Studies of Anticancer Activities In Vitro and In Vivo for Butyltin(IV)-Iridium(III) Imidazole-Phenanthroline Complexes with Aggregation-Induced Emission Properties.

Organotin(IV) and iridium(III) complexes have shown good application potential in the field of anticancer; however, the aggregation-caused quenching (ACQ) effect induced by high concentration or dose has limited the research on their targeting and anticancer mechanism. Then, a series of aggregation-induced emission (AIE)-activated butyltin(IV)-iridium(III) imidazole-phenanthroline complexes were prepared in this study. Complexes exhibited significant fluorescence improvement in the aggregated state because of the restricted intramolecular rotation (RIR), accompanied by an absolute fluorescence quantum yield of up to 29.2% (IrSn9). Complexes demonstrated potential in vitro antiproliferative and antimigration activity against A549 cells, following a lysosomal-mitochondrial apoptotic pathway. Nude mouse models further confirmed that complexes had favorable in vivo antitumor and antimigration activity in comparison to cisplatin. Therefore, butyltin(IV)-iridium(III) imidazole-phenanthroline complexes possess the potential as potential substitutes for platinum-based drugs.

Predictive value of serum soluble ST2 in adult patients undergoing cardiac surgery for acute kidney injury.

INTRODUCTION: Cardiac surgery is related to an increased risk of postoperative acute kidney injury (AKI). Serum soluble ST2 (sST2) is highly predictive of several cardiovascular diseases and may also be involved in renal injury. This study explored the relationship between serum sST2 levels measured at ICU admission and the development of AKI after cardiac surgery. METHODS: We prospectively conducted an investigation on consecutive patients who underwent cardiac surgery. sST2 was immediately measured at ICU admission. The relationship between the levels of sST2 and the development of AKI was explored using stepwise logistic regression. RESULTS: Among the 500 patients enrolled, AKI was observed in 207 (41%) patients. Serum sST2 levels in AKI patients were higher than those without AKI (61.46 ng/ml [46.52, 116.25] versus 38.91 ng/ml [28.74, 50.93], P < 0.001). Additionally, multivariable logistic regression analysis showed that as progressively higher tertiles of serum sST2, the odds ratios (ORs) of AKI gradually increased (adjusted ORs of 1.97 [95% CI, 1.13-3.45], and 4.27 [95% CI, 2.36-7.71] for tertiles 2 and 3, respectively, relative to tertile 1, P < 0.05). The addition of sST2 further improved reclassification (P < 0.001) and discrimination (P < 0.001) over the basic model, which included established risk factors. CONCLUSION: Serum sST2 levels at ICU admission were associated with the development of postoperative AKI and improved the identification of AKI after cardiac surgery.

Design and anticancer behaviour of cationic/neutral half-sandwich iridium(III) imidazole-phenanthroline/phenanthrene complexes.

Considerable attention has been devoted to the exploration of organometallic iridium(III) (IrIII) complexes for their potential as metallic anticancer drugs. In this study, twelve half-sandwich IrIII imidazole-phenanthroline/phenanthrene complexes were prepared and characterized. Complexes exhibited promising in-vitro anti-proliferative activity, and some are obviously superior to cisplatin towards A549 cells. These complexes possessed suitable fluorescence, and a non-energy-dependent uptake pathway was identified, subsequently leading to their accumulation in the lysosome and the lysosomal damage. Additionally, complexes could inhibit the cell cycle (G1-phase) and catalyze intracellular NADH oxidation, thus substantiating the elevation of intracellular reactive oxygen species (ROS) level, which confirming the oxidative mechanism. Western blotting further confirmed that complexes could induce A549 cell apoptosis through the lysosomal-mitochondrial anticancer pathway, which was inconsistent with cisplatin. In summary, these complexes offer fresh concepts for the development of organometallic non­platinum anticancer drugs.

Ferrocene-modified half-sandwich iridium(III) and ruthenium(II) propionylhydrazone complexes and anticancer application.

Ferrocene, ruthenium(II) and iridium(III) organometallic complexes, potential substitutes for platinum-based drugs, have shown good application prospects in the field of cancer therapy. Therefore, in this paper, six ferrocene-modified half-sandwich ruthenium(II) and iridium(III) propionylhydrazone complexes were prepared, and the anticancer potential was evaluated and compared with cisplatin. These complexes showed potential in-vitro anti-proliferative activity against A549 cancer cells, especially for Ir-based complexes, and showing favorable synergistic anticancer effect. Meanwhile, these complexes showed little cytotoxicity and effective anti-migration activity. Ir3, the most active complex (ferrocene-appended iridium(III) complex), could accumulate in the intracellular mitochondria, disturb the cell cycle (S-phase), induce the accumulation of reactive oxygen species, and eventually cause the apoptosis of A549 cells. Then, the design of these complexes provides a good structural basis for the multi-active non­platinum organometallic anticancer complexes.

The anticancer application of half-sandwich iridium(III) ferrocene-thiosemicarbazide Schiff base complexes.

Ferrocenyl derivatives and organometallic iridium(III) complexes have been prospective substitutes for platinum-based anticancer drugs. Eight half-sandwich iridium(III) ferrocene-thiosemicarbazide (Fc-TSC) Schiff base anticancer complexes were prepared in this study. These complexes displayed a dimeric structure and exhibited a particular fluorescence due to the "enol" orientation of the TSC pro-ligand. An energy-dependent pathway of the uptake mechanism was ascertained, which ended in the lysosome and led to lysosome damage and apoptosis. Flow cytometry confirmed that the complexes could block the cell cycle (G1 phase) and improve the levels of intracellular reactive oxygen species, indicating an anticancer mechanism of oxidation. Then, a lysosomal-mitochondrial anticancer pathway was verified through western blotting. In vivo toxicity assays confirmed that these complexes showed better anti-migration ability and less toxicity in comparison to cisplatin. Thus, these complexes provide a new strategy for the design of non-platinum organometallic anticancer drugs.

Configurationally regulated half-sandwich iridium(III)-ferrocene heteronuclear metal complexes: Potential anticancer agents.

Half-sandwich iridium(III) (IrIII) complexes and ferrocenyl (Fc) derivatives are becoming the research hotspot in the field of anticancer because of their good bioactivity and unique anticancer mechanism different from platinum-based drugs. Then, a series of half-sandwich IrIII-Fc pyridine complexes have been prepared through the structural regulation in this study. The incorporation of half-sandwich IrIII complex with Fc unit successfully improves their anticancer activity, and the optimal performance (IrFc5) is almost 3-fold higher than that of cisplatin against A549 cells, meanwhile, which also shows better anti-proliferative activity against A549/DDP cells. Complexes can aggregate in the intracellular lysosome of A549 cells and induce lysosomal damage, disrupt the cell cycle, increase the level of intracellular reactive oxygen species, and eventually lead to cell apoptosis. Half-sandwich IrIII-Fc heteronuclear metal complexes possess a different anticancer mechanism from cisplatin, which can serve as a potential alternative to platinum-based drugs and show a good application prospect.

In Vitro and In Vivo Antitumor Assay of Mitochondrially Targeted Fluorescent Half-Sandwich Iridium(III) Pyridine Complexes.

Half-sandwich iridium(III) complexes show potential value in the anticancer field. However, complexes with favorable luminescence performance are rare, which limits further investigation of the anticancer mechanism. In this paper, 10 triphenylamine-modified fluorescent half-sandwich iridium(III) pyridine complexes {[(η5-Cpx)Ir(L)Cl2]} (Ir1-Ir10) were prepared and showed potential antiproliferative activity, effectively inhibiting the migration of A549 cells. Ir6, showing the best activity among these complexes, exhibited excellent fluorescence performance (absolute fluorescence quantum yield of 15.17%) in solution. Laser confocal detection showed that Ir6 followed an energy-dependent cellular uptake mechanism, specifically accumulating in mitochondria (Pearson co-localization coefficient of 0.95). A Western blot assay further confirmed the existence of a mitochondrial apoptotic channel. Additionally, Ir6 could arrest the cell cycle at the G2/M phase, catalyze NADH oxidation, reduce the mitochondrial membrane potential, induce an increase in the level of intracellular reactive oxygen species, and exhibit a mechanism of oxidation. An in vivo antitumor assay confirmed that Ir6 can effectively inhibit tumor growth and is safer than cisplatin.

Mitochondrial targeting half-sandwich iridium(III) and ruthenium(II) dppf complexes and in vitro anticancer assay.

Considering the potential application of half-sandwich and ferrocenyl-containing organometallic complexes in the area of anticancer, four half-sandwich iridium(III) (IrIII) and ruthenium(II) (RuII) diphenylphosphino ferrocene (dppf) complexes were prepared in this study. Complexes showed favorable anti-proliferation activity towards A549 cell lines compared to cisplatin, meanwhile, which could effectively inhibit cell migration. These complexes followed an energy dependence uptake mechanism, effectively accumulated in mitochondria with a Pearson's Colocalization Coefficient (PCC) of 0.77, decreased the mitochondrial membrane potential, induced a surge of reactive oxygen species, disturbed cell cycle, and eventually led to apoptosis. Western blot assay further confirmed that these complexes induced apoptosis following a mitochondrial pathway. Above all, half-sandwich IrIII and RuII dppf complexes show the prospect of becoming a new multifunctional therapeutic platform for mitochondrial targeted imaging and anticancer drugs.

Identification of RUNX1 and IFNGR2 as prognostic-related biomarkers correlated with immune infiltration and subtype differentiation of low-grade glioma.

Immune cell infiltration occurs in the tumor microenvironment (TME) and influences cancer progression through interaction with tumor cells. Runt-related transcription factors (RUNXs), RUNX1-3, are the master regulators of development and differentiation and are all important to the development of immune cells. However, the role of RUNXs in the immune cells of TME remains unclear. In this study, we first used online related databases and related LGG data from TCGA and CGGA to conduct bioinformatics analysis, which confirmed that RUNXs were significantly and positively correlated with immune infiltration in multiple tumors, especially in low-grade glioma (LGG) and there was the highest correlation between RUNXs and the progress and prognosis of LGG. Furthermore, the functional enrichment analysis revealed that RUNXs might be involved in the inflammatory and immune responses of the biological processes, and RUNXs were tightly associated with the multiple immune checkpoint molecules. Subsequent results confirmed that RUNX1, as an independent prognostic factor for LGG, may target interferon-gamma receptor 2 (IFNGR2) to regulate glioma cell proliferation, invasion, and migration. Besides, we also found that the expression levels of RUNX1 and IFNGR2 were significantly reduced, and their correlation was enhanced in the IDH-mutant subtype. Patients with a high expression of RUNX1 and/or IFNGR2 (HH/H) in the IDH-mutant subtype showed poorer prognosis and significantly increased infiltration of M2 macrophages. This finding implied the possible key role of RUNX1 in the differentiation of IDH mutant subtypes as well as in the formation of tumor microenvironment (TME) infiltration signatures by monitoring IFNGR2.

Fluorescent COFs with a Highly Conjugated Structure for Combined Starvation and Gas Therapy.

Covalent organic frameworks (COFs) show great potential in biomedicine, but the synthesis of fluorescent ones with a highly conjugated structure in mild conditions remains a challenge. Herein, we reported a facile method to synthesize a nanosized, highly conjugated, and N-enriched COF material with bright fluorescence and further integrated it as a novel nanoplatform for efficient cancer starvation/gas therapy. High surface area and a porous structure endowed COFs with large loading capacity for both glucose oxidase and l-arginine, while conjugated monomer and N-doping guaranteed bright fluorescence and relatively strong interactions between loaded cargos. Well-designed size allowed easy cell uptake of drug-loaded COFs, which finally resulted in a highly efficient starvation therapy by consuming large amounts of glucose in cancer cells. H2O2, the byproduct during glucose consumption, was made full use of oxidizing l-arginine to generate toxic NO. This constructed combined starvation and gas therapy and exhibited emerging antimigration performance. Both in vitro and in vivo experiments confirmed an excellent cancer therapeutic effect than a single therapy, and the novel therapeutic platform showed good biocompatibility. Detailed mechanism study demonstrated that cell apoptosis and lysosomal damage contributed most to the synergistic treatment. Our study developed a new strategy to synthesize highly conjugated COFs with fluorescence and reported the potential applications in cancer therapy.

Anticancer application of ferrocene appended configuration-regulated half-sandwich iridium(III) pyridine complexes.

Ferrocenyl derivatives and half-sandwich iridium(III) complexes have received extensive attention in the field of anticancer. In this paper, series of configuration-controlled ferrocene-modified half-sandwich iridium(III) pyridine complexes were prepared. The combination of half-sandwich iridium(III) complexes and ferrocenyl unit successfully improved the anticancer activity of these complexes, especially for trans-configurational one towards A549 cells, and the best-performing (FeIr5) was almost 3.5 times more potent than that of cisplatin. In addition, these complexes could inhibit the migration of A549 cells. Complexes can accumulate in intracellular lysosomes (PCC: >0.75), induce lysosomal damage, disturb the cell circle, decrease the mitochondrial membrane potential, improve the intracellular reactive oxygen species (ROS) levels, and eventually lead to apoptosis. Meanwhile, complexes could bind to serum protein following a static quenching mechanism and transport through it. Then, ferrocene-modified half-sandwich iridium(III) pyridine complexes hold the promise as potential organometallic anticancer agents for further investigation.

Novel GIRlncRNA Signature for Predicting the Clinical Outcome and Therapeutic Response in NSCLC.

Background: Non-small cell lung cancer (NSCLC) is highly malignant with driver somatic mutations and genomic instability. Long non-coding RNAs (lncRNAs) play a vital role in regulating these two aspects. However, the identification of somatic mutation-derived, genomic instability-related lncRNAs (GIRlncRNAs) and their clinical significance in NSCLC remains largely unexplored. Methods: Clinical information, gene mutation, and lncRNA expression data were extracted from TCGA database. GIRlncRNAs were screened by a mutator hypothesis-derived computational frame. Co-expression, GO, and KEGG enrichment analyses were performed to investigate the biological functions. Cox and LASSO regression analyses were performed to create a prognostic risk model based on the GIRlncRNA signature (GIRlncSig). The prediction efficiency of the model was evaluated by using correlation analyses with mutation, driver gene, immune microenvironment contexture, and therapeutic response. The prognostic performance of the model was evaluated by external datasets. A nomogram was established and validated in the testing set and TCGA dataset. Results: A total of 1446 GIRlncRNAs were selected from the screen, and the established GIRlncSig was used to classify patients into high- and low-risk groups. Enrichment analyses showed that GIRlncRNAs were mainly associated with nucleic acid metabolism and DNA damage repair pathways. Cox analyses further identified 19 GIRlncRNAs to construct a GIRlncSig-based risk score model. According to Cox regression and stratification analyses, 14 risk lncRNAs (AC023824.3, AC013287.1, AP000829.1, LINC01611, AC097451.1, AC025419.1, AC079949.2, LINC01600, AC004862.1, AC021594.1, MYRF-AS1, LINC02434, LINC02412, and LINC00337) and five protective lncRNAs (LINC01067, AC012645.1, AL512604.3, AC008278.2, and AC089998.1) were considered powerful predictors. Analyses of the model showed that these GIRlncRNAs were correlated with somatic mutation pattern, immune microenvironment infiltration, immunotherapeutic response, drug sensitivity, and survival of NSCLC patients. The GIRlncSig risk score model demonstrated good predictive performance (AUCs of ROC for 10-year survival was 0.69) and prognostic value in different NSCLC datasets. The nomogram comprising GIRlncSig and tumor stage exhibited improved robustness and feasibility for predicting NSCLC prognosis. Conclusion: The newly identified GIRlncRNAs are powerful biomarkers for clinical outcome and prognosis of NSCLC. Our study highlights that the GIRlncSig-based score model may be a useful tool for risk stratification and management of NSCLC patients, which deserves further evaluation in future prospective studies.

Hub genes associated with immune cell infiltration in breast cancer, identified through bioinformatic analyses of multiple datasets.

OBJECTIVE: The aim of this study was to identify hub genes associated with immune cell infiltration in breast cancer through bioinformatic analyses of multiple datasets. METHODS: Nonparametric (NOISeq) and robust rank aggregation-ranked parametric (EdgeR) methods were used to assess robust differentially expressed genes across multiple datasets. Protein-protein interaction network, GO, KEGG enrichment, and sub-network analyses were performed to identify immune-associated hub genes in breast cancer. Immune cell infiltration was evaluated with the CIBERSORT, XCELL, and TIMER methods. The association between the hub gene-based risk signature and survival was determined through Kaplan-Meier survival analysis, multivariate Cox analysis, and a nomogram with external verification. RESULTS: We identified 163 robust differentially expressed genes in breast cancer through applying both nonparametric and parametric methods to multiple GEO (n = 2,212) and TCGA (n = 1,045) datasets. Integrated bioinformatic analyses further identified 10 hub genes: CXCL10, CXCL9, CXCL11, SPP1, POSTN, MMP9, DPT, COL1A1, ADAMDEC1, and RGS1. The 10 hub-gene-based risk signature significantly correlated with the prognosis of patients with breast cancer. Moreover, these hub genes were strongly associated with the extent of infiltration of CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and myeloid dendritic cells into breast tumors. CONCLUSIONS: Integrated analyses of multiple databases led to the discovery of 10 robust hub genes that together may serve as a risk factor characteristic of the immune microenvironment in breast cancer.

5-HT2B-mediated serotonin activation in enterocytes suppresses colitis-associated cancer initiation and promotes cancer progression.

Rationale: Serotonin (5-hydroxytryptamine, 5-HT) is generally considered to be involved in colitis-associated cancer (CAC), but previous research has yielded inconsistent results regarding the effect of 5-HT on CAC. 5-HT2B is one of the receptors of 5-HT, and the receptor is expressed in intestinal epithelial cells (IECs). However, the functions of 5-HT2B in CAC remain unclear. Our work demonstrates the variable functions of 5-HT/5-HT2B signaling in the initiation and progression of CAC in mice. Methods: We constructed two types of mutant mice homozygous knockout of Htr2b, the gene encoding 5-HT2B, in IECs (Htr2bΔIEC and Htr2bΔIEC-ER) to study the role of 5-HT2B in AOM/DSS-induced CAC model. Inflammation was measured using the body weight, colon length, and colitis severity score, and by histologic analysis of colon tissues. Tumor severity was assessed by tumor quantity, load, and histologic analysis of colon tumor tissues. Results: In Htr2bΔIEC mice, AOM/DSS induced an enhancement of colitis and tumor severity. This process was due to the inhibition of TGF-ß/SMAD signaling pathway and activation of IL-6/STAT3 signaling pathway. IL-6 antibody treatment reversed the stimulating effect of Htr2b deletion on tumorigenesis. However, tumor severity decreased in Htr2bΔIEC-ER mice injected with tamoxifen on day 48 of AOM/DSS treatment. Knockout Akt1 eliminated the function of 5-HT in promoting tumor cells. Conclusion: Our work elucidates 5-HT/5-HT2B/TGF-ß signaling as a critical tumor suppressing axis during CAC initiation but as a promoter of cancer progression in the late-stage of CAC. Our findings provide a new understanding of the role of 5-HT in the initiation and progression of CAC, offering a new perspective on the long-standing debate on whether the 5-HT signal promotes or inhibits tumors.

Lysosomal Targeted Cyclometallic Iridium(â ¢) Salicylaldehyde-Coumarin Schiff Base Complexes and Anticancer Application.

Natural coumarin derivatives and cyclometallic iridium (Ⅲ) (IrⅢ) complexes have attracted much attention in the field of anticancer. In this study, six coumarin-modified cyclometallic IrⅢ salicylaldehyde Schiff base complexes ([(ppy)2Ir(O^N)]/[(ppy-CHO)2Ir(O^N)]) were designed and synthesized. Compared with coumarin and IrⅢ complex monomers, target complexes exhibited favorable cytotoxic activity toward A549 and BEAS-2B cells. These complexes could induce extensive apoptosis of A549 cell (late apoptosis), which was represented by the disturbance of cell cycle (G1-phase) and the accumulation of intracellular reactive oxygen species, exhibiting an anticancer mechanism of oxidation. With the help of suitable fluorescence of these complexes, no conflict with the probes, confocal detection confirmed that complexes showed an energy-dependent cellular uptake mechanism and triggered lysosome-mediated apoptosis in A549 cell line. Above all, our findings reveal the design of a lysosomal targeting cyclometallic IrⅢ Schiff base complexes and provide a new idea for the design of integrated drugs for diagnosis and treatment.

Cyclometalated iridium(III) dithioformic acid complexes as mitochondria-targeted imaging and anticancer agents.

Four neutral cyclometalated iridium(III) (IrIII) dithioformic acid complexes ([(ppy)2Ir(S^S)], Ir1-Ir4) were designed and synthesized. Toxicity assay revealed that these complexes showed favorable anticancer activity, especially for human non-small cell lung cancer cells (A549). Ir1 exhibited the best anticancer activity (11.0 ± 0.4 µM) was about twice that of cisplatin, meanwhile, which could availably restrain A549 cells migration. Complexes could target mitochondria, induce a decrease in mitochondrial membrane potential (MMP), result in an increase of intracellular reactive oxygen species (ROS) and disruption of the cell cycle, and ultimately generate apoptosis. Western blotting experiment indicated that complexes could inhibit the expression of B cell CLL/lymphoma-2 protein (Bcl-2), induce the expression of BCL2-associated X protein (Bax) and lead to a massive release of Cytochrome C (Cyt-c), which amplified apoptosis signals by activating downstream pathway to promote apoptosis. All these confirmed the existence of mitochondrial anticancer channels for these complexes. Above all, cyclometalated iridium(III) dithioformic acid complexes possess the prospect of becoming a multifunctional cancer therapeutic platform, including mitochondria-targeted imaging, anti-migration, and anticancer agents.

Preparation and antitumor application of N-phenylcarbazole/triphenylamine-modified fluorescent half-sandwich iridium(III) Schiff base complexes.

Four N-phenylcarbazole/triphenylamine-appended half-sandwich iridium(III) salicylaldehyde Schiff base complexes ([(η5-Cpx)Ir(O^N)Cl]) were prepared and characterized. The complexes exhibited similar antitumor activity to cisplatin and effectively inhibited the migration of tumor cells. Furthermore, the complexes showed favourable hydrolytic activity, while remaining relatively stable in the plasma environment, which facilitated the binding of serum proteins and transport through them. These complexes could decrease the mitochondrial membrane potential, catalyze the oxidation of nicotinamide adenine dinucleotide, induce an increase in intracellular reactive oxygen species (ROS), and eventually result in apoptosis. Aided by their suitable fluorescence property, laser confocal detection showed that the complexes followed an energy-dependent mechanism for their cellular uptake, effectively accumulating in the lysosome and leading to lysosomal damage. In summary, the half-sandwich iridium(III) salicylaldehyde Schiff base complexes could induce lysosomal damage, increase intracellular ROS, and lead to apoptosis, which contributed to their antitumor mechanism of oxidation.

In Vitro and In Vivo of Triphenylamine-Appended Fluorescent Half-Sandwich Iridium(III) Thiosemicarbazones Antitumor Complexes.

Half-sandwiched structure iridium(III) complexes appear to be an attractive organometallic antitumor agents in recent years. Here, four triphenylamine-modified fluorescent half-sandwich iridium(III) thiosemicarbazone (TSC) antitumor complexes were developed. Because of the "enol" configuration of the TSC ligands, these complexes formed a unique dimeric configuration. Aided by the appropriate fluorescence properties, studies found that complexes could enter tumor cells in an energy-dependent mode, accumulate in lysosomes, and result in the damage of lysosome integrity. Complexes could block the cell cycle, improve the levels of intrastitial reactive oxygen species, and lead to apoptosis, which followed an antitumor mechanism of oxidation. Compared with cisplatin, the antitumor potential in vivo and vitro confirmed that Ir4 could effectively inhibit tumor growth. Meanwhile, Ir4 could avoid detectable side effects in the experiments of safety evaluation. Above all, half-sandwich iridium(III) TSC complexes are expected to be an encouraging candidate for the treatment of malignant tumors.

Bmi1 Regulates Wnt Signaling in Hematopoietic Stem and Progenitor Cells.

Polycomb group protein Bmi1 is essential for hematopoietic stem cell (HSC) self-renewal and terminal differentiation. However, its target genes in hematopoietic stem and progenitor cells are largely unknown. We performed gene expression profiling assays and found that genes of the Wnt signaling pathway are significantly elevated in Bmi1 null hematopoietic stem and progenitor cells (HSPCs). Bmi1 is associated with several genes of the Wnt signaling pathway in hematopoietic cells. Further, we found that Bmi1 represses Wnt gene expression in HSPCs. Importantly, loss of ß-catenin, which reduces Wnt activation, partially rescues the HSC self-renewal and differentiation defects seen in the Bmi1 null mice. Thus, we have identified Bmi1 as a novel regulator of Wnt signaling pathway in HSPCs. Given that Wnt signaling pathway plays an important role in hematopoiesis, our studies suggest that modulating Wnt signaling may hold potential for enhancing HSC self-renewal, thereby improving the outcomes of HSC transplantation.

Metastable interface biomimetic synthesis of a smart nanosystem for enhanced starvation/gas therapy.

Glucose oxidase (GOx)-mediated starvation therapy holds great promise in cancer treatment. However, the worse hypoxia conditions result into low therapeutic efficiency, and undegradability of carriers poses potential threats to living bodies. To address this, herein a bioinspired MnO2 nanosystem with controllable surface was developed for highly efficient starvation/gas synergistic enhanced therapy. Biomimetic design and further surface modification unprecedentedly endowed the nanosystem with ultrahigh loading capacity for GOx and l-Arginine (l-Arg) and special selectivity toward cancer cells. Especially, the dissipative O2 during starvation therapy was well replenished by a positive cycle formed by the nanosystem, which continuously reproduced O2 and accelerated glucose consumption. The abundant H2O2 was further used to oxidize l-Arg into nitric oxide to realize gas therapy. In vitro and in vivo testing confirmed that this new treatment effectively blocked the nutrition and energy sources of cells to obtain excellent therapeutic effect. We reported the first experimental item of this nanosystem for inhibiting cancer cell migration. Considering the novel design concept with facile biomimetic methods, effective co-loading of endogenous substances, and good anti-tumor and anti-migration effects, this work provided new theoretical and experimental basis for starvation therapy and inspired people to design more delicate platform for cancer treatment.