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Background Relapsed/refractory acute lymphoblastic leukemia (R/R ALL) continues to be a major cause of mortality in children worldwide, with around 15% of ALL patients experiencing relapse and approximately 10% eventually dying from the disease. Early identification of R/R ALL in children has posed a longstanding clinical challenge.Method Genetic analysis of survival outcomes in pediatric patients with ALL from the TARGET-ALL dataset revealed five risk score factors identified through the intersection of differential genes (relapse/non-relapse) from the GSE17703 and GSE6092 databases. A risk score equation was formulated using these factors and validated against prognostic data from 46 ALL cases at our institution. Patients from multiple datasets were stratified into high and low-score groups based on this equation. Protein–protein interaction networks (PPI) were then constructed using the intersecting differential genes from all three datasets to identify hub nodes and predict interacting transcription factors. Additionally, genes related to cell pyroptosis with varying expression across these datasets were screened, and a multifactorial ROC curve (incorporating risk score and differential expression of pyroptosis-related genes) was generated. Furthermore, relationships among variables in the predictive model were depicted using a nomogram, and model efficacy was assessed through decision curve analysis (DCA).Results By analyzing the TARGET-ALL, GSE17703, and GSE6092 databases, we developed a prognostic risk assessment model for pediatric ALL incorporating BAG2, EPHA4, FBXO9, SNX10, and WNK1. Validation of this model was conducted using data from 46 pediatric ALL cases obtained from our institution. Following the identification of 27 differentially expressed genes, we constructed a PPI and identified the top 10 hub genes (PTPRC, BTK, LCK, PRKCQ, CD3D, CD27, CD3G, BLNK, RASGRP1, VPREB1). Using this network, we predicted the top 5 transcription factors (HOXB4, MYC, SOX2, E2F1, NANOG). ROC and DCA were conducted on pyroptosis-related genes exhibiting differential expression and risk scores. Subsequently, a nomogram was generated, demonstrating the effectiveness of the risk score in predicting prognosis for pediatric ALL patients.Conclusions We have developed a risk prediction model for pediatric R/R ALL utilizing the genes BAG2, EPHA4, FBXO9, SNX10, and WNK1. This model provides a scientific foundation for early identification of R/R ALL in children.

The antitumor immune response induced by chemotherapy has attracted considerable attention. However, the immunosuppressive tumor microenvironment hinders the immune activation effect of cancer chemotherapy. TGF-β plays a key role in driving tumor immunosuppression and can prevent effective antitumor immune response through multiple roles. In this study, a dual-responsive prodrug micelle (PAOL) is designed to co-deliver LY2109761 (a TGF-β receptor I/II inhibitor) and oxaliplatin (OXA, a conventional chemotherapy) to remodel tumor microenvironment and trigger immunogenic cell death (ICD) to induce antitumor immunity response. Under hypoxia tumor environment, the polyethylene glycol shell of the micelle cleavages, along with the release of LY2109761 and OXA prodrug. Cytotoxic effect of OXA is then activated by glutathione-mediated reduction in tumor cells and the activated OXA significantly enhances tumor immunogenicity and promotes intratumoral accumulation of cytotoxic T lymphocytes. Meanwhile, TGF-β blockade through LY2109761 reprograms tumor microenvironment by correcting the immunosuppressive state and regulating tumor extracellular matrix, which further maintaining OXA induced immune response. Therefore, due to the capability of boosting tumor-specific antitumor immunity, the bifunctional micelle presents markedly synergistic antitumor efficacies and provides a potent therapeutic strategy for chemoimmunotherapy of solid tumors.

Diabetic nephropathy (DN) is a common complication of diabetes. Yishen capsule, composed of Chinese herbs, improves the clinical outcome in DN patients. However, its therapeutic potential and underlying mechanisms require further elucidation. Hence, our study aimed to investigate the underlying mechanisms and therapeutic potential of Yishen capsule in DN. Streptozotocin-induced DN rats were treated with Yishen capsules (1.25 g/kg/day) for 8 weeks. Then, blood glucose and urine protein levels were measured. Hematoxylin and eosin staining and western blot assays were used to examine the histologic changes and gene expression, respectively, in kidney samples. Mouse podocytes were treated with rat serum containing Yishen capsule and transmission electron microscopy was used to examine autophagosome formation. Cell counting kit-8 assay was performed to examine cell proliferation. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were conducted to detect changes in gene expression. The localization of SIRT1 was examined in the podocytes using immunocytofluorescence assay. We found that Yishen capsule relieved pathological changes, decreased urine protein, increased SIRT1, LC3-II, and Beclin-1 expression, and reduced acetylated NF-κB p65 expression in vivo. In addition, rat serum containing Yishen capsule showed improved podocyte proliferation, promoted the mRNA and protein levels of LC3-II and Beclin-1, and induced nuclear translocation of SIRT1. Furthermore, it increased SIRT1 expression and decreased mRNA level of NF-κB in the serum. SIRT1 inhibitor increased the mRNA level of NF-κB. Our data suggests that Yishen capsule improves DN by promoting podocyte autophagy via the SIRT1/NF-κB pathway.

Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer’s disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 µM; 15j, eqBChE IC50 = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.

Gambogic acid (GA) is a naturally derived potent anticancer agent with extremely poor biocompatibility. In the present study, a novel of redox/pH dual-responsive multifunctional magnetic complex micelle (sPEG/HA/CSO-SS-Hex/Fe3O4/GA), which consisted of a reducible hexadecanol-modified chitosan oligosaccharide polymer micelle (CSO-SS-Hex) coated with hyaluronic acid (HA) and DCA grafted sheddable PEG-PLL (sPEG) copolymers and loaded with gambogic acid (GA) and Fe3O4 nanoparticles were developed for parenteral delivery for the treatment of triple negative breast cancer (TNBC). The ex vivo study showed that the sPEG shielded cationic HA/CSO-SS-Hex/Fe3O4/GA core at physiological pH but quickly shed off to re-expose the core due to its charge reversible property. The sPEG/HA/CSO-SS-Hex/Fe3O4/GA micelles effectively facilitated tumor-targeted GA delivery by HA, which is a targeting ligand for CD44 receptor of TNBC cells, meanwhile increase GA uptake at the acidic condition but diminished the drug uptake at neutral pH. The in vitro cellular uptake study and in vivo biodistribution and antitumor activity of the formulations were determined, all results showed that the complex micelle enhanced TNBC tumor cellular uptake and fast drug release due to the combined effect of magnet targeting, CD44 receptor-mediated internalization and redox/pH dual-responsive drug release. Hence, tumor-targeted delivery of GA with redox/pH dual-responsive multifunctional magnetic complex micelle sPEG/HA/CSO-SS-Hex/Fe3O4/GA might have potential implications for the chemotherapy of TNBC.