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Ferroptosis, a newly identified form of regulated cell death, can be induced following the inhibition of cystine-glutamate antiporter system X because of the impaired uptake of cystine. However, the outcome following the accumulation of endogenous glutamate in lung adenocarcinoma (LUAD) has not yet been determined. Yes-associated protein (YAP) is sustained by the hexosamine biosynthesis pathway (HBP)-dependent O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation), and glutamine-fructose-6-phosphate transaminase (GFPT1), the rate-limiting enzyme of the HBP, can be phosphorylated and inhibited by adenylyl cyclase (ADCY)-mediated activation of protein kinase A (PKA). However, whether accumulated endogenous glutamate determines ferroptosis sensitivity by influencing the ADCY/PKA/HBP/YAP axis in LUAD cells is not understood. Cell viability, cell death and the generation of lipid reactive oxygen species (ROS) and malondialdehyde (MDA) were measured to evaluate the responses to the induction of ferroptosis following the inhibition of system X . Tandem mass tags (TMTs) were employed to explore potential factors critical for the ferroptosis sensitivity of LUAD cells. Immunoblotting (IB) and quantitative RT-PCR (qPCR) were used to analyze protein and mRNA expression. Co-immunoprecipitation (co-IP) assays were performed to identify protein-protein interactions and posttranslational modifications. Metabolite levels were measured using the appropriate kits. Transcriptional regulation was evaluated using a luciferase reporter assay, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift assay (EMSA). Drug administration and limiting dilution cell transplantation were performed with cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. The associations among clinical outcome, drug efficacy and ADCY10 expression were determined based on data from patients who underwent curative surgery and evaluated with patient-derived primary LUAD cells and tissues. The accumulation of endogenous glutamate following system X inhibition has been shown to determine ferroptosis sensitivity by suppressing YAP in LUAD cells. YAP O-GlcNAcylation and expression cannot be sustained in LUAD cells upon impairment of GFPT1. Thus, Hippo pathway-like phosphorylation and ubiquitination of YAP are enhanced. ADCY10 acts as a key downstream target and diversifies the effects of glutamate on the PKA-dependent suppression of GFPT1. We also discovered that the protumorigenic and proferroptotic effects of ADCY10 are mediated separately. Advanced-stage LUADs with high ADCY10 expression are sensitive to ferroptosis. Moreover, LUAD cells with acquired therapy resistance are also prone to higher ADCY10 expression and are more likely to respond to ferroptosis. Finally, a varying degree of secondary labile iron increase is caused by the failure to sustain YAP-stimulated transcriptional compensation for ferritin at later stages further explains why ferroptosis sensitivity varies among LUAD cells. Endogenous glutamate is critical for ferroptosis sensitivity following the inhibition of system X in LUAD cells, and ferroptosis-based treatment is a good choice for LUAD patients with later-stage and/or therapy-resistant tumors.

HBP‐A is the main active component of a traditional Chinese medicine Huaizhen Yanggan Capsule, for the remarkable treatment of knee osteoarthritis (KOA). This study aimed to elucidate the ameliorative effect of HBP‐A on meniscus hypertrophy and mineralisation in KOA and the molecular mechanism of its action. An Hartley guinea pig model of KOA that underwent anterior cruciate ligament transection (ACLT) and a model of rat primary meniscus fibrochondrocytes (PMFs) were used to investigate the ameliorative effect of HBP‐A on meniscal hypertrophy and calcification and its signal transduction mechanism of action. The results show that Guinea pig's meniscus width, as well as the area of meniscus calcification and meniscus and articular cartilage injury score, were significantly reduced in the HBP‐A intervention group compared to the ACLT group. The expression levels of mtrix metalloproteinase 13 (MMP13), runt‐related transcription factor 2 (Runx2), Indian hedgehog (Ihh), alkaline phosphatase (ALP), and ankylosis homologue (ANKH) at the protein and gene level significantly decreased in the HBP‐A intervention group compared to the ACLT group. In vitro study, apoptosis, hypertrophy, and calcification of rat PMFs after 10% stretch force were significantly improved with HBP‐A intervention. Western blot and RT‐qPCR showed that hypertrophy, calcification, and p38 MAPK signalling pathway‐related markers of PMFs were incredibly depressed in the HBP‐A intervention group compared to the 10% stretch force group. In conclusion, HBP‐A can slow down meniscus hypertrophy and mineralisation induced by abnormal mechanical loading, and its mechanism of action may be through the p38‐MAPK signalling pathway.

BackgroundHeparin-Binding Protein (HBP), released during neutrophil activation and degranulation, functions in antimicrobial defense, vascular integrity regulation, and immune signal amplification. As a key effector of the innate immune system, HBP is rapidly released in response to infectious stimuli and plays a pivotal role in the pathogenesis of infectious diseases. This study aimed to evaluate the diagnostic value of HBP in periprosthetic joint infection (PJI) and compare its performance with commonly used inflammatory biomarkers.MethodsIn this prospective study, 156 patients undergoing revision surgery for either aseptic loosening or PJI following joint arthroplasty were enrolled. Serum samples were collected within 24 hours preoperatively. Levels of HBP, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), and procalcitonin (PCT) were measured. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performance of each marker, and univariate logistic regression was used to evaluate their association with PJI.ResultsSerum HBP levels were significantly higher in the PJI group compared to the aseptic group (P < 0.001). The area under the ROC curve (AUC) for HBP in diagnosing PJI was 0.968 (95% CI: 0.943–0.993), outperforming CRP (0.760, 95% CI: 0.680–0.840), ESR (0.825, 95% CI: 0.753–0.896), IL-6 (0.875, 95% CI: 0.816–0.935), and PCT (0.663, 95% CI: 0.567–0.759). HBP also yielded the highest Wald χ² value (32.414) among all tested variables, with the clearest discrimination between groups in the fitted model.ConclusionThis study demonstrates that HBP is a superior diagnostic biomarker for PJI compared to traditional inflammatory indicators, offering higher sensitivity and greater cost-effectiveness. Its diagnostic advantage lies in its ability to rapidly reflect early neutrophil activation and immune initiation at the onset of infection, enabling earlier detection than conventional markers such as CRP and ESR. Given its simplicity, low cost, and strong diagnostic utility, HBP is particularly valuable for early screening of indolent infections caused by low-virulence pathogens, where traditional markers may fail.

Left ventricular hypertrophy (LVH) is often used as an indicator to assess hypertension‐mediated organ damage (HMOD), alongside hypertensive retinopathy (HR) and nephropathy. Assessment of HMOD is crucial when making decisions about treatment optimization. Despite longstanding debate over its reliability to detect LVH, it is common practice to perform an electrocardiogram (ECG) instead of directly assessing left ventricular mass with echocardiography. In this study, the presence of LVH was evaluated using both ECG and echocardiography among consecutive patients suspected of therapy‐resistant hypertension or secondary hypertension in the outpatient clinic of the Department of Internal Medicine at the Diakonessen Hospital, Utrecht, the Netherlands, between July 15, 2017, and July 31, 2020. The primary endpoints were the specificity and sensitivity of ECG as a diagnostic tool for LVH, with echocardiography serving as the reference method. Among the 329 participants, we identified 70 individuals (21.3%) with true LVH based on echocardiography. The ECG displayed a sensitivity of 47.9% and a specificity of 75.3%. Moreover, the area under the receiver operating characteristics curve was 0.604. In conclusion, ECG demonstrates limited value in identifying LVH. Considering the importance of accurately assessing HMOD for treatment optimization of hypertension, the role of ECG as a diagnostic tool for LVH is, therefore, questionable. Instead, we recommend employing standard echocardiography as a more reliable diagnostic.

The decisions about diagnosis and treatment targets were based on the office blood pressure (OBP) with the mercury sphygmomanometer. Another paper titled, “Could 130/80 mmHg be adopted as the diagnostic threshold and management goal of hypertension in consideration of the characteristics of Asian populations?” 2 discusses the practical feasibility of the 2017 AHA/ACC guidelines 3 for the management of hypertension for achieving a goal of zero cardiovascular events in Asia. [...]it says that routine OBP should not be used for the diagnosis and management of hypertension unless standardized BP measurement protocol is followed and adds that this is generally not applicable in busy clinics. [...]HBPM is recommended as the foundation for the diagnosis and grading of hypertension and also for the treatment thresholds and targets. 4 The Hypertension Canada Guidelines give definite preference to AOBP and define hypertension at 135/85 mmHg for mean AOBP, HBP or awake ABP readings but 140/90 mmHg for mean OBP readings. 5 The 2018 ESC/ESH Guidelines 6 for the management of arterial hypertension gives similar definitions for hypertension for the various methods as the Canadian guidelines but mention OBP only and not AOBP. The 2019 NICE guidelines 7 of hypertension from UK recommend that if clinic BP is between 140/90 mmHg and 180/120 mmHg, offer ABPM to confirm the diagnosis of hypertension and if ABPM is unsuitable, offer home blood pressure monitoring (HBPM) to confirm the diagnosis of hypertension.

Background Hepatitis B virus (HBV) infection is a crucial risk factor for hepatocellular carcinoma (HCC). However, its underlying mechanism remains understudied. Methods Microarray analysis was conducted to compare the genes and miRNAs in liver tissue from HBV-positive and HBV-negative HCC patients. Biological functions of these biomarkers in HBV-related HCC were validated via in vitro and in vivo experiments. Furthermore, we investigated the effect of HBV on the proliferation and migration of tumor cells in HBV-positive HCC tissue. Bioinformatics analysis was then performed to validate the clinical value of the biomarkers in a large HCC cohort. Results We found that a gene, MINPP1 from the glycolytic bypass metabolic pathway, has an important biological function in the development of HBV-positive HCC. MINPP1 is down-regulated in HBV-positive HCC and could inhibit the proliferation and migration of the tumor cells. Meanwhile, miRNA-30b-5p was found to be a stimulator for the proliferation of tumor cell through glycolytic bypass in HBV-positive HCC. More importantly, miRNA-30b-5p could significantly downregulate MINPP1 expression. Metabolic experiments showed that the miRNA-30b-5p/MINPP1 axis is able to accelerate the conversion of glucose to lactate and 2,3-bisphosphoglycerate (2,3-BPG). In the HBV-negative HCC cells, miRNA-30b-5p/MINPP1 could not regulate the glycolytic bypass to promote the tumorigenesis. However, once HBV was introduced into these cells, miRNA-30b-5p/MINPP1 significantly enhanced the proliferation, migration of tumor cells, and promoted the glycolytic bypass. We further revealed that HBV infection promoted the expression of miRNA-30b-5p through the interaction of HBV protein P (HBp) with FOXO3. Bioinformatics analysis on a large cohort dataset showed that high expression of MINPP1 was associated with favorable survival of HBV-positive HCC patients, which could lead to a slower progress of this disease. Conclusion Our study found that the HBp/FOXO3/miRNA-30b-5p/MINPP1 axis contributes to the development of HBV-positive HCC cells through the glycolytic bypass. We also presented miRNA-30b-5p/MINPP1 as a novel biomarker for HBV-positive HCC early diagnosis and a potential pharmaceutical target for antitumor therapy.

Accurately modeling debris flow behavior remains challenging, particularly for highly viscous flows, due to limitations in conventional rheological models and uncalibrated field data. This study integrates the Herschel-Bulkley-Papanastasiou (HBP) model with Smoothed Particle Hydrodynamics (SPH) using the DualSPHysics framework, combining numerical simulations with experimental and field investigations to improve debris flow modeling. A flume-based experimental setup was used to analyze flow initiation, velocity evolution, and deposition patterns under controlled conditions, providing crucial calibration data for the numerical model. Geotechnical and geophysical site investigations further refined key rheological parameters, ensuring accurate representation of material behavior. The calibrated model was then applied to the 2020 Pettimudi debris flow in Kerala, India, capturing key flow characteristics such as a peak velocity of 16 m/s, hydrodynamic pressures of 80–200 kPa, and a deposition width of 110 m. These predictions were validated through field surveys and historical data, demonstrating the model’s reliability in replicating real-world debris flow behavior. The study highlights the effectiveness of SPH combined with the HBP model in addressing limitations in traditional methods, providing a flexible and scalable framework for simulating debris flows. The methodology offers valuable insights into flow mechanics and has significant potential for hazard assessment, mitigation planning, and back-analysis of past debris flows in vulnerable regions worldwide This study highlights the novelty of integrating experimental, numerical, and field-based approaches to improve debris flow modeling. The findings demonstrate that SPH, combined with the HBP model, provides a flexible framework for simulating viscous debris flows, addressing limitations in traditional methods.

Cancer cells, as well as surrounding stromal and inflammatory cells, form an inflammatory tumor microenvironment (TME) to promote all stages of carcinogenesis. As an emerging post-translational modification (PTM) of serine and threonine residues of proteins, O-linked-N-Acetylglucosaminylation (O-GlcNAcylation) regulates diverse cancer-relevant processes, such as signal transduction, transcription, cell division, metabolism and cytoskeletal regulation. Recent studies suggest that O-GlcNAcylation regulates the development, maturation and functions of immune cells. However, the role of protein O-GlcNAcylation in cancer-associated inflammation has been less explored. This review summarizes the current understanding of the influence of protein O-GlcNAcylation on cancer-associated inflammation and the mechanisms whereby O-GlcNAc-mediated inflammation regulates tumor progression. This will provide a theoretical basis for further development of anti-cancer therapies.

Background Oncogenic KRAS mutation, the most frequent mutation in non-small cell lung cancer (NSCLC), is an aggressiveness risk factor and leads to the metabolic reprogramming of cancer cells by promoting glucose, glutamine, and fatty acid absorption and glycolysis. Lately, sotorasib was approved by the FDA as a first-in-class KRAS -G12C inhibitor. However, sotorasib still has a derivative barrier, which is not effective for other KRAS mutation types, except for G12C. Additionally, resistance to sotorasib is likely to develop, demanding the need for alternative therapeutic strategies. Methods KRAS mutant, and wildtype NSCLC cells were used in vitro cell analyses. Cell viability, proliferation, and death were measured by MTT, cell counting, colony analyses, and annexin V staining for FACS. Cell tracker dyes were used to investigate cell morphology, which was examined by holotomograpy, and confocal microscopes. RNA sequencing was performed to identify key target molecule or pathway, which was confirmed by qRT-PCR, western blotting, and metabolite analyses by UHPLC-MS/MS. Zebrafish and mouse xenograft model were used for in vivo analysis. Results In this study, we found that nutlin-3a, an MDM2 antagonist, inhibited the KRAS-PI3K/Akt-mTOR pathway and disrupted the fusion of both autophagosomes and macropinosomes with lysosomes. This further elucidated non-apoptotic and catastrophic macropinocytosis associated methuosis-like cell death, which was found to be dependent on GFPT2 of the hexosamine biosynthetic pathway, specifically in KRAS mutant / p53 wild type NSCLC cells. Conclusion These results indicate the potential of nutlin-3a as an alternative agent for treating KRAS mutant/ p53 wild type NSCLC cells.