Rapid measurement of ethyl carbamate in Chinese liquor by fast gas chromatography photoionization-induced chemical ionization mass spectrometry.

As a common by-product during the production of alcoholic beverages, such as Chinese liquor, ethyl carbamate (EC) poses potential genotoxicity and is associated with the risk of various cancers. Hence, rapidly and accurately measuring the content of EC in liquor is critical to assess the product quality and risks of mass samples during the production process. In this study, a feasible method based on fast gas chromatography photoionization-induced chemical ionization mass spectrometry (FastGC-PICI-TOFMS) was developed for the analysis of EC in Chinese liquor. The rapid separation of EC in Chinese liquor was conducted using FastGC based on a thermostatic column set at 150 °C to eliminate the interferences of matrix effects. The PICI-TOFMS could realize accurate quantification of EC without any sample pre-treatment due to the efficient ionization of EC by the PICI source. As a result, the total analysis time for EC in Chinese liquor was less than 4 min. The limit of detection (LOD) for EC was 4.4 µg L-1. And the intra-day and inter-day precision were 3.2%-3.7 % and 1.6 %, respectively. Finally, the ability of the proposed method was preliminarily proved by high-throughput and accurate measurement of EC in four different flavors of Chinese liquors.

Experimental and Modeling Analysis of Polypropylene Fiber Reinforced Concrete Subjected to Alkali Attack and Freeze-Thaw Cycling Effect.

The durability of concrete materials in harsh environmental conditions, particularly in cold regions, has garnered significant attention in civil engineering research in recent years. Concrete structures in these areas are often damaged by the combined effects of alkali-silica reaction (ASR) and freeze-thaw cycles, leading to structural cracks and significant safety hazards. Numerous studies have demonstrated that polypropylene fiber concrete exhibits excellent crack resistance and durability, making it promising for applications in cold regions. This study elucidates the impact of alkali content on concrete durability by comparing the mechanical properties and durability of different alkali-aggregate concretes. The principal experimental methodologies employed include freeze-thaw cycle experiments, which examine patterns of mass loss; fluctuations in the dynamic modulus of elasticity; and changes in mechanical properties before and after freeze cycles. The findings indicate that increased alkali content in concrete reduces its strength and durability. At 100% alkali-aggregate content, compressive strength decreases by 35.5%, flexural strength by 32.9%, mass loss increases by 35.85%, relative dynamic elastic modulus by 39.4%, and residual strength by 97.28%, indicating higher alkali content leads to diminished durability. Additionally, this paper introduces a constitutive damage model, validated by a strong correlation with experimental stress-strain curves, to effectively depict the stress-strain relationship of concrete under varying alkali contents. This research contributes to a broader understanding of concrete durability in cold climates and guides the selection of materials for sustainable construction in such environments.

Inhibition of calpain reduces oxidative stress and attenuates pyroptosis and ferroptosis in Clostridium perfringens Beta-1 toxin-induced macrophages.

Clostridium perfringens Beta-1 toxin (CPB1) is a lethal toxin, which can lead to necrotic enteritis, but the pathological mechanism has not been elucidated. We investigated whether reactive oxygen species (ROS) participated in CPB1-induced pyroptosis and ferroptosis, and investigated the effects of calpain on CPB1-induced oxidative stress and inflammation. Scavenging ROS by N-Acetyl-L cysteine (NAC) led to the reduction of ROS, inhibited the death of macrophages, cytoplasmic swelling and membrane rupture, the expression of pyroptosis-related proteins and proinflammatory factor, while increased the expression of anti-inflammatory factors in cells treated with rCPB1. Adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 (ATP5A1) was identified specifically interact with rCPB1. Silencing ATP5A1 inhibited accumulation of ATP and ROS, leaded to less cytoplasmic swelling and membrane rupture, attenuated pyroptosis and inflammation in rCPB1-treated cells. We also found that rCPB1 induces ferroptosis in macrophages, and the level of ferroptosis was similar with H2O2. Of note, H2O2 is a major ROS source, indicated that ROS production may play a major role in the regulation of ferroptosis in macrophages treated with rCPB1. This finding was further corroborated in rCPB1- induced human acute monocytic leukemia cells, which were treated with NAC. In addition, the inhibition of ferroptosis using liproxstatin-1 inhibited the shriveled mitochondrial morphology, increased the expression of glutathione peroxidase 4, nicotinamide adenine dinucleotide (phosphate) hydrogen: quinone oxidoreductase 1 and cysteine/glutamic acid reverse transport solute carrier family 7 members 11, decreased the expression of heme oxygenase 1, nuclear receptor coactivator 4 and transferrin receptor proteins, reduced malondialdehyde and lipid peroxidation levels, and increased intracellular L-glutathione levels in cells treated with rCPB1. Furthermore, calpain inhibitor PD151746 was used to investigate how pyroptosis and ferroptosis were involved simultaneously in rCPB1-treated macrophages. We showed that PD151746 inhibited ATP and ROS production, reversed the representative pyroptosis/ferroptosis indicators and subsequently reduced inflammation. The above findings indicate that rCPB1 might lead to macrophage pyroptosis and ferroptosis through the large and sustained increase in intracellular calpain and oxidative stress, further lead to inflammation.

Structural damage and organelle destruction: Mechanisms of pseudolaric acid B against S. parasitica.

This study aimed to investigate the potential of Chinese herbs in treating aquatic diseases. More particularly, the antibacterial properties and mechanisms of Chinese herbs and their monomers against Saprolegnia parasitica were investigated. In vitro antibacterial testing revealed that Cortex pseudolaricis exhibited significant antibacterial activity, with a minimum inhibitory concentration (MIC) of 0.98 mg/mL. The primary monomer responsible for this antibacterial effect was identified as pseudolaric acid B (PAB), with an MIC of 0.03 mg/mL. SEM and TEM analyses demonstrated that treatment with PAB resulted in structural damage to the cell wall and cell membrane of hyphae, leading to lysis of the cell wall and membrane of spores, organelle destruction, and vacuole formation within the cells. Analysis of the transcriptome and metabolome revealed that PAB disrupts amino acid, lipid, and nucleic acid metabolism in S. parasitica. This disruption impacts the biosynthesis and metabolism of various amino acids, including arginine, proline, glycine, serine, cysteine, methionine, glutamate, lysine, histidine, phenylalanine, tyrosine, and tryptophan. PAB also results in increased energy consumption and hindered energy generation in S. parasitica, as well as interference with the synthesis of membrane components such as DAG and phytosphingosine. Furthermore, PAB disrupts RNA, DNA, and ATP production in S. parasitica. Consequently, protein synthesis, energy supply, immune function and barrier structure in S. parasitica are weakened, and potentially leading to death. This study identifies potential antibacterial agents for environmentally friendly solutions for controlling fish saprolegniasis.

The first embryonic landscape of G-quadruplexes related to myogenesis.

BACKGROUND: DNA G-quadruplexes (G4s) represent a distinctive class of non-canonical DNA secondary structures. Despite their recognition as potential therapeutic targets in some cancers, the developmental role of G4 structures remains enigmatic. Mammalian embryonic myogenesis studies are hindered by limitations, prompting the use of chicken embryo-derived myoblasts as a model to explore G4 dynamics. This study aims to reveal the embryonic G4s landscape and elucidate the underlying mechanisms for candidate G4s that influence embryonic myogenesis. RESULTS: This investigation unveils a significant reduction in G4s abundance during myogenesis. G4s stabilizer pyridostatin impedes embryonic myogenesis, emphasizing the regulatory role of G4s in this process. G4 Cut&Tag sequencing and RNA-seq analyses identify potential G4s and DEGs influencing embryonic myogenesis. Integration of G4 and DEG candidates identifies 32 G4s located in promoter regions capable of modulating gene transcription. WGBS elucidates DNA methylation dynamics during embryonic myogenesis. Coordinating transcriptome data with DNA G4s and DNA methylation profiles constructs a G4-DMR-DEG network, revealing nine interaction pairs. Notably, the NFATC2 promoter region sequence is confirmed to form a G4 structure, reducing promoter mCpG content and upregulating NFATC2 transcriptional activity. CONCLUSIONS: This comprehensive study unravels the first embryonic genomic G4s landscape, highlighting the regulatory role of NFATC2 G4 in orchestrating transcriptional activity through promoter DNA methylation during myogenesis.

Unlocking the potential of methionine: a dietary supplement for preventing colitis.

The incidence rate of colitis and conversion of colitis into colorectal cancer is increasing. However, the results of drug treatments are inconsistent with variable side effects; therefore, it is necessary to find alternative ways of treating colitis, e.g. through dietary supplements. One such dietary supplement could be sulfur-containing amino acids, which are known to have anti-inflammatory, antioxidant, and gut microbiota homeostasis effects. Therefore, the aim of the present study was to explore the effect of methionine supplementation in the diet of mice on experimental dextran sulfate sodium (DSS)-induced colitis. Here, 24 male C57BL/6J mice were split into three experimental treatment groups in such a way that each treatment group had four replicates and each replicate had two mice. The control group was colitis-free, while colitis was induced by the administration of DSS in the DSS groups. In the DSS and DSS plus methionine (DSS + Met) groups, DSS was provided in drinking water containing 3% DSS on days 1-5 and later provided with purified water on days 6-7. It was found that supplementing with methionine could activate pathways like Nrf2, and inhibit pathways like TLR4 and Nlrp3 to realize anti-inflammatory and antioxidant effects. Moreover, methionine could alter the microbiota of the gut in the experimental mice, whereby exploration of the gut microbiota demonstrated that methionine supplementation in the diet increased the abundance of parabacteroides and the production of propionate and butyrate. The current study shows that the dietary prophylactic supplementation of methionine has a beneficial effect on resisting colitis, providing new insights for the prevention of colitis.

Black phosphorus nanosheets induce autophagy dysfunction by a size- and surface modification-related impairment of lysosomes in macrophages.

The widespread application of black phosphorus nanosheets (BPNSs) raises concerns about their potential impact on human health. Although that the autophagy-inducing properties of BPNSs in cancer cells are documented, their effects on macrophages-key components of the immune system and the mechanisms involved remain obscure, especially in terms of the influences of BPNS the size and surface modifications on the autophagic process. This study investigated the effects of bare BPNSs and PEGylated BPNSs (BP-PEG) on macrophage autophagy and its underlying mechanisms by comprehensive biochemical analyses. The results indicated that both BPNSs and BP-PEG are internalized by RAW264.7 cells through phagocytosis and caveolin-dependent endocytosis, leading to lysosomal accumulation. The internalized BPNSs induced mitochondrial dysfunction, which subsequently elevated the NAD+/NADH ratio and activated the SIRT-1 pathway, initiating autophagy. However, BPNSs disrupted the autophagic flux by impairing autolysosome formation, leading to apoptosis in a size-dependent manner. In contrast, BP-PEG preserved lysosomal integrity, maintaining autophagic activity and cell viability. These findings deepen our understanding of the influence of nanosheet size and surface modifications on macrophage autophagy, contributing to the formulation of regulatory guidelines to minimize the potential adverse effects and health risks associated with BPNS utilization in various applications.

High sensitivity profiling of N-glycans from mouse serum using fluorescent imidazolium tags by HILIC electrospray ionisation spectrometry.

N-linked glycosylation is a ubiquitous protein post-translational modification in which aberrant glycan biosynthesis has been linked to severe conditions like cancer. Accurate qualitative and quantitative analysis of N-glycans are crucial for investigating their physiological functions. Owing to the intrinsic absence of chromophores and high polarity of the glycans, current detection methods are restricted to liquid chromatography and mass spectrometry. Herein, we describe three new imidazolium-based glycan tags: 2'GITag, 3'GITag, and 4'GITag, that significantly improve both the limit of detection and limit of quantification of derivatized oligosaccharides, in terms of fluorescence intensity and ionisation efficiency. Our top-performing derivatisation agent, 4'GITag, shifted the detection sensitivity range from high femtomole to sub-femtomole levels in ESI-MS compared to traditional glycan label, 2AB, enabling the identification of 24 N-glycans in mouse serum, including those bearing sialic acids. Additionally, 4'GITag stabilized Na-salt forms of sialic acids, simplifying the simultaneous analysis of neutral and negative charged N-glycans significantly, avoiding the need for complex derivatisation procedures typically required for the detection of sialylated species. Overall, the favorable performance of imidazolium tags in the derivatisation and sensitive profiling of glycans has the potential for labeling tissue or live cells to explore disease biomarkers and for developing new targeted therapeutic strategies.

Clinical characteristics and treatment of Marjolin's ulcer at a major burn center in northwest China: a retrospective review of 126 cases.

OBJECTIVE: Marjolin's ulcer (MU) is a rare, aggressive skin tumor. There are numerous case reports but large long-term studies are lacking, necessitating further exploration of its treatment. This study aimed to summarize and analyze the characteristics, treatment methods, and prognosis of MU. METHODS: We retrospectively analyzed the clinical data of 126 patients with MU, treated between January 2013 and January 2023 at the burn center. Demographic data, clinical characteristics, treatment, and prognosis were statistically analyzed. RESULTS: Of the 126 included patients, 104 were followed up for 0.1-10.2 years. The most common cause of the primary injury was flame burn (50.8%). Lesions were commonly observed on the lower limbs (47.6%). The predominant histopathological type was squamous cell carcinoma (92.8%). Among the 126 patients, 35 (27.8%) presented with bone invasion, 37 (29.4%) presented with enlarged lymph nodes, and 9 (7.1%) had lymph node metastasis. Extensive local excision (83.3%) was the most common surgical procedure; the defect was repaired using skin grafting (41.9%), free flaps (37.1%), and local flaps (21.0%). Multivariate analysis revealed that bone invasion and lymph node involvement were risk factors for postoperative recurrence. Survival analysis showed that age, latency period, pathological type, and recurrence were significant risk factors for survival. CONCLUSIONS: Extensive local resection is necessary to eradicate tumors, and patient follow-up should be more frequent within 1 year postoperatively. As MU is preventable, it is essential to reach a quick diagnosis and avoid delayed management before the occurrence of deadly metastases.

Quantitative assessment of intertarget position variations based on 4D-CT and 4D-CBCT simulations in single-isocenter multitarget lung stereotactic body radiation therapy.

BACKGROUND: In single-isocenter multitarget stereotactic body radiotherapy (SBRT), geometric miss risks arise from uncertainties in intertarget position. However, its assessment is inadequate, and may be interfered by the reconstructed tumor position errors (RPEs) during simulated CT and cone beam CT (CBCT) acquisition. This study aimed to quantify intertarget position variations and assess factors influencing it. METHODS: We analyzed data from 14 patients with 100 tumor pairs treated with single-isocenter SBRT. Intertarget position variation was measured using 4D-CT simulation to assess the intertarget position variations (ΔD) during routine treatment process. Additionally, a homologous 4D-CBCT simulation provided RPE-free comparison to determine the impact of RPEs, and isolating purely tumor motion induced ΔD to evaluate potential contributing factors. RESULTS: The median ΔD was 4.3 mm (4D-CT) and 3.4 mm (4D-CBCT). Variations exceeding 5 mm and 10 mm were observed in 31.1% and 5.5% (4D-CT) and 20.4% and 3.4% (4D-CBCT) of fractions, respectively. RPEs necessitated an additional 1-2 mm safety margin. Intertarget distance and breathing amplitude variability showed weak correlations with variation (Rs = 0.33 and 0.31). The ΔD differed significantly by locations (upper vs. lower lobe and right vs. Left lung). Notably, left lung tumor pairs exhibited the highest risk. CONCLUSIONS: This study provide a reliable way to assess intertarget position variation by using both 4D-CT and 4D-CBCT simulation. Consequently, single-isocenter SBRT for multiple lung tumors carries high risk of geometric miss. Tumor motion and RPE constitute a substantial portion of intertarget position variation, requiring correspondent strategies to minimize the intertarget uncertainties.

A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis.

Drug resistance and tumor recurrence remain clinical challenges in the treatment of urothelial carcinoma (UC). However, the underlying mechanism is not fully understood. Here, we performed single-cell RNA sequencing and identified a subset of urothelial cells with epithelial-mesenchymal transition (EMT) features (EMT-UC), which is significantly correlated with chemotherapy resistance and cancer recurrence. To validate the clinical significance of EMT-UC, we constructed EMT-UC like cells by introducing overexpression of two markers, Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and Desmin (DES), and examined their histological distribution characteristics and malignant phenotypes. EMT-UC like cells were mainly enriched in UC tissues from patients with adverse prognosis and exhibited significantly elevated EMT, migration and gemcitabine tolerance in vitro. However, EMT-UC was not specifically identified from tumorous tissues, certain proportion of them were also identified in adjacent normal tissues. Tumorous EMT-UC highly expressed genes involved in malignant behaviors and exhibited adverse prognosis. Additionally, tumorous EMT-UC was associated with remodeled tumor microenvironment (TME), which exhibited high angiogenic and immunosuppressive potentials compared with the normal counterparts. Furthermore, a specific interaction of COL4A1 and ITGB1 was identified to be highly enriched in tumorous EMT-UC, and in the endothelial component. Targeting the interaction of COL4A1 and ITGB1 with specific antibodies significantly suppressed tumorous angiogenesis and alleviated gemcitabine resistance of UC. Overall, our findings demonstrated that the driven force of chemotherapy resistance and recurrence of UC was EMT-UC mediated COL4A1-ITGB1 interaction, providing a potential target for future UC treatment.

Development of a live attenuated vaccine candidate for equid alphaherpesvirus 1 control: a step towards efficient protection.

Equid alphaherpesvirus 1 (EqAHV1) is a viral pathogen known to cause respiratory disease, neurologic syndromes, and abortion storms in horses. Currently, there are no vaccines that provide complete protection against EqAHV1. Marker vaccines and the differentiation of infected and vaccinated animals (DIVA) strategy are effective for preventing and controlling outbreaks but have not been used for the prevention of EqAHV1 infection. Glycoprotein 2 (gp2), located on the envelope of viruses (EqAHV1), exhibits high antigenicity and functions as a molecular marker for DIVA. In this study, a series of EqAHV1 mutants with deletion of gp2 along with other virulence genes (TK, UL24/TK, gI/gE) were engineered. The mutant viruses were studied in vitro and then in an in vivo experiment using Golden Syrian hamsters to assess the extent of viral attenuation and the immune response elicited by the mutant viruses in comparison to the wild-type (WT) virus. Compared with the WT strain, the YM2019 Δgp2, ΔTK/gp2, and ΔUL24/TK/gp2 strains exhibited reduced growth in RK-13 cells, while the ΔgI/gE/gp2 strain exhibited significantly impaired proliferation. The YM2019 Δgp2 strain induced clinical signs and mortality in hamsters. In contrast, the YM2019 ΔTK/gp2 and ΔUL24/TK/gp2 variants displayed diminished pathogenicity, causing no observable clinical signs or fatalities. Immunization with nasal vaccines containing YM2019 ΔTK/gp2 and ΔUL24/TK/gp2 elicited a robust immune response in hamsters. In particular, compared with the vaccine containing the ΔTK/gp2 strain, the vaccine containing the ΔUL24/TK/gp2 strain demonstrated enhanced immune protection upon challenge with the WT virus. Furthermore, an ELISA for gp2 was established and refined to accurately differentiate between infected and vaccinated animals. These results confirm that the ΔUL24/TK/gp2 strain is a safe and effective live attenuated vaccine candidate for controlling EqAHV1 infection.

A Study on the Growth and Physiological Toxicity Effects of the Combined Exposure of Microplastics and Cadmium on the Vicia faba L. Seedlings.

To investigate the toxicological effects of polystyrene microplastics (PS-MPs), cadmium (Cd), and their combined contamination on the growth and physiological responses of V. faba seedlings, this experiment employed a hydroponic method. The Hoagland nutrient solution served as the control, changes in root growth, physiological and biochemical indicators of V. faba seedlings under different concentrations of PS-MPs (10, 100 mg/L) alone and combined with 0.5 mg/L Cd. The results demonstrated that the root biomass, root vitality, generation rate of superoxide radicals (O2·-), malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity increased with increasing concentration under the influence of PS-MPs alone, while the soluble sugar content and peroxidase (POD) activity decreased. In the combined treatment with Cd, the trends of these indicators are generally similar to the PS-MPs alone treatment group. However, root vitality and SOD activity showed an inverse relationship with the concentration of PS-MPs. Furthermore, laser confocal and electron microscopy scanning revealed that the green fluorescent polystyrene microspheres entered the root tips of the V. faba and underwent agglomeration in the treatment group with a low concentration of PS-MPs alone and a high concentration of composite PS-MPs with Cd.

Amphiphilic Polymer Electrolyte Blocking Lattice Oxygen Evolution from High-Voltage Nickel-rich Cathodes for Ultra-Thermal Stabile Batteries.

Ni-rich cathodes have been intensively adopted in Li-ion batteries to pursuit high energy density, which still suffering irreversible degradation at high voltage. Some unstable lattice O2- species in Ni-rich cathodes would be oxidized to singlet oxygen 1O2 and released at high volt, which lead to irreversible phase transfer from the layered rhombohedral (R) phase to a spinel-like (S) phase. To overcome the issue, the amphiphilic copolymers (UMA-Fx) electrolyte were prepared by linking hydrophobic C-F side chains with hydrophilic subunits, which could self-assemble on Ni-rich cathode surface and convert to stable cathode-electrolyte interphase layer. Thereafter, the oxygen releasing of polymer coated cathode was obviously depressed and substituted by the Co oxidation (Co3+→Co4+) at high volt (>4.2 V), which could suppressed irreversible phase transfer and improve cycling stability. Moreover, the amphiphilic polymer electrolyte was also stable with Li anode and had high ion conductivity. Therefore, the NCM811//UMA-F6//Li pouch cell exhibited outstanding energy density (362.97 Wh/kg) and durability (cycled 200 times at 4.7 V), which could be stalely cycled even at 120°C without short circuits or explosions.

Efficacy and safety of different cycles of neoadjuvant immunotherapy in resectable non-small cell lung cancer: A systematic review and meta-analysis.

Background: There is no standard consensus on the optimal number of cycles of neoadjuvant immunotherapy prior to surgery for patients with locoregionally advanced non-small cell lung cancer (NSCLC). We carried out a systematic review to evaluate the efficacy and safety of neoadjuvant immunotherapy with different treatment cycles in order to provide valuable information for clinical decision-making. Methods: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov were systematically searched before May 2023. The included studies were categorized based on different treatment cycles of neoadjuvant immunotherapy to assess their respective efficacy and safety in patients with resectable NSCLC. Results: Incorporating data from 29 studies with 1331 patients, we found major pathological response rates of 43 % (95%CI, 34-52 %) with two cycles and 33 % (95%CI, 22-45 %) with three cycles of neoadjuvant immunotherapy. Radiological response rates were 39 % (95%CI, 28-50 %) and 56 % (95%CI, 44-68 %) for two and three cycles, respectively, with higher incidence rates of severe adverse events (SAEs) in the three-cycle group (32 %; 95%CI, 21-50 %). Despite similar rates of R0 resection between two and three cycles, the latter showed a slightly higher surgical delay rate (1 % vs. 7 %). Neoadjuvant treatment modes significantly affected outcomes, with the combination of immunotherapy and chemotherapy demonstrating superiority in improving pathological and radiological response rates, while the incidence of SAEs in patients receiving combination therapy remained within an acceptable range (23 %; 95%CI, 15-35 %). However, regardless of the treatment mode administered, an increase in the number of treatment cycles did not result in substantial improvement in pathological response rates. Conclusion: There are clear advantages of combining immunotherapy and chemotherapy in neoadjuvant settings. Increasing the number of cycles of neoadjuvant immunotherapy from two to three primarily may not substantially improve the overall efficacy, while increasing the risk of adverse events. Further analysis of the outcomes of four cycles of neoadjuvant immunotherapy is necessary.

Targeting senescent HDF with the USP7 inhibitor P5091 to enhance DFU wound healing through the p53 pathway.

OBJECTIVE: The objective of this study was to examine the potential of USP7 as a target for senolytic therapy and to investigate the molecular mechanism by which its inhibitor selectively induced apoptosis in senescent HDF and enhanced DFU wound healing. METHODS: Clinical samples of DFU were collected to detect the expression of USP7 and aging-related proteins using immunohistochemistry and Western blot. In addition, ß-galactosidase staining, qPCR, flow cytometry, ROS and MMP kits, and Western blot were used to analyze the biological functions of P5091 on senescence, cycle, and apoptosis. RNAseq was employed to further analyze the molecular mechanism of P5091. Finally, the DFU rat model was established to evaluate the effect of P5091 on wound healing. RESULTS: The expression of USP7 and p21 were increased in DFU clinical samples. After treatment with d-glucose (30 mM, 7 days), ß-galactosidase staining was deepened, proliferation rate decreased. USP7 inhibitors (P5091) could reduce the release of SASP factors, activate the production of ROS, and reduce MMP. In addition, it induced apoptosis and selectively clears senescent cells through the p53 signaling pathway. Finally, P5091 can improve diabetic wound healing in rats. CONCLUSION: This study clarified the molecular mechanism of USP7 inhibitor (P5091) selectively inducing apoptosis of high glucose senescent HDF cells. This provides a new senolytics target and experimental basis for promoting DFU wound healing.

A perylene diimide probe for NIR-II fluorescence imaging guided photothermal and type I/type II photodynamic synergistic therapy.

Phototherapy has garnered significant attention in the past decade. Photothermal and photodynamic synergistic therapy combined with NIR fluorescence imaging has been one of the most attractive treatment options because of the deep tissue penetration, high selectivity and excellent therapeutic effect. Benefiting from the superb photometrics and ease of modification, perylene diimide (PDI) and its derivatives have been employed as sensing probes and therapeutic agents in the biological and biomedical research fields, and exhibiting excellent potential. Herein, we reported the development of a novel organic small-molecule phototherapeutic agent, PDI-TN. The absorption of PDI-TN extends into the NIR region, which provides feasibility for NIR phototherapy. PDI-TN overcomes the traditional Aggregation-Caused Quenching (ACQ) effect and exhibits typical characteristics of Aggregation-Induced Emission (AIE). Subsequently, PDI-TN NPs were obtained by using an amphiphilic triblock copolymer F127 to encapsulate PDI-TN. Interestingly, the PDI-TN NPs not only exhibit satisfactory photothermal effects, but also can generate O2•- and 1O2 through type I and type II pathways, respectively. Additionally, the PDI-TN NPs emit strong fluorescence in the NIR-II region, and show outstanding therapeutic potential for in vivo NIR-II fluorescence imaging. To our knowledge, PDI-TN is the first PDI derivative used for NIR-II fluorescence imaging-guided photodynamic and photothermal synergistic therapy, which suggests excellent potential for future biological/biomedical applications.

Development of stemness-related signature to optimize prognosis prediction and identify XMD8-85 as a novel therapeutic compound for glioma.

Glioma is a highly invasive and aggressive type of brain cancer with poor treatment response. Stemness-related transcription factors form a regulatory network that sustains the malignant phenotype of gliomas. We conducted an integrated analysis of stemness-related transcription factors using The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets, established the characteristics of stemness-related transcription factors, including Octamer-Binding Protein 4 (OCT4), Meis Homeobox 1 (MEIS1), E2F Transcription Factor 1 (E2F1), Transcription Factor CP2 Like 1 (TFCP2L1), and RUNX Family Transcription Factor 1 (RUNX1). The characteristic of stemness-related transcription factors was identified as an independent prognostic factor for glioma patients. Patients in the high-risk group have a worse prognosis than those in the low-risk group. The glioma microenvironment in the high-risk group exhibited a more active immune status. Single-cell level analysis revealed that stem cell-like cells exhibited stronger intercellular communication than glioma cells. Meanwhile, patients in different risk stratification exhibited varying sensitivities to immunotherapy and small molecule drug therapy. XMD8-85 was more effective in the high-risk group, and its antitumor effects were validated both in vivo and in vitro. Our results indicate that this prognostic feature will assist clinicians in predicting the prognosis of glioma patients, guiding immunotherapy and personalized treatment, as well as the potential clinical application of XMD8-85 in glioma treatment, and helping to develop effective treatment strategies.

Discovery of Potential Drug Targeting Key Genes in Alzheimer's Disease: Insights from Transcriptome Analysis and Molecular Docking.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that presents a significant global health challenge. To explore drugs targeting key genes in AD, R software was used to analyze the data of single nuclei transcriptome from human cerebral frontal cortex in AD, and the differentially expressed genes (DEGs) were screened. Then the gene ontology (GO) analysis, Kyoto gene and genome encyclopedia (KEGG) pathway enrichment and protein-protein interaction (PPI) network were analyzed. The hub genes were calculated by Cytoscape software. Molecular docking and molecular dynamics simulation were used to evaluate and visualize the binding between candidate drugs and key genes. A total of 564 DEGs were screened, and the hub genes were ISG15, STAT1, MX1, IFIT3, IFIT2, RSAD2, IFIT1, IFI44, IFI44L and DDX58. Enrichment terms mainly included response to virus, IFN-γ signaling pathway and virus infection. Diclofenac had good binding effect with IFI44 and IFI44L. Potential drugs may act on key gene targets and then regulate biological pathways such as virus response and IFN-γ-mediated signal pathway, so as to achieve anti-virus, improve immune balance and reduce inflammatory response, and thus play a role in anti-AD.

Machine learning-based integration develops an immunogenic cell death-derived lncRNA signature for predicting prognosis and immunotherapy response in lung adenocarcinoma.

Accumulating evidence demonstrates that lncRNAs are involved in the regulation of the immune microenvironment and early tumor development. Immunogenic cell death occurs mainly through the release or increase of tumor-associated antigen and tumor-specific antigen, exposing "danger signals" to stimulate the body's immune response. Given the recent development of immunotherapy in lung adenocarcinoma, we explored the role of tumor immunogenic cell death-related lncRNAs in lung adenocarcinoma for prognosis and immunotherapy benefit, which has never been uncovered yet. Based on the lung adenocarcinoma cohorts from the TCGA database and GEO database, the study developed the immunogenic cell death index signature by several machine learning algorithms and then validated the signature for prognosis and immunotherapy benefit of lung adenocarcinoma patients, which had a more stable performance compared with published signatures in predicting the prognosis, and demonstrated predictive value for benefiting from immunotherapy in multiple cohorts of multiple cancers, and also guided the utilization of chemotherapy drugs.