With a low autoimmune risk and dedicated induction of type Ⅰ interferon production in immunotherapy, "STING therapy" holds broad prospects in the treatment of aggressive and metastatic cancers such as ovarian cancer (OC). Inducing pyroptosis constitutes a promising approach for activating the anti-tumor immune response. Nevertheless, compared to combination therapies, "single-molecule multitarget" drugs possess the merits of a lower interaction risk, more predictable pharmacokinetics and a lower cost of clinical trials. Therefore, the present study was conducted to construct a structurally stable nanoparticles (TPAQu-Pt@HA NPs) with controlled drug release behavior and active targeting ability based on a self-designed and synthesized photo-platinum compound (TPAQu-Pt) with aggregation-induced emission (AIE) effect without excipients. The NPs attained "single-molecule multitarget" effect via three mechanisms: 1) causing nuclear and mitochondrial DNA damage and cytoplasmic leakage of double-stranded DNA (dsDNA), effectively activating cGAS-STING pathway; 2) inducing pyroptosis benefited from the AIE effect conferring a stronger ROS-generating capacity; 3) photothermal therapy worsened mitochondrial dysfunction and intensified pyroptosis, amplifying activation of cGAS-STING pathway and the subsequent anti-tumor immune response. In conclusion, this study provided a scientific basis for the molecular modification of cisplatin, which was expected to improve the treatment status of OC.

IntroductionHistone acetylation modifications can regulate gene transcription and play crucial roles in multiple tumorigeneses processes. YEATS domain proteins are one important type of acetylation readers. We have found significant mutations and copy number amplifications of YEATS domain containing 2 (YEATS2) gene in esophageal squamous cell carcinoma (ESCC) through whole genome sequencing (WGS). However, the function and molecular mechanism of YEATS2 in ESCC remain elusive.MethodsChi-squared test and Kaplan-Meier methods were used to analyze the clinical significance of YEATS2. MTT, Colony Formation Assay, Transwell, Scratch Wound Healing, subcutaneous tumorigenesis model and lung metastatic tumor model were performed to detect YEATS2 effect on the proliferation and migration ability of ESCC cells in vivo and in vitro Co-IP-based mass spectrum (MS) assays and Chromatin immunoprecipitation (ChIP) were performed to explore the molecular mechanism of YEATS2 function in ESCC.ResultsESCC patients with copy number amplification of YEATS2 had shorter postoperative survival. Furthermore, YEATS2 expression was positively correlated with copy number amplification. We have also found that YEATS2 expression was significantly upregulated in ESCC tissues and was correlated closely with the differentiation degree of ESCC cells. The results of in vivo and in vitro experiments revealed that YEATS2 enhanced the abilities of ESCC cells to proliferate and migrate. Mechanistically, YEATS2 activated NF-κB signaling to promote ESCC progression. YEATS2 and H3K27 acetylation (H3K27ac) were both enriched in the promoter region of IL6ST, which is involved in the regulation of YEATS2 on NF-κB signaling. Additionally, YEATS2 could recruit TAF15 and KAT5 to enhance H3K27ac enrichment in the promoter region of IL6ST to regulate its expression.ConclusionIn conclusion, YEATS2 might function as a potential driver gene and a potential therapeutic target in ESCC.

Cancer remains one of the greatest challenges in modern medicine. Traditional chemotherapy drugs often cause severe side effects, including nausea, vomiting, diarrhea, neurotoxicity, liver damage, and nephrotoxicity. In addition to these adverse effects, high recurrence and metastasis rates following treatment pose significant challenges for clinicians. There is an urgent need for novel therapeutic strategies to improve cancer treatment outcomes. In this context, nanozymes-artificial enzyme mimetics-have attracted considerable attention due to their unique advantages, including potent tumor-killing effects, enhanced biocompatibility, and reduced toxicity. Notably, nanozymes can dynamically monitor tumors through imaging and tracing. The multifunctional nanozyme (MN) is a promising research focus, integrating multiple catalytic activities, signal enhancement, sensing capabilities, and diverse modifications within a single nanozyme system. MNs can selectively target tumor regions, facilitating synergistic effects with other cancer therapies while enabling real-time imaging and tumor tracking. In this review, we first categorize MNs based on their composition and structural characteristics. We then discuss the primary mechanisms by which MNs exert their anticancer effects. Additionally, we review three types of MN biosensors and four MN-based therapeutic approaches applied in cancer treatment. Finally, we highlight the current challenges in MN research and provide an outlook on future developments in this field.

Platinum-based chemotherapy is the cornerstone of ovarian cancer (OC) treatment. However, decrease of cellular concentration of the drug, glutathione (GSH)-mediated drug inactivation, and severe toxic side effects contribute to its clinical chemotherapy failure. Cisplatin has the ability to induce endoplasmic reticulum stress (ERS) production in OC, and sustained ERS can potentiate the cytotoxic effects of chemotherapy. Herein, platinum(IV) prodrug nanoparticles (IPD NPs) are prepared as nanocarriers of isoliquiritigenin (ISL, traditional Chinese medicine) with redox-responsive degradation properties and synergistic ERS amplification for enhanced OC treatment. Notably, IPD NPs contain docosahexaenoic acid (DHA) which enhanced cellular uptake as well as generated reactive oxygen species (ROS), thereby breaking redox homeostasis and further augmenting the effect of ERS. This current strategy of sustained ERS amplification for enhanced cisplatin-based chemotherapy overcomes the low cellular uptake, GSH-mediated drug detoxification, avoids the dose-dependent nephrotoxicity of cisplatin, and is promising for OC treatment.

Hypoimmunogenicity and the immunosuppressive microenvironment of ovarian cancer severely restrict the capability of immune-mediated tumor killing. Immunogenic cell death (ICD) introduces a theoretical principle for antitumor immunity by increasing antigen exposure and presentation. Despite recent research progress, the currently available ICD inducers are still very limited, and many of them can hardly induce sufficient ICD based on traditional endoplasmic reticulum (ER) stress. Accumulating evidence indicates that inducing mitochondrial stress usually shows a higher efficiency in evoking large-scale ICD than that via ER stress. Inspired by this, herein, a mitochondria-targeted polyprodrug nanoparticle (named Mito-CMPN) serves as a much superior ICD inducer, effectively inducing chemo-photodynamic therapy-caused mitochondrial stress in tumor cells. The rationally designed stimuli-responsive polyprodrugs, which can self-assemble into nanoparticles, were functionalized with rhodamine B for mitochondrial targeting, cisplatin and mitoxantrone (MTO) for synergistic chemo-immunotherapy, and MTO also serves as a photosensitizer for photodynamic immunotherapy. The effectiveness and robustness of Mito-CMPNs in reversing the immunosuppressive microenvironment is verified in both an ovarian cancer subcutaneous model and a high-grade serous ovarian cancer model. Our results support that the induction of abundant ICD by focused mitochondrial stress is a highly effective strategy to improve the therapeutic efficacy of immunosuppressive ovarian cancer.

Purpose:Pyroptosis, a new form of inflammatory programmed cell death, has recently gained attention. However, the impact of the expression levels of pyroptosis-related genes (PRGs) on the overall survival (OS) of osteosarcoma patients remains unclear. This study aims to investigate the impact of the expression levels of PRGs on the OS of pediatric and young adult patients with osteosarcoma. Patients and Methods:Transcriptome matrix datasets of normal muscle or skeletal tissues from the Genotype-Tissue Expression (GTEx) project and osteosarcoma specimen the National Cancer Institute's (NCI) Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database were used to identify pyroptosis-related genes (PRGs) associated with prognosis. The National Center for Biotechnology Information's (NCBI) GSE21257 dataset was employed to validate the predictive value of the pyroptosis-related signature (PRS). Additionally, reverse transcription polymerase chain reaction (RT-qPCR) experiment was performed in normal and osteosarcoma cell lines. Results:The study identified 18 differentially expressed PRGs (DEPRGs) between normal muscle or skeletal tissues and tumor samples. Multiple machine learning techniques were used to select PRGs, resulting in the identification of four hub PRGs. A PRS-score was calculated for each sample based on the expression of these four hub PRGs, and samples were categorized into low and high PRS-score level groups. It was confirmed that metastatic status and PRS-score level are independent prognostic predictors. A nomogram model for predicting OS of osteosarcoma patients was constructed. Single-cell RNA-sequencing data display the expression patterns of the hub PRGs. RT-qPCR data results were found to be consistent with the differential expression analysis performed on TARGET and GTEx samples. Conclusion:The study developed a novel pyroptosis-related gene signature that can stratify pediatric and young adult osteosarcoma patients into different risk groups, thus predicting their response to immunotherapy and chemotherapy.

The Cp*Rh-catalyzed C-H arylation of indoles with arylsilanes is developed. This C-H activation transformation allows for the Rh-catalyzed indole C2 arylation to overcome the limitations of requiring strong directing group assistance and high-temperature conditions, achieving a room-temperature transformation driven by a weak directing group. Cp*Rh/MeOH catalytic media are considered a key factor enabling this transformation to occur under mild conditions, and experimental studies and theoretical calculations were performed to rationalize the reaction mechanisms and the influence of methanol as a solvent in promoting the reaction.

The gasdermin (GSDM) family comprises six proteins, including GSDMA‑GSDME and Pejvakin. Most of these proteins have a crucial role in inducing pyroptosis; in particular, GSDMD and GSDME are the most extensively studied proteins as the executioners of the pyroptosis process. Pyroptosis is a highly pro‑inflammatory form of programmed cell death and is closely associated with the incidence, development and prognosis of multiple cancer types. The present review focused on the current knowledge of the molecular mechanism of GSDM‑mediated pyroptosis, its intricate role in cancer and the potential therapeutic value of its anti‑tumor effects.

Ovarian cancer (OC) is one of the most common and recurring malignancies in gynecology. Patients with relapsed OC always develop ''cascade drug resistance'' (CDR) under repeated chemotherapy, leading to subsequent failure of chemotherapy. To overcome this challenge, amphiphiles (P1) carrying a nitric oxide (NO) donor (Isosorbide 5-mononitrate, ISMN) and high-density disulfide are synthesized for encapsulating mitochondria-targeted tetravalent platinum prodrug (TPt) to construct a nanocomposite (INP@TPt). Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum, depleting glutathione, and preventing apoptosis escape through generating highly toxic peroxynitrite anion (ONOO−). To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor, an OC patient-derived tumor xenograft (PDXOC) model in BALB/c nude mice was established. INP@TPt showed the best therapeutic effects in the PDXOC model. The corresponding tumor tissues contained high ONOO− levels, which were attributed to the simultaneous release of O2•− and NO in tumor tissues. Taken together, INP@TPt-based systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR, providing practical applications for ovarian therapy.

Background Brucella species are Gram-negative intracellular bacteria that causes severe inflammatory diseases in animals and humans. Two major lipoproteins (L19 and L16) of Brucella outer membrane proteins were studied to explore the association with inflammatory response of human monocytes (THP-1). Methods Activated THP-1 cells induced with recombinant L19 and L16 were analyzed in comparison with unlipidated forms (U19 and U16) and lipopolysaccharide (LPS) of Brucella melitensis, respectively. Results Secretion of inflammatory factors tumor necrosis factor-α, interleukin (IL)-6, and IL-1β was significantly increased from L19, L16, or both stimulated THP-1 cells. High secretion of IL-18 was detected only from L19-induced cells. Signaling of those cytokine responses was identified mainly through the P38-mitogen-activated protein kinase pathway, and signaling of L19-induced IL-1β response partly occurred via necrosis factor-κB. While exploring different forms of IL-18, we found that L19-induced production of active IL-18 (18 kD) occurred through upregulating NLRP3 and activating caspase-1, whereas L16-induced production of inactive IL-18 fragments (15 kD and 16 kD) occurred through activating caspase-8/3. We also found that L19 upregulated phosphorylation of XIAP for inhibiting caspase-3 activity to cleave IL-18, whereas L16 activated caspase-3 for producing GSDME-N and leading to pyroptosis of THP-1 cells. Conclusions Brucella L19 and L16 differentially induce IL-18 response or pyroptosis in THP-1 cells, respectively.

OBJECTIVE:To analyze the factors influencing the diagnosis and treatment of tracheobronchial foreign bodies (TFBs) in children. METHODS:The clinical data of 300 consecutive children with suspected TFBs who were admitted to our department between January 2016 and December 2019 were retrospectively collected, including demographics, diagnosis, history of foreign body inhalation, preoperative chest computed tomography (CT) findings, duration of foreign body retention, time from admission to operation, operation duration, duration of hospitalization, and complications. RESULTS:Among the 300 cases, the male:female ratio was 193:107, and the age range was 6 months to 12 years (median age: 19 months). A total of 291 cases (97.0%) involved TFBs confirmed by rigid bronchoscopy, while the other 9 cases (3.0%) involved bronchopneumonia. The diagnostic accuracy, sensitivity, and specificity of a history of foreign body inhalation and chest CT were 96.0%, 98.6%, and 11.1% and 97.7%, 97.6%, and 100%, respectively. The duration of hospitalization, time from admission to operation, and operation duration were all related to bronchopneumonia (P < .05). CONCLUSIONS:A detailed history, adequate physical examination, and preoperative imaging examination help improve the diagnostic accuracy. Preoperative bronchopneumonia in children with TFBs will increase the surgical risks and treatment costs, prolonging the duration of hospitalization.

Brucellosis is a serious zoonosis occurring mainly in developing countries, and its diagnosis is largely dependent on serologic detection and bacterial culture. In this study, we developed the murine monoclonal antibodies (mAbs) against a conserved and major outer membrane protein 25 (Omp25) of Brucella species (B. spp.) for use in clinical diagnosis. The mAbs to Omp25 were produced by hybridoma technique, which were utilized for developing various immunoassays for detection of Brucellae, including Western blot (WB), enzyme-linked immunosorbent assay (ELISA), immunochemical staining (ICS), immunofluorescence staining (IFS), and flow cytometry assay (FCM). A number of five mAbs (2B10, 4A12, 4F10, 6C12, and 8F3) specific to Omp25 were selected, including 2 IgG1, 2 IgG2a, and 1 IgG2b. Among them, mAbs 6C12, 8F3, and 4A12 reacted highly with B. melitensis (M5-90), B. abortus (S19, 104M, and 2308), and B. suis strain (S2). No cross-reactivity with Yersinia enterocolitica O:9, Salmonella spp., and Escherichia coli was found. By mapping Omp25 epitopes, mAb 6C12 was found as reacting with a semi-conformational epitope, and mAbs 4A12 and 8F3 as recognizing a different linear epitope, respectively. The paired mAbs were tested for detecting Brucella species, suggesting that 8F3 was suitable for solid phase capture and 6C12 or 4A12 was suitable for conjugation with HRP for detection of Brucella Omp25 in ELISA. The FCM was established by mAb 6C12 for detecting intracellular Brucellae-infected peripheral blood mononuclear cells (PBMCs) from brucellosis patients. In conclusion, mAbs against Omp25 are precious reagents for detection of Brucellae in clinical samples with various immunoassays. mAb 6C12-based FCM could be potentially used for the monitoring of therapeutic efficacy for brucellosis in clinical practice.

Objectives The inhibition of pyroptosis has a protective effect in sepsis-associated encephalopathy (SAE). However, the mechanisms underlying pyroptosis in SAE remain to be elucidated. Methods Here, we investigated the effects of the caspase inhibitors, Belnacasan (Beln) and Wedelolactone (Wede), on an induced model of SAE in P12 cells, using immunofluorescence, ELISA, western blotting, and flow cytometry. Results The cell viability decreased, IL-1β and IL-18 secretion increased, and the levels of the caspase cleavage products, N-terminal gasdermin D, cleaved caspase-1, and cleaved caspase-11, increased in P12 cells following combined treatment with lipopolysaccharides (LPS) and adenosine triphosphate (ATP). However, treatment with Beln or Wede ameliorated the effects induced by LPS and ATP. Neither Beln nor Wede notably affected the levels of cell apoptosis-associated proteins but these inhibitors regulated the levels of cell pyroptosis-associated proteins. Further, the combination of Beln and Wede exerted greater inhibitory effects on cell pyroptosis than either Beln or Wede alone. Conclusions The results demonstrated that both the canonical and non-canonical signaling pathways of cell pyroptosis are involved in LPS-induced cell damage and that the non-canonical signaling pathway may be involved to a greater extent. This suggests that the inhibition of pyroptosis may exert potential therapeutic effects on SAE.