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The persistent transactivation of epidermal growth factor receptor (EGFR) causes subsequent activation of the TGF‐β/Smad3 pathway, which is closely associated with fibrosis and cell proliferation in diabetic nephropathy (DN), but the exact mechanism of persistent EGFR transactivation in DN remains unclear. ARAP1, a susceptibility gene for type 2 diabetes, can regulate the endocytosis and ubiquitination of membrane receptors, but the effect of ARAP1 and its natural antisense long non‐coding RNA (lncRNA), ARAP1‐AS2, on the ubiquitination of EGFR in DN is not clear. In this study, we verified that the expression of ARAP1 and ARAP1‐AS2 was significantly up‐regulated in high glucose‐induced human proximal tubular epithelial cells (HK‐2 cells). Moreover, we found that overexpression or knockdown of ARAP1‐AS2 could regulate fibrosis and HK‐2 cell proliferation through EGFR/TGF‐β/Smad3 signalling. RNA pulldown assays revealed that ARAP1‐AS2 directly interacts with ARAP1. Coimmunoprecipitation, dual‐immunofluorescence and ubiquitination assays showed that ARAP1 may maintain persistent EGFR activation by reducing EGFR ubiquitination through competing with Cbl for CIN85 binding. Taken together, our results suggest that the lncRNA ARAP1‐AS2 may promote high glucose‐induced proximal tubular cell injury via persistent EGFR/TGF‐β/Smad3 pathway activation by interacting with ARAP1.

In chronic kidney disease (CKD), renal fibrosis is an unavoidable result of various manifestations. However, its pathogenesis is not yet fully understood. Here, we revealed the novel role of Homeobox D10 (HOXD10) in CKD-related fibrosis. HOXD10 expression was downregulated in CKD-related in vitro and in vivo fibrosis models. UUO model mice were administered adeno-associated virus (AAV) containing HOXD10, and HOXD10 overexpression plasmids were introduced into human proximal tubular epithelial cells induced by TGF-β1. The levels of iron, reactive oxygen species (ROS), lipid ROS, the oxidized glutathione/total glutathione (GSSG/GSH) ratio, malonaldehyde (MDA), and superoxide dismutase (SOD) were determined using respective assay kits. Treatment with AAV–HOXD10 significantly attenuated fibrosis and renal dysfunction in UUO model mice by inhibiting NOX4 transcription, ferroptosis pathway activation, and oxidative stress. High levels of NOX4 transcription, ferroptosis pathway activation and profibrotic gene expression induced by TGF-β1/erastin (a ferroptosis agonist) were abrogated by HOXD10 overexpression in HK-2 cells. Moreover, bisulfite sequencing PCR result determined that HOXD10 showed a hypermethylated level in TGF-β1-treated HK-2 cells. The binding of HOXD10 to the NOX4 promoter was confirmed by chromatin immunoprecipitation (ChIP) analysis and dual-luciferase reporter assays. Targeting HOXD10 may represent an innovative therapeutic strategy for fibrosis treatment in CKD.

Ten previously undescribed pyrrolidine alkaloids, namely penicipyrrolidines O–X (1–10), were isolated from the mangrove-derived fungus Penicillium sp. DM27, along with five known compounds (11–15). Their structures were determined by comprehensive analysis of HRESIMS and NMR spectroscopic data, and the absolute configurations were established based on biosynthetic considerations and TDDFT-ECD calculations. All isolates were evaluated for their glucose uptake capacity. Notably, penicipyrrolidine P (2) significantly enhanced cellular glucose uptake in L6 myotubes by 3.83-fold, demonstrating activity comparable to that of metformin, whereas penicipyrrolidines Q and R (3 and 4) showed relatively weaker effects.

Objectives: Dimeric pyruvate kinase (PK) M2 (PKM2) plays an important role in promoting the accumulation of hypoxia-inducible factor (HIF)-1α, mediating aberrant glycolysis and inducing fibrosis in diabetic kidney disease (DKD). The aim of this work was to dissect a novel regulatory mechanism of Yin and Yang 1 (YY1) on lncRNA-ARAP1-AS2/ARAP1 to regulate EGFR/PKM2/HIF-1α pathway and glycolysis in DKD. Materials and methods: We used adeno-associated virus (AAV)-ARAP1 shRNA to knocked down ARAP1 in diabetic mice and overexpressed or knocked down YY1, ARAP1-AS2 and ARAP1 expression in human glomerular mesangial cells. Gene levels were assessed by Western blotting, RT-qPCR, immunofluorescence staining and immunohistochemistry. Molecular interactions were determined by RNA pull-down, co-immunoprecipitation, ubiquitination assay and dual-luciferase reporter analysis. Results: YY1, ARAP1-AS2, ARAP1, HIF-1α, glycolysis and fibrosis genes expressions were upregulated and ARAP1 knockdown could inhibit dimeric PKM2 expression and partly restore tetrameric PKM2 formation, while downregulate HIF-1α accumulation and aberrant glycolysis and fibrosis in in-vivo and in-vitro DKD models. ARAP1 knockdown attenuates renal injury and renal dysfunction in diabetic mice. ARAP1 maintains EGFR overactivation in-vivo and in-vitro DKD models. Mechanistically, YY1 transcriptionally upregulates ARAP1-AS2 and indirectly regulates ARAP1 and subsequently promotes EGFR activation, HIF-1α accumulation and aberrant glycolysis and fibrosis. Conclusion: Our results first highlight the role of the novel regulatory mechanism of YY1 on ARAP1-AS2 and ARAP1 in promoting aberrant glycolysis and fibrosis by EGFR/PKM2/HIF-1α pathway in DKD and provide potential therapeutic strategies for DKD treatments.

During on-site welding operations, the sealant coated on anchor bolt surfaces can be ignited by hot particles or localized sparks, potentially triggering a fire hazard. This combustion process involves a complex multi-physics coupling among sealant combustion, convective and radiative heat transfer, and three-dimensional heat conduction in solids. To resolve this coupling, a simulation strategy is proposed that correspondingly integrates the Fire Dynamics Simulator (FDS, version 6.7.6) for modeling combustion and radiation with ABAQUS (2024) for simulating conductive heat transfer in solids. The proposed method is validated against experimental measurements, showing close agreement in temperature evolution. It also demonstrates robustness across varying geometric scales, thereby confirming its reliability for predicting thermal response. Using this validated method, simulations are performed to analyze the fire behavior of an anchor rod-sealant system. Results show that the burning sealant can raise anchor rod temperatures above 900 °C and lead to rapid flame spread between adjacent rods. Furthermore, a sensitivity analysis of thermophysical parameters identifies critical thresholds for fire safety optimization: sealants with an ignition temperature > 280 °C and thermal conductivity ≥ 0.26 W/(m·K) demonstrate effective self-extinguishing properties, while specific heat capacity can retard flame growth. These findings provide a robust numerical framework and quantitative guidelines for the fire-safe design of bridge anchorage systems.

Background There were limited data investigating platelet indices in predicting peritoneal dialysis (PD) outcomes on comorbidities. The aim of this study was to evaluate the association between platelet indices and new-onset comorbidity and all-cause mortality in PD patients. Methods A single-center, retrospective observational cohort study was conducted in incident PD patients from 28 December 2011 to 24 January 2018, and followed up until 31 December 2022. Time to the first new-onset cardiovascular disease (CVD) and time to the first new-onset infection event after PD were identified as the primary outcomes. All-cause mortality was identified as the secondary endpoint. The correlation between platelet indices and comorbidities and all-cause mortality were assessed by Cox model. Data of liver disease status was not collected and analyzed. Survival curves were performed by Kaplan-Meier method with log-rank tests. Results A total of 250 incident PD patients with a median follow-up of 6.79 (inter-quarter range 4.05, 8.89) years was included. A total of 81 and 139 patients experienced the first new-onset CVD and infection event respectively during the follow-up period. High mean platelet volume (MPV) was independently associated with high risk of time to the first new-onset CVD (HR 1.895, 95% CI 1.174–3.058, p  = 0.009) and all-cause mortality (HR 1.710, 95% CI 1.155–2.531, p  = 0.007). Patients with low mean platelet volume to platelet count ratio (MPV/PC) were prone to occur the new-onset infection events (log rank 5.693, p  = 0.017). Low MPV/PC (HR 0.652, 95% CI 0.459–0.924, p  = 0.016) was significantly associated with the time to the first new-onset infection event on PD. Conclusions Platelet indices were associated with the new-onset CVD, infectious comorbidities and all-cause mortality on PD. Low MPV/PC was associated with time to the first new-onset infection event in PD patients. Moreover, high MPV was associated with new-onset CVD and all-cause mortality in the incident PD patients.

Since the conventional solid proppant has many defects, such as poor migration and its rigid structures easy to plug cracks, liquid proppant has become a key development direction. A phase change proppant is developed based on the emulsified thermosetting resin system and evaluated in this paper. On the basis of the bisphenol A type epoxy resin, the phase change proppant system adopts the adduct of diethylene triamine and butyl glycidyl ether as epoxy resin curing agent and the SiO 2 particles (1% of the resin mass) as the emulsifier, and then adds the hollow glass microspheres (1.25% of the resin mass) and the absolute ethyl alcohol (25% of the resin mass) as the thinner to reduce resin density and dilute resin. Proppant particles with major sizes of 4.5mm, 3mm, 2-2.5mm, 2mm, 1mm and 0.5mm are obtained through process optimization. After evaluation, the obtained proppants are of low density and high compressive strength, and their migration capability and flow conductivity are qualified for the exploitation of unconventional reservoirs with high closure pressures.

Guangsangon E (GSE) is a novel Diels–Alder adduct isolated from leaves of Morus alba L, a traditional Chinese medicine widely applied in respiratory diseases. It is reported that GSE has cytotoxic effect on cancer cells. In our research, we investigated its anticancer effect on respiratory cancer and revealed that GSE induces autophagy and apoptosis in lung and nasopharyngeal cancer cells. We first observed that GSE inhibits cell proliferation and induces apoptosis in A549 and CNE1 cells. Meanwhile, the upregulation of autophagosome marker LC3 and increased formation of GFP–LC3 puncta demonstrates the induction of autophagy in GSE-treated cells. Moreover, GSE increases the autophagy flux by enhancing lysosomal activity and the fusion of autophagosomes and lysosomes. Next, we investigated that endoplasmic reticulum (ER) stress is involved in autophagy induction by GSE. GSE activates the ER stress through reactive oxygen species (ROS) accumulation, which can be blocked by ROS scavenger NAC. Finally, inhibition of autophagy attenuates GSE-caused cell death, termed as “autophagy-mediated cell death.” Taken together, we revealed the molecular mechanism of GSE against respiratory cancer, which demonstrates great potential of GSE in the treatment of representative cancer.

Objective To investigate the association between admission blood glucose and atypical angina in patients with coronary artery disease (CAD), and to investigate the risk factors associated with atypical angina in coronary heart disease. Methods A total of 729 patients who underwent coronary angiography at Xuancheng People’s Hospital between December 2018 and December 2024 were enrolled. According to clinical presentation during CAD onset, patients were classified into a typical angina group and an atypical angina group. Clinical variables including admission blood glucose levels, and monocyte-to-lymphocyte ratio (MLR) were collected and compared between groups. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for atypical angina in patients with CAD. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of admission blood glucose and diabetes status for atypical angina. Mediation analysis was conducted to assess the mediating role of admission blood glucose in the association between diabetes and atypical angina. Restricted cubic spline analysis was applied to characterize the dose–response relationship between admission blood glucose and atypical angina. Results Both univariate and multivariate logistic regression analyses demonstrated that a history of diabetes, elevated admission blood glucose, and increased MLR were independent risk factors for atypical angina in patients with CAD (all P  < 0.05). ROC curve analysis indicated that history of diabetes and admission blood glucose exhibited modest predictive value for the occurrence of atypical angina in CAD patients ( P  < 0.05). Mediation analysis revealed that admission blood glucose significantly mediated the association between diabetes and atypical angina. Furthermore, restricted cubic spline analysis showed a significant linear relationship between admission blood glucose levels and the risk of atypical angina. Conclusions Admission blood glucose, a history of diabetes, and MLR are independently associated with the occurrence of atypical angina in patients with CAD. Admission blood glucose plays a significant mediating role in the relationship between diabetes and atypical angina. Both admission blood glucose and diabetes history demonstrate modest predictive value for atypical angina, suggesting their potential utility as early warning indicators in patients with CAD.

Accumulating evidence indicates that microRNAs (miRNAs) are aberrantly expressed in human cancer and contribute to the tumorigenesis, but their roles in pancreatic cancer are still largely unknown. In this study, our data showed that miR-130b was significantly downregulated in 52 pairs of pancreatic cancer tissues and five cell lines. Furthermore, the deregulated miR-130b was correlated with worse prognosis, increased tumor size, late TNM stage, lymphatic invasion and distant metastasis. Multivariate analysis showed that miR-130b expression was a significant and independent prognostic predictor for pancreatic cancer patients. Functional studies indicated that the overexpression of miR-130b dramatically suppressed the proliferation of pancreatic cancer cells both in vitro and in vivo, which could be attributed to the induction of apoptosis and cell cycle arrest at S phase. Meanwhile, an overexpressed miR-130b remarkably inhibited the invasive ability of pancreatic cancer cells. Moreover, the dual luciferase assay revealed that STAT3 was directly targeted by miR-130b, which was further confirmed by the inverse expression of miR-130b and STAT3 in pancreatic cancer samples. Our findings suggested that miR-130b might have a considerable potential in prognosis identification and application of therapy for pancreatic cancer.