Metrnl: a promising biomarker and therapeutic target for cardiovascular and metabolic diseases.

Modern human society is burdened with the pandemic of cardiovascular and metabolic diseases. Metrnl is a widely distributed secreted protein in the body, involved in regulating glucose and lipid metabolism and maintaining cardiovascular system homeostasis. In this review, we present the predictive and therapeutic roles of Metrnl in various cardiovascular and metabolic diseases, including atherosclerosis, ischemic heart disease, cardiac remodeling, heart failure, hypertension, chemotherapy-induced myocardial injury, diabetes mellitus, and obesity.

Atlas of metastatic gastric cancer links ferroptosis to disease progression and immunotherapy response.

BACKGROUND & AIMS: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve GAC patients poses a significant challenge, limiting the scope of current research, which has predominantly focused on localized tumors. This gap hinders a deeper insight into the metastatic dynamics of GAC. METHODS: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary-metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment (TME) during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, employing cell lines, multiple PDX and novel mouse models of GAC. RESULTS: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of TME phenotypes, supporting the notion that cancer cells and their local TMEs co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 upregulation during GAC progression. Conditional depletion of Gpx4 or pharmacological inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. Additionally, ferroptosis-resensitizing treatments augmented the efficacy of CAR T-cell therapy. CONCLUSIONS: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with CAR T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.

Development and validation of a nomogram for predicting lymph node metastasis in early gastric cancer.

BACKGROUND: Lymph node metastasis (LNM) significantly impacts the treatment and prognosis of early gastric cancer (EGC). Consequently, the precise prediction of LNM risk in EGC patients is essential to guide the selection of appropriate surgical approaches in clinical settings. AIM: To develop a novel nomogram risk model for predicting LNM in EGC patients, utilizing preoperative clinicopathological data. METHODS: Univariate and multivariate logistic regression analyses were performed to examine the correlation between clinicopathological factors and LNM in EGC patients. Additionally, univariate Kaplan-Meier and multivariate Cox regression analyses were used to assess the influence of clinical factors on EGC prognosis. A predictive model in the form of a nomogram was developed, and its discrimination ability and calibration were also assessed. RESULTS: The incidence of LNM in the study cohort was 19.6%. Multivariate logistic regression identified tumor size, location, degree of differentiation, and pathological type as independent risk factors for LNM in EGC patients. Both tumor pathological type and LNM independently affected the prognosis of EGC. The model's performance was reflected by an area under the curve of 0.750 [95% confidence interval (CI): 0.701-0.789] for the training group and 0.763 (95%CI: 0.687-0.838) for the validation group. CONCLUSION: A clinical prediction model was constructed (using tumor size, low differentiation, location in the middle-lower region, and signet ring cell carcinoma), with its score being a significant prognosis indicator.

Distribution Characteristics of Atmospheric Microplastics in Typical Desert Agricultural Regions.

We examined the distribution characteristics of atmospheric microplastics in typical desert agricultural regions, with a focus on the agricultural areas surrounding the Taklamakan Desert, Xinjiang, China. We collected samples of total suspended particulate matter (TSP), atmospheric deposition, and atmospheric dust using both active and passive collection methods. The chemical composition, particle size, shape, and color of atmospheric microplastics were examined using a stereomicroscope and a Fourier-transform infrared spectrometer to analyze their characteristics. The results showed that the primary chemical compositions of microplastics included polypropylene (PP), polyethylene, polyethylene terephthalate, polymethylmethacrylate, and cellophane. Particle sizes were mainly within the range of 0 to 1000 µm. Fibrous microplastics constituted the majority of the TSP and atmospheric deposition, whereas film-like microplastics constituted the largest proportion of atmospheric dustfall. The deposition flux of atmospheric microplastics in the first quarter was measured at 103.21 ± 22.12 particles/m2/day, which was lower than that observed in conventional agricultural areas. The abundance of microplastics in atmospheric dustfall was found to be 1.36 particles/g. The proportion of PP microplastics in atmospheric dustfall can be as high as 35%. Through a comparison of microplastic content in TSP during dust storms and under normal weather conditions, it was found that dust storms can lead to an increase in the abundance of microplastics within the atmospheric TSP. The present study provides a scientific basis for understanding the distribution of atmospheric microplastics in typical desert agricultural regions. Environ Toxicol Chem 2024;00:1-14. © 2024 SETAC.

The role of reactive oxygen species in gastric cancer.

Gastric cancer (GC) ranks fifth in cancer incidence and fourth in cancer-related mortality worldwide. Reactive oxygen species (ROS) are highly oxidative oxygen-derived products that have crucial roles in cell signaling regulation and maintaining internal balance. ROS are closely associated with the occurrence, development, and treatment of GC. This review summarizes recent findings on the sources of ROS and the bidirectional regulatory effects on GC and discusses various treatment modalities for GC that are related to ROS induction. In addition, the regulation of ROS by natural small molecule compounds with the highest potential for development and applications in anti-GC research is summarized. The aim of the review is to accelerate the clinical application of modulating ROS levels as a therapeutic strategy for GC.

CRISPR/Cas12a-Responsive Smart DNA Hydrogel for Sensitive Electrochemiluminescence Detection of the Huanglongbing Outer Membrane Protein Gene.

Citrus Huanglongbing (HLB) is known as the cancer of citrus, where Candidatus Liberibacter asiaticus (CLas) is the most prevalent strain causing HLB. In this study, we report a novel electrochemiluminescence (ECL) biosensor for the highly sensitive detection of the CLas outer membrane protein (Omp) gene by coupling rolling circle amplification (RCA) with a CRISPR/Cas12a-responsive smart DNA hydrogel. In the presence of the target, a large number of amplicons are generated through RCA. The amplicons activate the trans-cleavage activity of CRISPR/Cas12a through hybridizing with crRNA, triggering the response of smart DNA hydrogel to release the encapsulated AuAg nanoclusters (AuAg NCs) on the electrode and therefore leading to a decreased ECL signal. The ECL intensity change (I0 - I) is positively correlated with the concentration of the target in the range 50 fM to 5 nM, with a limit of detection of 40 fM. The performance of the sensor has also been evaluated with 10 samples of live citrus leaves (five HLB negative and five HLB positive), and the result is in excellent agreement with the gold standard qPCR result. The sensing strategy has expanded the ECL versatility for detecting varying levels of dsDNA or ssDNA in plants with high sensitivity.

Development and validation of a deep learning model for predicting gastric cancer recurrence based on CT Imaging: a multicenter study.

INTRODUCTION: The postoperative recurrence of gastric cancer has a significant impact on the overall prognosis of patients. Therefore, accurately predicting the postoperative recurrence of gastric cancer is crucial. METHODS: This retrospective study gathered data from 2,813 gastric cancer patients who underwent radical surgery between 2011 and 2017 at two medical centers. Follow-up was extended until May 2023, and cases were categorized as recurrent or non-recurrent based on postoperative outcomes. Clinical pathological information and imaging data were collected for all patients. A new deep learning signature (DLS) was generated using pretreatment CT images, based on a pre-trained baseline (a customized Resnet50), for predicting postoperative recurrence. The deep learning fusion signature (DLFS) was created by combining the score of DLS with the weighted values of identified clinical features. The predictive performance of the model was evaluated based on discrimination, calibration, and clinical usefulness. Survival curves were plotted to investigate the differences between DLFS and prognosis. RESULTS: In this study, 2813 patients with gastric cancer (GC) were recruited and allocated into training, internal validation, and external validation cohorts. The DLFS was developed and assessed for its capability in predicting the risk of postoperative recurrence. The DLFS exhibited excellent performance with AUCs of 0.833 (95% CI, 0.809-0.858) in the training set, 0.831 (95% CI, 0.792-0.871) in the internal validation set, and 0.859 (95% CI, 0.806-0.912) in the external validation set, along with satisfactory calibration across all cohorts (P>0.05). Furthermore, the DLFS model significantly outperformed both the clinical model and DLS (P<0.05). High-risk recurrent patients exhibit a significantly poorer prognosis compared to low-risk recurrent patients (P<0.05). CONCLUSIONS: The integrated model developed in this study, focusing on GC patients undergoing radical surgery, accurately identifies cases at high risk of postoperative recurrence and highlights the potential of DLFS as a prognostic factor for GC patients.

F-box proteins and gastric cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects.

Gastric cancer (GC) is a prevalent malignancy characterized by significant morbidity and mortality, yet its underlying pathogenesis remains elusive. The etiology of GC is multifaceted, involving the activation of oncogenes and the inactivation of antioncogenes. The ubiquitin-proteasome system (UPS), responsible for protein degradation and the regulation of physiological and pathological processes, emerges as a pivotal player in GC development. Specifically, the F-box protein (FBP), an integral component of the SKP1-Cullin1-F-box protein (SCF) E3 ligase complex within the UPS, has garnered attention for its prominent role in carcinogenesis, tumor progression, and drug resistance. Dysregulation of several FBPs has recently been observed in GC, underscoring their significance in disease progression. This comprehensive review aims to elucidate the distinctive characteristics of FBPs involved in GC, encompassing their impact on cell proliferation, apoptosis, invasive metastasis, and chemoresistance. Furthermore, we delve into the emerging role of FBPs as downstream target proteins of non-coding RNAs(ncRNAs) in the regulation of gastric carcinogenesis, outlining the potential utility of FBPs as direct therapeutic targets or advanced therapies for GC.

Mutation characteristics and molecular evolution of ovarian metastasis from gastric cancer and potential biomarkers for paclitaxel treatment.

Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo.

Effects of Different Drying Methods on Drying Characteristics, Microstructure, Quality, and Energy Consumption of Apricot Slices.

An appropriate drying method is crucial for producing high-quality dried apricots. In this study, the effects of four drying methods, hot air drying (HAD), infrared drying (IRD), pulse vacuum drying (PVD), and vacuum freeze-drying (VFD), on the drying kinetics and physical and nutritional characteristics of apricot slices were evaluated. PVD required the shortest time (16.25 h), followed by IRD (17.54 h), HAD (21.39 h), and VFD (34.64 h). VFD resulted in the best quality of apricot slices, with the smallest color difference (ΔE = 13.64), lowest water activity (0.312 ± 0.015) and browning degree (0.35), highest color saturation (62.84), lowest hardness (8.35 ± 0.47 N) and shrinkage (9.13 ± 0.65%), strongest rehydration ability (3.58 ± 0.11 g/g), a good microstructure, and high nutrient-retention rates (ascorbic acid content: 53.31 ± 0.58 mg/100 g, total phenolic content: 12.64 ± 0.50 mg GAE/g, and carotenoid content: 24.23 ± 0.58 mg/100 g) and antioxidant activity (DPPH: 21.10 ± 0.99 mmol Trolox/g and FRAP: 34.10 ± 0.81 mmol Trolox/g). The quality of PVD-treated apricot slices was second-best, and the quality of HAD-treated apricot slices was the worst. However, the energy consumption required for VFD was relatively high, while that required for PVD was lower. The results of this study provide a scientific basis for the large-scale industrial production of dried apricots.

Synthetic CT generation based on CBCT using improved vision transformer CycleGAN.

Cone-beam computed tomography (CBCT) is a crucial component of adaptive radiation therapy; however, it frequently encounters challenges such as artifacts and noise, significantly constraining its clinical utility. While CycleGAN is a widely employed method for CT image synthesis, it has notable limitations regarding the inadequate capture of global features. To tackle these challenges, we introduce a refined unsupervised learning model called improved vision transformer CycleGAN (IViT-CycleGAN). Firstly, we integrate a U-net framework that builds upon ViT. Next, we augment the feed-forward neural network by incorporating deep convolutional networks. Lastly, we enhance the stability of the model training process by introducing gradient penalty and integrating an additional loss term into the generator loss. The experiment demonstrates from multiple perspectives that our model-generated synthesizing CT(sCT) has significant advantages compared to other unsupervised learning models, thereby validating the clinical applicability and robustness of our model. In future clinical practice, our model has the potential to assist clinical practitioners in formulating precise radiotherapy plans.

Characterization of NMCR-3, NMCR-4 and NMCR-5, three novel non-mobile colistin resistance determinants: Implications for MCR-3, MCR-7, and MCR-5 progenitors, respectively.

In this study, the progenitors of MCR-3, MCR-7 and MCR-5, namely NMCR-3, NMCR-4 and NMCR-5, were firstly discovered and indicating Aeromonas was a natural reservoir for MCR-3 and MCR-7. Furthermore, different evolutionary models for MCR-3, MCR-7 and MCR-5 were proposed.

Functional Property and Regulatory Mechanism of Macrophages in Complementary and Alternative Medicine: From Bench to Clinic.

Complementary and alternative medicine (CAM) includes a wide range of treatments that are gaining acceptance among the public. It is increasingly being recognized as a viable option for treating various diseases with minimal side effects. Common avenues of this therapy include herbal medicine, acupuncture, physical exercise, aromatherapy, dietary therapy, and homeopathy etc. Macrophages are highly heterogeneous cells that play multiple regulatory roles. Practices such as herbal medicine, acupuncture, physical exercise, aromatherapy and dietary therapy exert curative effects by modulating the polarization status and the secretory phenotype of macrophages directly. Furthermore, herbal medicine, acupuncture, and physical exercise influence the crosstalk between macrophages and other types of cells, including cancer cells and T cells. Mechanistically, herbal medicine and acupuncture produce curative effects in diverse diseases, including inflammatory diseases and tumors, mainly by influencing the phosphorylation of signaling proteins in macrophages. Therefore, targeting macrophages offers theoretical support for advancing the scientific understanding of this therapy and aids in identifying potential therapeutic options. Hence, in this review, we systematically summarize the different regulations of macrophages in herbal medicine, acupuncture, physical exercise, aromatherapy, dietary therapy and homeopathy, and further highlight the therapeutic potential of targeting macrophages in complementary and alternative medicine.

Isthmin-1 alleviates cardiac ischaemia/reperfusion injury through cGMP-PKG signalling pathway.

AIMS: Ischaemia/reperfusion (I/R) injury is an important complication of reperfusion therapy for acute myocardial infarction, extremely compromising the cardiac benefits of revascularization; however, specific and efficient treatment for cardiac I/R injury is still lacking. Isthmin-1 (ISM1) is a novel adipokine and plays indispensable roles in regulating glycolipid metabolism and cell survival. The present study aims to investigate the potential role and molecular mechanism of ISM1 in cardiac I/R injury using gain- and loss-of-function approaches. METHODS AND RESULTS: Cardiac-specific ISM1 overexpression and silence were achieved using an adeno-associated virus serotype 9 system, and then these mice were subjected to I/R surgery, followed by biochemical test, echocardiography and histopathologic examinations, etc. Meanwhile, neonatal rat cardiomyocytes (NRCMs) with ISM1 silence or overexpression also received simulated I/R (sI/R) injury to further verify its role in vitro. The potential downstream pathways and molecular targets of ISM1 were screened by RNA sequencing. We also treated injured mice and NRCMs with recombinant ISM1 (rISM1) to explore whether supplementation with ISM1 was sufficient to protect against I/R injury. Furthermore, acute myocardial infarction patients with percutaneous coronary intervention (PCI) and paired healthy controls were included to reveal the clinical relevance of circulating ISM1. Cardiac-specific ISM1 silencing aggravated while ISM1 overexpression alleviated I/R-induced acute cardiac injury and cardiac remodelling and dysfunction. Mechanistically, ISM1 targeted αvß5 integrin to facilitate the nuclear accumulation of nuclear transcription factor Y subunit alpha, transcriptionally increased soluble guanylyl cyclase beta subunit expression, and eventually enhanced cGMP generation. Besides, we confirmed that treatment with rISM1 before or after reperfusion could confer cardioprotective effects in mice. Clinically, lower ISM1 levels post-PCI was associated with worse outcome in patients. CONCLUSION: ISM1 can protect against cardiac I/R injury through cGMP-PKG signalling pathway, and it is a promising therapeutic and predictive target of cardiac I/R injury.

Experimental Study on the Migration and Distribution of Microplastics in Desert Farmland Soil Under Drip Irrigation.

The microplastics (MPs) formed by broken plastic film may migrate in the soil under drip irrigation. To investigate the migration distribution of MPs in desert farmland soil under drip irrigation conditions, our study was conducted on farmland in Xinjiang (China). A MP drip irrigation penetration migration testing device was set up in combination with Xinjiang farmland irrigation methods to conduct a migration simulation experiment. The results showed that the migration amount of MPs in soil was significantly positively correlated with the amount of drip irrigation, and significantly negatively correlated with the soil depth; in addition, the relationship between the migration amount of MPs in different types of soil was: clay < sandy loam < sandy soil. Under drip irrigation conditions, the migration rates of MPs were 30.51%, 19.41%, and 10.29% in sandy soil, sandy loam soil, and clay, respectively. The migration ability of these three particle sizes of polyethylene MPs in soil was ranked as follows: 25 to 147 µm > 0 to 25 µm > 147 to 250 µm. When the drip irrigation volume was 2.6 to 3.2 L, horizontal migration distances of MPs exceeded 5 cm, and vertical migration distances reached more than 30 cm. Our findings provide reference data for the study of soil MP migration. Environ Toxicol Chem 2024;43:1250-1259. © 2024 SETAC.

Elimination of subtelomeric repeat sequences exerts little effect on telomere essential functions in Saccharomyces cerevisiae.

Telomeres, which are chromosomal end structures, play a crucial role in maintaining genome stability and integrity in eukaryotes. In the baker's yeast Saccharomyces cerevisiae, the X- and Y'-elements are subtelomeric repetitive sequences found in all 32 and 17 telomeres, respectively. While the Y'-elements serve as a backup for telomere functions in cells lacking telomerase, the function of the X-elements remains unclear. This study utilized the S. cerevisiae strain SY12, which has three chromosomes and six telomeres, to investigate the role of X-elements (as well as Y'-elements) in telomere maintenance. Deletion of Y'-elements (SY12YΔ), X-elements (SY12XYΔ+Y), or both X- and Y'-elements (SY12XYΔ) did not impact the length of the terminal TG1-3 tracks or telomere silencing. However, inactivation of telomerase in SY12YΔ, SY12XYΔ+Y, and SY12XYΔ cells resulted in cellular senescence and the generation of survivors. These survivors either maintained their telomeres through homologous recombination-dependent TG1-3 track elongation or underwent microhomology-mediated intra-chromosomal end-to-end joining. Our findings indicate the non-essential role of subtelomeric X- and Y'-elements in telomere regulation in both telomerase-proficient and telomerase-null cells and suggest that these elements may represent remnants of S. cerevisiae genome evolution. Furthermore, strains with fewer or no subtelomeric elements exhibit more concise telomere structures and offer potential models for future studies in telomere biology.

Safety and efficacy of a programmed cell death 1 inhibitor combined with oxaliplatin plus S-1 in patients with Borrmann large type III and IV gastric cancers.

BACKGROUND: Gastric cancer (GC) is the fifth most common and the fourth most lethal malignant tumour in the world. Most patients are already in the advanced stage when they are diagnosed, which also leads to poor overall survival. The effect of postoperative adjuvant chemotherapy for advanced GC is unsatisfactory with a high rate of distant metastasis and local recurrence. AIM: To investigate the safety and efficacy of a programmed cell death 1 (PD-1) inhibitor combined with oxaliplatin and S-1 (SOX) in the treatment of Borrmann large type III and IV GCs. METHODS: A retrospective analysis (IRB-2022-371) was performed on 89 patients with Borrmann large type III and IV GCs who received neoadjuvant therapy (NAT) from January 2020 to December 2021. According to the different neoadjuvant treatment regimens, the patients were divided into the SOX group (61 patients) and the PD-1 + SOX (P-SOX) group (28 patients). RESULTS: The pathological response (tumor regression grade 0/1) in the P-SOX group was significantly higher than that in the SOX group (42.86% vs 18.03%, P = 0.013). The incidence of ypN0 in the P-SOX group was higher than that in the SOX group (39.29% vs 19.67%, P = 0.05). The use of PD-1 inhibitors was an independent factor affecting tumor regression grade. Meanwhile, the use of PD-1 did not increase postoperative complications or the adverse effects of NAT. CONCLUSION: A PD-1 inhibitor combined with SOX could significantly improve the rate of tumour regression during NAT for patients with Borrmann large type III and IV GCs.

Clinical and Radiological Factors for Predicting Clinically Significant Prostate Cancer in Biopsy-Naive Patients With PI-RADS 3 Lesions.

OBJECTIVE: This study intends to examine the anticipatory power of clinical and radiological parameters in detecting clinically significant prostate cancer in patients demonstrating Prostate Imaging Reporting and Data System 3 lesions. METHODS: This was a retrospective study. The study included participation from 453 patients at the First Affiliated Hospital of Soochow University, sampled between September 2017 through August 2022. Each patient underwent a routine 12-core prostate biopsy followed by a 2 to 5 core fusion-targeted biopsy. We utilized both univariate and multivariate logistic regression analyses to identify the parameters that have a correlation with clinically significant prostate cancer. The predictive ability of these parameters was assessed using the receiver operating characteristic curve, leading to the creation of a nomogram. RESULTS: Clinically significant prostate cancer was detected in 68 out of 453 patients with Prostate Imaging Reporting and Data System 3 lesions (15.01%). Among Prostate Imaging Reporting and Data System 3a and 3b patients, 4.78% (3.09% of the total) and 33.75% (11.92% of the total), respectively, had clinically significant prostate cancer. Systematic biopsy improved prostate cancer and clinically significant prostate cancer detection rates by 7.72% and 3.09%, respectively, compared to targeted biopsy. Without systematic biopsy, there would be an undetected rate of 15% for prostate cancer and 8.13% for clinically significant prostate cancer in Prostate Imaging Reporting and Data System 3b patients. Several clinical parameters, including age, prostate-specific antigen density, lesion volume, apparent diffusion coefficient, and digital rectal examination, were statistically significant in the logistic regression analysis for clinically significant prostate cancer. The individual diagnostic accuracies of these parameters for clinically significant prostate cancer were 0.648, 0.645, 0.75, 0.763, and 0.7, respectively, but their combined accuracy improved to 0.866. A well-fit nomogram based on the identified risk factors was constructed (χ2 = 10.254, P = .248). CONCLUSION: The combination of age, prostate-specific antigen density, lesion volume, apparent diffusion coefficient, and digital rectal examination presented a higher diagnostic value for clinically significant prostate cancer than any single parameter in patients with Prostate Imaging Reporting and Data System 3 lesions. Systematic biopsy proved crucial for biopsy-naive patients with Prostate Imaging Reporting and Data System 3 lesions and should not be omitted.

Blocking Ubiquitin-Specific Protease 7 Induces Ferroptosis in Gastric Cancer via Targeting Stearoyl-CoA Desaturase.

Gastric cancer (GC) presents a formidable global health challenge, and conventional therapies face efficacy limitations. Ubiquitin-specific protease 7 (USP7) plays pivotal roles in GC development, immune response, and chemo-resistance, making it a promising target. Various USP7 inhibitors have shown selectivity and efficacy in preclinical studies. However, the mechanistic role of USP7 has not been fully elucidated, and currently, no USP7 inhibitors have been approved for clinical use. In this study, DHPO is identified as a potent USP7 inhibitor for GC treatment through in silico screening. DHPO demonstrates significant anti-tumor activity in vitro, inhibiting cell viability and clonogenic ability, and preventing tumor migration and invasion. In vivo studies using orthotopic gastric tumor mouse models validate DHPO's efficacy in suppressing tumor growth and metastasis without significant toxicity. Mechanistically, DHPO inhibition triggers ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde (MDA) accumulation, and iron overload. Further investigations unveil USP7's regulation of Stearoyl-CoA Desaturase (SCD) through deubiquitination, linking USP7 inhibition to SCD degradation and ferroptosis induction. Overall, this study identifies USP7 as a key player in ferroptosis of GC, elucidates DHPO's inhibitory mechanisms, and highlights its potential for GC treatment by inducing ferroptosis through SCD regulation.

Oxygen-producing and pH-responsive targeted DNA nanoflowers for enhanced chemo-sonodynamic therapy of lung cancer.

Lung cancer is the deadliest kind of cancer in the world, and the hypoxic tumor microenvironment can significantly lower the sensitivity of chemotherapeutic drugs and limit the efficacy of different therapeutic approaches. In order to overcome these problems, we have designed a drug-loaded targeted DNA nanoflowers encoding AS1411 aptamer and encapsulating chemotherapeutic drug doxorubicin and oxygen-producing drug horseradish peroxidase (DOX/HRP-DFs). These nanoflowers can release drugs in response to acidic tumor microenvironment and alleviate tumor tissue hypoxia, enhancing the therapeutic effects of chemotherapy synergistic with sonodynamic therapy. Owing to the encoded drug-loading sequence, the doxorubicin loading rate of DNA nanoflowers reached 73.24 ± 3.45%, and the drug could be released quickly by disintegrating in an acidic environment. Furthermore, the AS1411 aptamer endowed DNA nanoflowers with exceptional tumor targeting properties, which increased the concentration of chemotherapeutic drug doxorubicin in tumor cells. It is noteworthy that both in vitro and in vivo experiments demonstrated DNA nanoflowers could considerably improve the hypoxia of tumor cells, which enabled the generation of sufficient reactive oxygen species in combination with ultrasound, significantly enhancing the therapeutic effect of sonodynamic therapy and evidently inhibiting tumor growth and metastasis. Overall, this DNA nanoflowers delivery system offers a promising approach for treating lung cancer.