α) expression is detected in the peripheral blood and tissue samples of patients with chemoresistant PC. Further studies reveal that Hsp90α promotes the proliferation, migration, and invasion of a chemoresistant pancreatic cell line (Panc-1-gem) by suppressing ferroptosis. Hsp90α competitively binds to Kelch-like ECH-associated protein 1 (Keap1), liberating nuclear factor erythroid 2-related factor 2 (Nrf2) from Keap1 sequestration. Nrf2 subsequently translocates into the nucleus and activates the glutathione peroxidase 4 (GPX4) pathway, thereby suppressing ferroptosis. This process further worsens the chemoresistance of PC cells. This study provides valuable insight into potential molecular targets to overcome chemoresistance in PC. It sheds light on the intricate mechanisms linking Hsp90α and ferroptosis to chemoresistance in PC and provides a theoretical foundation for the development of novel therapeutic strategies.

Mechanistic insights into lanthipeptide modification by a distinct subclass of LanKC enzyme that forms dimers.

Naturally occurring lanthipeptides, peptides post-translationally modified by various enzymes, hold significant promise as antibiotics. Despite extensive biochemical and structural studies, the events preceding peptide modification remain poorly understood. Here, we identify a distinct subclass of lanthionine synthetase KC (LanKC) enzymes with distinct structural and functional characteristics. We show that PneKC, a member of this subclass, forms a dimer and possesses GTPase activity. Through three cryo-EM structures of PneKC, we illustrate different stages of peptide PneA binding, from initial recognition to full binding. Our structures show the kinase domain complexed with the PneA core peptide and GTPγS, a phosphate-bound lyase domain, and an unconventional cyclase domain. The leader peptide of PneA interact with a gate loop, transitioning from an extended to a helical conformation. We identify a dimerization hot spot and propose a "negative cooperativity" mechanism toggling the enzyme between tense and relaxed conformation. Additionally, we identify an important salt bridge in the cyclase domain, differing from those in in conventional cyclase domains. These residues are highly conserved in the LanKC subclass and are part of two signature motifs. These results unveil potential differences in lanthipeptide modification enzymes assembly and deepen our understanding of allostery in these multifunctional enzymes.

Unearthing the Potential Therapeutic Effects of Oxyresveratrol Based on Intrinsic Links between Pharmacological Effects: Implications for the Gut-Liver-Brain Axis.

Oxyresveratrol is a stilbene compound with a simple chemical structure and various therapeutic potentials. This study summarized and analyzed the multiple pharmacological effects and mechanisms of oxyresveratrol, identifying its prominent performance in neuroprotection, hepatoprotection, and anti-inflammatory activities in the intestines. By integrating the pharmacological effects of oxyresveratrol with insights from the network pharmacology and molecular docking of its interactions with targets linked to gut-liver-brain axis disorders, it has been shown that oxyresveratrol may hold promise for the treatment of gut-liver-brain axis-related disorders. The synergistic effect between various mechanisms has inspired further research and the development of oxyresveratrol's application value.

Cross-sectional study of hepatitis B virus infection in female breast cancer patients in China for the first time diagnosed.

BACKGROUND: The correlation between breast cancer and hepatitis B virus (HBV) remains inconclusive. This study aims to explore the serological status of HBV infection and past infection in different age groups of female breast cancer patients, patients with benign breast diseases, and individuals undergoing routine physical examinations. METHODS: Serum data on HBV serological markers were collected and analyzed from 6072 female breast cancer patients first diagnosed from September 2012 to July 2020 at the First Affiliated Hospital of Chongqing Medical University, along with 4019 women with benign breast diseases and 54,740 healthy females undergoing routine physical examinations in the same period. The data were stratified by age for comparison between groups. RESULTS: The prevalence of HBV infection and past infection in the breast cancer group (7.9%, 55.1%) was higher than that in the benign breast disease group (6.5%, 39.1%) and the healthy females group(5.0%, 17.6%);the rate of only HBV surface antibody positivity (HBsAb ( +)) in the breast cancer group (10.3%) was lower than that in the benign breast disease group (26.9%) and the healthy females group (49.2%), with significant differences between the three groups (p < 0.05). Stratified by age, the prevalence of HBV infection in the breast cancer group (8%, 8.9%) and benign breast disease group (7.75%, 8.1%)was higher than that in the healthy females group (4.5%, 6.3%) in the 30-39 and 40-49 age group, respectively. The past infection rate of HBV in the breast cancer group (24.8%, 45.0%) was higher than that in the benign breast disease group (16.1%, 35.4%) in the ≤ 29 and 30-39 age group, respectively.. The past infection rate of HBV in the breast cancer group was higher than that in the healthy females group in all age groups, while the rate of only HBsAb ( +) in the breast cancer group was lower than that in the benign breast disease group and the routine physical examination group in all age groups. CONCLUSIONS: Breast cancer women and women with benign breast diseases have higher rates of hepatitis B virus infection and previous infections, with more significant differences among middle-aged women. Breast cancer women and women with benign breast diseases have lower rates of only HBsAb ( +) for HBV.

GCPDFFNet: Small Object Detection for Rice Blast Recognition.

Early detection of rice blast disease is pivotal to ensure rice yield. We collected in situ images of rice blast and constructed a rice blast dataset based on variations in lesion shape, size, and color. Given that rice blast lesions are small and typically exhibit round, oval, and fusiform shapes, we proposed a small object detection model named GCPDFFNet (global context-based parallel differentiation feature fusion network) for rice blast recognition. The GCPDFFNet model has three global context feature extraction modules and two parallel differentiation feature fusion modules. The global context modules are employed to focus on the lesion areas; the parallel differentiation feature fusion modules are used to enhance the recognition effect of small-sized lesions. In addition, we proposed the SCYLLA normalized Wasserstein distance loss function, specifically designed to accelerate model convergence and improve the detection accuracy of rice blast disease. Comparative experiments were conducted on the rice blast dataset to evaluate the performance of the model. The proposed GCPDFFNet model outperformed the baseline network CenterNet, with a significant increase in mean average precision from 83.6 to 95.4% on the rice blast test set while maintaining a satisfactory frames per second drop from 147.9 to 122.1. Our results suggest that the GCPDFFNet model can accurately detect in situ rice blast disease while ensuring the inference speed meets the real-time requirements.

The UF-5000 Atyp.C parameter is an independent risk factor for bladder cancer.

Bladder carcinoma (BC) accounts for > 90% of all urothelial cancers. Pathological diagnosis through cytoscopic biopsy is the gold standard, whereas non-invasive diagnostic tools remain lacking. The "Atyp.C" parameter of the Sysmex UF-5000 urine particle analyzer represents the ratio of nucleus to cytoplasm and can be employed to detect urinary atypical cells. The present study examined the association between urinary Atyp.C values and BC risk. This two-center, retrospective case-control study identified clinical primary or newly recurrent BC (study period, 2022-2023; n = 473) cases together with controls with urinary tract infection randomly matched by age and sex (1:1). Urinary sediment differences were compared using non-parametric tests. The correlations between urinary Atyp.C levels and BC grade or infiltration were analyzed using Spearman's rank correlation. The BC risk factor odds ratio of Atyp.C was calculated using conditional logistic regression, and potential confounder effects were adjusted using stepwise logistic regression (LR). Primary risk factors were identified by stratified analysis according to pathological histological diagnosis. The mean value of urinary Atyp.C in BC cases (1.30 ± 3.12) was 8.7 times higher than that in the controls (0.15 ± 0.68; P < 0.001). Urinary Atyp.C values were positively correlated with BC pathological grade and invasion (r = 0.360, P < 0.001; r = 0.367, P < 0.001). Urinary Atyp.C was an independent risk factor for BC and closely related with BC pathological grade and invasion. Elevated urinary Atyp.C values was an independent risk factor for BC. Our findings support the use of Atyp.C as a marker that will potentially aid in the early diagnosis and long-term surveillance of new and recurrent BC cases.

Optimal Glycated Hemoglobin Cutoff for Diagnosis of Diabetes and Prediabetes in Chinese Breast Cancer Women.

Purpose: Glycated hemoglobin (HbA1c) is widely used in diabetes management and now recommended for diagnosis and risk assessment. Our research focused on investigating the optimal cutoff points of HbA1c for diagnosis of diabetes and prediabetes in Chinese breast cancer women, aiming to enhance early detection and tailor treatment strategies. Patients and Methods: This study involved 309 breast cancer women without diabetes history in China. Patients were categorized into groups of newly diagnosed diabetes, prediabetes, and normal glucose tolerance using oral glucose tolerance test (OGTT) according to the 2010 ADA criteria. HbA1c data were collected from all patients. Receiver operating characteristic (ROC) curve analysis was used to assess the effectiveness of the HbA1c screening. Results: Among the 309 breast cancer women without diabetes history, 96 (31.0%) were identified with diabetes and 130 (42.1%) had prediabetes according to OGTT, and the incidence of normal glucose tolerance was only 26.9% (83). ROC curve analysis, using OGTT as a reference, revealed that the area under the curve of 0.903 (P<0.001, 95% CI, 0.867-0.938) for HbA1c alone, indicating high accuracy. The optimal HbA1c cutoff for identifying diabetes was determined to be 6.0%, with a sensitivity of 78.1% and specificity of 86.4%. For prediabetes, the ROC curve for HbA1c alone showed that the area under the ROC curve of 0.703 (P<0.001, 95% CI, 0.632-0.774), with an optimal cutoff of 5.5% (sensitivity of 76.9% and specificity of 51.8%). Conclusion: The prevalence of undiagnosed diabetes is very high in breast cancer women without diabetes history in China. The optimal cutoff points of HbA1c for identifying diabetes and prediabetes are 6.0% and 5.5% in Chinese breast cancer women, respectively.

Alcohol inducing macrophage M2b polarization in colitis by modulating the TRPV1-MAPK/NF-κB pathways.

BACKGROUND: Macrophages exhibit different phenotypes in inflammatory bowel disease (IBD) and promote inflammation or tissue repair depending on their polarization state. Alcohol is a widely used solvent in pharmaceutical formulations, and its consumption is associated with an increased risk of colitis; however, its effects on macrophages in IBD remain poorly understood. PURPOSE: This study aimed to investigate the effect of alcohol on macrophages in dextran sodium sulfate (DSS)-induced colitis and understand the underlying mechanisms. METHODS: DSS-treated C57BL/6 mice were exposed to varying concentrations of alcohol, transient receptor potential vanilloid 1 (TRPV1) antagonist, and 5-aminosalicylic acid. The distal colon was resected, fixed, stained, and histologically analyzed, through hematoxylin and eosin (H&E) staining and immunofluorescence staining. Ratio [Ca2+]i measurements, western blotting, quantitative polymerase chain reaction, cytokine measurements, and RNA sequencing analyses were also performed. Peritoneal macrophages and RAW264.7 cells were used for in vitro experiments, and various assays were performed to evaluate cellular responses, gene expression, and signaling pathways. RESULTS: Alcohol exacerbated DSS-treated mice colitis and promoted the secretion of various inflammatory cytokines from colonic macrophages. Alcohol enhances the calcium ion influx induced by lipopolysaccharide (LPS) in peritoneal macrophages, while the TRPV1 antagonist capsazepine (CPZ) inhibits LPS- and/or alcohol- induced calcium influx in macrophages. Alcohol and LPS activate the MAPK/P38, MAPK/ERK, and NF-κB signaling pathways and induce the macrophage M2b polarization, resulting in the increased expression level of inflammatory cytokines such as Tnf, Il1b, and Il10. Additionally, CPZ can inhibit the facilitatory effects of alcohol or LPS on the abovementioned pathways and inflammatory factors, reversing macrophage M2b polarization and promoting alcohol-induced colitis. The inhibition of nucleotide binding oligomerization domain containing 2 (NOD2) partially suppressed the alcohol and LPS effects on macrophages. CONCLUSION: Alcohol exacerbates experimental colitis and induces M2b polarization of macrophage via TRPV1-MAPK/NF-κB. Our study provides new insights into the potential therapeutic targets for IBD treatment by elucidating the role of TRPV1 in alcohol-exacerbated colitis, using CPZ as a potential therapeutic option. The identification of transient receptor potential ankyrin subtype 1 (TRPA1) as a therapeutic target expands the scope of future research.

Precise Gene Knock-In Tools with Minimized Risk of DSBs: A Trend for Gene Manipulation.

Gene knock-in refers to the insertion of exogenous functional genes into a target genome to achieve continuous expression. Currently, most knock-in tools are based on site-directed nucleases, which can induce double-strand breaks (DSBs) at the target, following which the designed donors carrying functional genes can be inserted via the endogenous gene repair pathway. The size of donor genes is limited by the characteristics of gene repair, and the DSBs induce risks like genotoxicity. New generation tools, such as prime editing, transposase, and integrase, can insert larger gene fragments while minimizing or eliminating the risk of DSBs, opening new avenues in the development of animal models and gene therapy. However, the elimination of off-target events and the production of delivery carriers with precise requirements remain challenging, restricting the application of the current knock-in treatments to mainly in vitro settings. Here, a comprehensive review of the knock-in tools that do not/minimally rely on DSBs and use other mechanisms is provided. Moreover, the challenges and recent advances of in vivo knock-in treatments in terms of the therapeutic process is discussed. Collectively, the new generation of DSBs-minimizing and large-fragment knock-in tools has revolutionized the field of gene editing, from basic research to clinical treatment.

Safety, tolerability, and pharmacokinetics of mitoxantrone hydrochloride injection for tracing in patients with gastric cancer: a single-blind, single-center, phase I clinical trial.

Mitoxantrone Hydrochloride Injection for Tracing (MHI), a modified new drug marketed in China, has been approved by the National Medical Products Administration for lymph node tracing in thyroid cancer and sentinel lymph node biopsy in breast cancer. This single-center, single-blind, dose-escalation phase I clinical trial aimed to investigate the safety of MHI on lymph node tracing in gastric cancer. In this study, four dose groups (1.0 mL, 1.5 mL, 2.0 mL, and 3.0 mL) with 3 gastric cancer patients in each group were set. The safety, tolerability, pharmacokinetics and preliminary efficacy of different doses were investigated. Results showed that none of the patients experienced dose-limiting toxicity or developed serious adverse events or adverse drug reactions. Pharmacokinetic analyses revealed minimal absorption of the tracer, resulting in low and transient blood drug concentrations across all participants. The mean time to peak concentration was (0.561 ± 0.3728) h (with mean peak concentration (Cmax) of 10.300 ng/mL), (0.500 ± 0.0167) h (mean Cmax of 13.687 ng/mL), (0.494 ± 0.0096) h (mean Cmax of 30.933 ng/mL), and (0.661 ± 0.2791) h (mean Cmax of 21.067 ng/mL) in the 1.0 mL, 1.5 mL, 2.0 mL, and 3.0 mL dose groups, respectively. The mean lymph node staining rates were 21.0%, 24.7%, 32.5%, and 44.5%, and the mean metastatic lymph node staining rates were 20.6%, 36.1%, 42.4%, and 21.0% in each group. This study confirmed that MHI was safe, well-tolerated, and had low systemic effects when used for lymphatic tracing of gastric cancer, and the tracing effect was better in the 3 mL dose group. This trail was registered on the website of Centre for Drug Evaluation State Drug and Food Administration (http://www.chinadrugtrials.org.cn/index.html) with the name of clinical study of lymphatic tracer in lymph node tracing of gastric cancer, the code was CTR20201906.

Prevalence and risk factors of thyroid nodules in breast cancer women with different clinicopathological characteristics: a cross-sectional study.

BACKGROUND: Association between breast cancer (BC) and thyroid nodules (TNs) is still unclear. This research was to estimate the prevalence and risk factors of TN in Chinese BC women at initial diagnosis. METHODS: 1731 Chinese early-stage BC women at initial diagnosis underwent thyroid ultrasound and 1:1 age-matched Chinese healthy women underwent health examination in corresponding period were enrolled for analysis. RESULTS: Prevalence of TN and TI-RADS ≥ 4 TN in BC patients (56.27% and 9.76%) were higher than healthy people (46.04% and 5.49%), respectively, P < 0.001. Among BC patients, prevalence of TN and TI-RADS ≥ 4 TN in hormone receptor (HR)-positive patients (59.57% and 11.81%) were higher than HR-negative patients (48.77% and 5.10%), respectively, P < 0.001, while without difference between HR-negative patients and healthy people. After adjusting for age and BMI, HR-positive patients had higher risk of TN (OR = 1.546, 95%CI 1.251-1.910, P < 0.001) and TI-RADS ≥ 4 TN (OR = 3.024, 95%CI 1.943-4.708, P < 0.001) than HR-negative patients. Furthermore, the risk of TI-RADS ≥ 4 TN was higher in patients with estrogen receptor (ER) positive (OR = 2.933, 95%CI 1.902-4.524), progesterone receptor (PR) positive (OR = 1.973, 95%CI 1.378-2.826), Ki-67 < 20% (OR = 1.797, 95%CI 1.280-2.522), and tumor size < 2 cm (OR = 1.804, 95%CI 1.276-2.552), respectively, P < 0.001. CONCLUSIONS: Prevalence of TN, especially TI-RADS ≥ 4 TN, in Chinese early-stage BC women was higher than healthy people. HR-positive patients had higher prevalence and risk of TN, while without difference between HR-negative patients and healthy people. The increased risk of TN was correlated with ER-positive, PR-positive, lower Ki-67 expression, and smaller tumor size.

Extrachromosomal circular DNA (eccDNA): from carcinogenesis to drug resistance.

Extrachromosomal circular DNA (eccDNA) is a circular form of DNA that exists outside of the chromosome. Although it has only been a few decades since its discovery, in recent years, it has been found to have a close relationship with cancer, which has attracted widespread attention from researchers. Thus far, under the persistent research of researchers from all over the world, eccDNA has been found to play an important role in a variety of tumors, including breast cancer, lung cancer, ovarian cancer, etc. Herein, we review the sources of eccDNA, classifications, and the mechanisms responsible for their biogenesis. In addition, we introduce the relationship between eccDNA and various cancers and the role of eccDNA in the generation and evolution of cancer. Finally, we summarize the research significance and importance of eccDNA in cancer, and highlight new prospects for the application of eccDNA in the future detection and treatment of cancer.

STK3 kinase activation inhibits tumor proliferation through FOXO1-TP53INP1/P21 pathway in esophageal squamous cell carcinoma.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is an aggressive disease with a poor prognosis, caused by the inactivation of critical cell growth regulators that lead to uncontrolled proliferation and increased malignancy. Although Serine/Threonine Kinase 3 (STK3), also known as Mammalian STE20-like protein kinase 2 (MST2), is a highly conserved kinase of the Hippo pathway, plays a critical role in immunomodulation, organ development, cellular differentiation, and cancer suppression, its phenotype and function in ESCC require further investigation. In this study, we report for the first time on the role of STK3 kinase and its activation condition in ESCC, as well as the mechanism and mediators of kinase activation. METHODS: In this study, we investigated the expression and clinical significance of STK3 in ESCC. We first used bioinformatics databases and immunohistochemistry to analyze STK3 expression in the ESCC patient cohort and conducted survival analysis. In vivo, we conducted a tumorigenicity assay using nude mouse models to demonstrate the phenotypes of STK3 kinase. In vitro, we conducted Western blot analysis, qPCR analysis, CO-IP, and immunofluorescence (IF) staining analysis to detect molecule expression, interaction, and distribution. We measured proliferation, migration, and apoptosis abilities in ESCC cells in the experimental groups using CCK-8 and transwell assays, flow cytometry, and EdU staining. We used RNA-seq to identify genes that were differentially expressed in ESCC cells with silenced STK3 or FOXO1. We demonstrated the regulatory relationship of the TP53INP1/P21 gene medicated by the STK3-FOXO1 axis using Western blotting and ChIP in vitro. RESULTS: We demonstrate high STK3 expression in ESCC tissue and cell lines compared to esophageal epithelium. Cellular ROS induces STK3 autophosphorylation in ESCC cells, resulting in upregulated p-STK3/4. STK3 activation inhibits ESCC cell proliferation and migration by triggering apoptosis and suppressing the cell cycle. STK3 kinase activation phosphorylates FOXO1Ser212, promoting nuclear translocation, enhancing transcriptional activity, and upregulating TP53INP1 and P21. We also investigated TP53INP1 and P21's phenotypic effects in ESCC, finding that their knockdown significantly increases tumor proliferation, highlighting their crucial role in ESCC tumorigenesis. CONCLUSION: STK3 kinase has a high expression level in ESCC and can be activated by cellular ROS, inhibiting cell proliferation and migration. Additionally, STK3 activation-mediated FOXO1 regulates ESCC cell apoptosis and cell cycle arrest by targeting TP53INP1/P21. Our research underscores the anti-tumor function of STK3 in ESCC and elucidates the mechanism underlying its anti-tumor effect on ESCC.

Screening for Active Compounds of Acorus calamus against SARS-CoV-2 Viral Protease and Mechanism Prediction.

COVID-19, caused by SARS-CoV-2, has emerged as the most destructive emerging infectious disease of the 21st century. Vaccination is an effective method to combat viral diseases. However, due to the constant mutation of the virus, new variants may weaken the efficacy of vaccines. In the current field of new coronavirus research, viral protease inhibitors have emerged as a highly regarded therapeutic strategy. Nevertheless, existing viral protease inhibitors do not fully meet the therapeutic needs. Therefore, this paper turned to traditional Chinese medicine to explore new active compounds. This study focused on 24 isolated compounds from Acorus calamus L. and identified 8 active components that exhibited significant inhibitory effects on SARS-CoV-2 PLpro. Among these, the compound 1R,5R,7S-guaiane-4R,10R-diol-6-one demonstrated the best inhibitory activity with IC50 values of 0.386 ± 0.118 µM. Additionally, menecubebane B and neo-acorane A exhibited inhibitory activity against both Mpro and PLpro proteases, indicating their potential as dual-target inhibitors. The molecular docking results confirmed the stable conformations of these compounds with the key targets and their good activity. ADMET and Lipinski's rule analyses revealed that all the small molecule ligands possessed excellent oral absorption properties. This study provides an experimental foundation for the discovery of promising antiviral lead compounds.

IGF-1-mediated FOXC1 overexpression induces stem-like properties through upregulating CBX7 and IGF-1R in esophageal squamous cell carcinoma.

Substantial evidence attests to the pivotal role of cancer stem cells (CSC) in both tumorigenesis and drug resistance. A member of the forkhead box (FOX) family, FOXC1, assumes significance in embryonic development and organogenesis. Furthermore, FOXC1 functions as an overexpressed transcription factor in various tumors, fostering proliferation, enhancing migratory capabilities, and promoting drug resistance, while maintaining stem-cell-like properties. Despite these implications, scant attention has been devoted to its role in esophageal squamous cell carcinoma. Our investigation revealed a pronounced upregulation of FOXC1 expression in ESCC, correlating with a poor prognosis. The downregulation of FOXC1 demonstrated inhibitory effects on ESCC tumorigenesis, proliferation, and tolerance to chemotherapeutic agents, concurrently reducing the levels of stemness-related markers CD133 and CD44. Further studies validated that FOXC1 induces ESCC stemness by transactivating CBX7 and IGF-1R. Additionally, IGF-1 activated the PI3K/AKT/NF-κB and MEK/ERK/NF-κB pathways through its binding to IGF-1R, thereby augmenting FOXC1 expression. Conversely, suppressing FOXC1 impeded ESCC stemness induced by IGF-1. The presence of a positive feedback loop, denoted by IGF-1-FOXC1-IGF-1R, suggests the potential of FOXC1 as a prognostic biomarker for ESCC. Taken together, targeting the IGF-1-FOXC1-IGF-1R axis emerges as a promising approach for anti-CSC therapy in ESCC.

TRPM8 inhibits substance P release from primary sensory neurons via PKA/GSK-3beta to protect colonic epithelium in colitis.

Transient receptor potential melastatin 8 (TRPM8) is a cold sensory receptor in primary sensory neurons that regulates various neuronal functions. Substance P (SP) is a pro-inflammatory neuropeptide secreted by the neurons, and it aggravates colitis. However, the regulatory role of TRPM8 in SP release is still unclear. Our study aimed to investigate TRPM8's role in SP release from primary sensory neurons during colitis and clarify the effect of SP on colonic epithelium. We analyzed inflammatory bowel disease patients' data from the Gene Expression Omnibus dataset. Dextran sulfate sodium (DSS, 2.5%)-induced colitis in mice, mouse dorsal root ganglion (DRG) neurons, ND7/23 cell line, and mouse or human colonic organoids were used for this experiment. Our study found that TRPM8, TAC1 and WNT3A expression were significantly correlated with the severity of ulcerative colitis in patients and DSS-induced colitis in mice. The TRPM8 agonist (menthol) and the SP receptor antagonist (Aprepitant) can attenuate colitis in mice, but the effects were not additive. Menthol promoted calcium ion influx in mouse DRG neurons and inhibited the combination and phosphorylation of PKAca from the cAMP signaling pathway and GSK-3ß from the Wnt/ß-catenin signaling pathway, thereby inhibiting the effect of Wnt3a-driven ß-catenin on promoting SP release in ND7/23 cells. Long-term stimulation with SP inhibited proliferation and enhanced apoptosis in both mouse and human colonic organoids. Conclusively, TRPM8 inhibits SP release from primary sensory neurons by inhibiting the interaction between PKAca and GSK-3ß, thereby inhibiting the role of SP in promoting colonic epithelial apoptosis and relieving colitis.

ELF4 contributes to esophageal squamous cell carcinoma growth and metastasis by augmenting cancer stemness via FUT9.

Esophageal squamous cell carcinoma (ESCC) commonly has aggressive properties and a poor prognosis. Investigating the molecular mechanisms underlying the progression of ESCC is crucial for developing effective therapeutic strategies. Here, by performing transcriptome sequencing in ESCC and adjacent normal tissues, we find that E74-like transcription factor 4 (ELF4) is the main upregulated transcription factor in ESCC. The results of the immunohistochemistry show that ELF4 is overexpressed in ESCC tissues and is significantly correlated with cancer staging and prognosis. Furthermore, we demonstrate that ELF4 could promote cancer cell proliferation, migration, invasion, and stemness by in vivo assays. Through RNA-seq and ChIP assays, we find that the stemness-related gene fucosyltransferase 9 ( FUT9) is transcriptionally activated by ELF4. Meanwhile, ELF4 is verified to affect ESCC cancer stemness by regulating FUT9 expression. Overall, we first discover that the transcription factor ELF4 is overexpressed in ESCC and can promote ESCC progression by transcriptionally upregulating the stemness-related gene FUT9.