技术资料

Accumulating data have shown that targeting breast cancer stem cells (CSCs) is an auspicious way for anticancer therapies. This study demonstrated that the antirheumatic drug auranofin is a potent CSC inhibitor with anti-CSC action on breast cancer. This research focused on investigating the effect of auranofin on breast cancer and CSCs and its cellular mechanism. Mammosphere formation,colony formation,levels of CD44 high /CD24 low,and aldehyde dehydrogenase 1 expression in the cells were evaluated after auranofin treatment. The anti-CSC properties of auranofin were further examined by gel shift assay and cytokine detection. Auranofin suppressed cell growth,colony formation,migration,and mammosphere formation and triggered apoptosis in breast cancer. Auranofin decreased the CD44 high /CD24 low - and aldehyde dehydrogenase-expressed subpopulations,as well as the Stat3-DNA interaction and phosphorylated Stat3 level. Auranofin also decreased the extracellular levels of interleukin-8 (IL-8) in the mammosphere media. Auranofin suppressed the Stat3/IL-8 signal and killed CSCs; therefore,it may be a potential target for CSCs. View Publication

Cystic Fibrosis (CF) is a common genetic disease in the United States,resulting from mutations in the Cystic Fibrosis transmembrane conductance regulator (cftr) gene. CFTR modulators,particularly Elexacaftor/Tezacaftor/Ivacaftor (ETI),have significantly improved clinical outcomes for patients with CF. However,many CFTR mutations are not eligible for CFTR modulator therapy due to their rarity. In this study,we report that a patient carrying rare complex CFTR mutations,c.1680-877G>T and c.3067_3072delATAGTG,showed positive clinical outcomes after ETI treatment. We demonstrate that ETI was able to increase the expression of CFTR harboring c.3067_3072delATAGTG in a heterologous system. Importantly,patient-derived nasal epithelial cells in an air–liquid interface (ALI) culture showed improved CFTR function following ETI treatment. These findings supported the initiation of ETI with the patient. Retrospective studies have suggested that the patient has shown small but steady improvement over the past two years in several clinical metrics,including lung function,body mass index (BMI),and sweat chloride levels. Our studies suggest that ETI could be beneficial for patients carrying c.3067_3072delATAGTG. View Publication

Histologic variant (HV) subtypes of bladder cancer are clinically aggressive tumors that are more resistant to standard therapy compared to conventional urothelial carcinoma (UC). Little is known about the transcriptional programs that account for their biological differences. Here we show using single cell analysis that HVs harbor a tumor cell state characterized by expression of MUC16 (CA125),MUC4,and KRT24 . This cell state is enriched in metastases,predicted to be highly resistant to chemotherapy,and linked with poor survival. We also find enriched expression of TM4SF1,a transmembrane protein,in HV tumor cells. Chimeric antigen receptor (CAR) T cells engineered against TM4SF1 protein demonstrated in vitro and in vivo activity against bladder cancer cell lines in a TM4SF1 expression-dependent manner,highlighting its potential as a therapeutic target. Subject terms: Bladder cancer,Tumour biomarkers,Targeted therapies View Publication

CD38,an ecto-enzyme involved in NAD + catabolism,is highly expressed in exhausted CD8 + T cells and has emerged as an attractive target to improve response to immune checkpoint blockade (ICB) by blunting T cell exhaustion. However,the precise role(s) and regulation of CD38 in exhausted T cells and the efficacy of CD38-directed therapeutic strategies in human cancer remain incompletely defined. Here,we show that CD38 + CD8 + T cells are induced by chronic TCR activation and type I interferon stimulation and confirm their association with ICB resistance in human melanoma. Disrupting CD38 restores cellular NAD + pools and improves T cell bioenergetics and effector functions. Targeting CD38 restores ICB sensitivity in a cohort of patient-derived organotypic tumor spheroids from explanted melanoma specimens. These results support further preclinical and clinical evaluation of CD38-directed therapies in melanoma and underscore the importance of NAD + as a vital metabolite to enhance those therapies. View Publication

Nanoplastics (NPs) are emerging environmental pollutants that pose growing concerns due to their potential health risks. However,the effects of inhaled NP exposure during pregnancy on fetal brain development remain poorly understood. In this study,we investigated the impact of maternal exposure to polypropylene nanoplastics (PP-NPs) on fetal brain development and neurobehavioral outcomes in a mouse model and further explored its mechanism in human cerebral organoids. Maternal exposure to PP-NPs significantly impaired neuronal differentiation and proliferation in the fetal cortex. Neurobehavioral assessments revealed significant deficits in offspring following maternal exposure,including impaired spatial memory,reduced motor coordination,and heightened anxiety-like behavior. Furthermore,human brain organoids exposed to PP-NPs exhibited reduced growth and neuronal differentiation,with significant downregulation of key neuronal markers such as TUJ1,MAP2,and PAX6. Transcriptomic analysis identified alterations in gene expression,particularly in neuroactive ligand-receptor interaction pathway. Molecular docking and fluorescence co-localization analysis further suggested CYSLTR1 and PTH1R as key molecular targets of PP-NPs. These findings provide novel insights into the toxicological effects of NPs on the developing brain and emphasize the need for preventive measures to protect fetal neurodevelopment during pregnancy. The online version contains supplementary material available at 10.1186/s12951-025-03561-1. View Publication

Our previous studies demonstrated that FOSL1 promotes glioblastoma (GBM) progression and stemness through pathways such as STAT3 and NF-κB signaling. Recently,we identified that FOSL1 physically interacts with the nuclear E3 ligase TRIM21. This study investigates the role of TRIM21 in GBM,including its interaction with FOSL1,its regulation of FOSL1 transactivation,and its ubiquitination-mediated degradation of tumor suppressor p27. Immunoprecipitation assays were used to evaluate the interactions between TRIM21,FOSL1,and p27. TRIM21 expression was manipulated through overexpression and siRNA-mediated knockdown to assess its effects on p27 levels and ubiquitination. TCGA and CGGA datasets were analyzed to explore correlations between TRIM21 expression,glioma subtypes,and patient survival. Glioma cell proliferation (MTT and colony formation) and invasion (transwell assays) were evaluated following TRIM21 manipulation. Immunohistochemistry on glioma patient tissue microarray (TMA) assessed TRIM21 expression and its association with FOSL1,IDH status,and glioma grade. The role of nuclear TRIM21 in FOSL1 promoter transactivation was analyzed via AP-1 binding sites. TCGA and CGGA revealed that TRIM21 is highly expressed in GBM,particularly in the mesenchymal subtypes,and correlates with poor survival outcomes. Functional assays demonstrated that TRIM21 enhances glioma cell proliferation and invasion. Immunohistochemistry confirmed elevated TRIM21 levels in gliomas,positively correlating with FOSL1 expression and glioma grade,and inversely correlating with IDH1 wild-type status. Mechanistically,TRIM21 physically interacts with FOSL1 and p27,driving tumorigenesis by transactivating FOSL1 via AP-1 binding sites and promoting p27 ubiquitination and degradation. These functions are mediated through TRIM21’s RING domain for p27 degradation and its PRYSPRY domain for FOSL1 regulation. TRIM21 functions as an oncogene in GBM by degrading the tumor suppressor p27 and promoting FOSL1 transactivation. These findings highlight TRIM21 as a promising therapeutic target in GBM. The online version contains supplementary material available at 10.1186/s12964-025-02325-6. View Publication

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of white blood cells. Tyrosine kinase inhibitors (TKIs) are the standard treatment; however,resistance to BCR::ABL1 mutations remains challenging. WEE1,a checkpoint kinase involved in mitosis and DNA repair,is a potential therapeutic target for CML treatment. Ponatinib-resistant CML cells were screened to identify candidates for overcoming drug resistance. The efficacy of the ABL TKI asciminib and the WEE1 inhibitor MK-1775 was evaluated using proliferation and colony formation assays. Public database analysis ( GSE100026 ) assessed WEE1/PKMYT1 expression in CML. In vitro screening identified MK-1775 as a promising therapeutic candidate. WEE1/PKMYT1 expression was elevated in CML cells compared to healthy cells. Both asciminib and MK-1775 inhibited CML cell proliferation after 72 h,with enhanced cytotoxicity when combined. Co-treatment reduced colony formation and induced G2/M arrest,whereas an increase in the sub-G1 cell population indicated apoptosis. Furthermore,the combination treatment disrupted the mitochondrial membrane potential. The combination of asciminib and WEE1 inhibition demonstrated greater efficacy than either drug alone,suggesting a novel therapeutic strategy for treating CML. These findings provide insights into overcoming TKI resistance and highlight a promising approach for future clinical applications. The online version contains supplementary material available at 10.1007/s12672-025-03036-7. View Publication

Immunosenescence describes the gradual remodeling of immune responses,leading to disturbed immune homeostasis and increased susceptibility of older adults for infections,neoplasia and autoimmunity. Decline in cellular immunity is associated with intrinsic changes in the T cell compartment,but can be further pushed by age-related changes in cells regulating T cell immunity. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of T cell activation and function,whose induction requires chronic inflammation. Since aging is associated with low grade inflammation (inflammaging) and increased myelopoiesis,age-induced changes in MDSC induction and function in relation to T cell immunity were analyzed. MDSC numbers and functions were compared between “healthy” young and old adults,who were negatively diagnosed for severe acute and chronic diseases known to induce MDSC accumulation. MDSCs were either isolated from peripheral blood or generated in vitro from blood-derived CD14 cells. Aging was associated with significantly increased MDSC numbers in the monocytic- (M-) and polymorphonuclear (PMN-) MDSC subpopulations. MDSCs could be induced more efficiently from CD14 cells of old donors and these MDSCs inhibited CD3/28-induced T cell proliferation significantly better than MDSCs induced from young donors. Serum factors of old donors supported MDSC induction comparable to serum factors from young donors,but increased immunosuppressive activity of MDSCs was only achieved by serum from old donors. Elevated immunosuppressive activity of MDSCs from old donors was associated with major metabolic changes and increased intracellular levels of neutral and oxidized lipids known to promote immunosuppressive functions. Independent of age,MDSC-mediated suppression of T cell proliferation required direct MDSC– T cell contact. Besides their increased ability to inhibit activation-induced T cell proliferation,MDSCs from old donors strongly shift the immune response towards Th2 immunity and might thereby further contribute to impaired cell-mediated immunity during aging. These results indicate that immunosenescence of innate immunity comprises accumulation and functional changes in the MDSC compartment,which directly impacts T cell functions and contribute to age-associated impaired T cell immunity. Targeting MDSCs during aging might help to maintain functional T cell responses and increase the chance of healthy aging. The online version contains supplementary material available at 10.1186/s12979-025-00524-w. View Publication

Genome‐wide association studies have implicated complement in Alzheimer's disease (AD). The CR1*2 variant of complement receptor 1 (CR1; CD35),confers increased AD risk. We confirmed CR1 expression on glial cells; however,how CR1 variants influence AD risk remains unclear. Induced pluripotent stem cell‐derived microglia and astrocytes were generated from donors homozygous for the common CR1 variants (CR1*1/CR1*1;CR1*2/CR1*2). CR1 expression was quantified and phagocytic activity assessed using diverse targets ( Escherichia coli bioparticles,amyloid β aggregates,and synaptoneurosomes),with or without serum opsonization. Expression of CR1*1 was significantly higher than CR1*2 on glial lines. Phagocytosis for all targets was markedly enhanced following serum opsonization,attenuated by Factor I‐depletion,demonstrating CR1 requirement for C3b processing. CR1*2‐expressing glia showed significantly enhanced phagocytosis of all opsonized targets compared to CR1*1‐expressing cells. CR1 is critical for glial phagocytosis of opsonized targets. CR1*2,despite lower expression,enhances glial phagocytosis,providing mechanistic explanation of increased AD risk. Induced pluripotent stem cell (iPSC)‐derived glia from individuals expressing the Alzheimer's disease (AD) risk variant complement receptor (CR) 1*2 exhibit lower CR1 expression compared to those from donors expressing the non‐risk form CR1*1. The iPSC‐derived glia from individuals expressing the AD risk variant CR1*2 exhibit enhanced phagocytic activity for opsonized bacterial particles,amyloid‐β aggregates and human synaptoneurosomes compared to those from donors expressing the non‐risk form CR1*1. We suggest that expression of the CR1*2 variant confers risk of AD by enhancing the phagocytic capacity of glia for opsonized targets. View Publication

Cell therapy is promising for heart failure treatment,with growing interest in cardiovascular progenitor cells (CPCs) from pluripotent stem cells. A major challenge is managing the immune response,due to their allogeneic source. Regulatory T cells (Treg) offer an alternative to pharmacological immunosuppression by inducing immune tolerance. This study assesses whether Treg therapy can mitigate the xeno-immune response,improving cardiac outcomes in a mouse model of human CPC intramyocardial transplantation. CPCs stimulated immune responses in allogeneic and xenogeneic settings,causing proliferation in T cell subsets. Tregs showed immunosuppressive effects on T lymphocyte populations when co-cultured with CPCs. Post infarction,CPCs were transplanted intramyocardially into an immune-competent mouse model 3 weeks after myocardial infarction. Human or murine Tregs were intravenously administered on transplantation day and three days later. Control groups received CPCs without Tregs or saline (PBS). CPCs with Tregs improved LV systolic function in three weeks,linked to reduced myocardial fibrosis and enhanced angiogenesis. This was accompanied by decreased splenocyte NK cell populations and pro-inflammatory cytokine levels in cardiac tissue. Treg therapy with CPC transplantation enhances cardiac functional and structural outcomes in mice. Though it does not directly avert graft rejection,it primarily affects NKG2D+ cytotoxic cells,indicating systemic immune modulation and remote heart repair benefits. View Publication

This study focuses on improving the identification of chicken primordial germ cells (PGCs),which are vital for genetic transmission and biotechnological applications. Traditional markers like SSEA1 and CVH have limitations—SSEA1 lacks specificity,and CVH is intracellular. A monoclonal antibody was generated by injecting chicken PGCs into mice,producing one that specifically binds to PGCs and decreases with cell differentiation. Mass spectrometry identified its target as the MYH9 protein. The resulting αMYH9 antibody effectively labels PGCs at various developmental stages,offering a valuable tool for isolating viable PGCs and advancing avian genetics,agriculture,and biotechnology. View Publication

Chronic myeloid leukemia (CML) is a leading example of a malignancy where a molecular targeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosine kinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We have recently identified miR-185 as a predictive biomarker where reduced expression in CD34 + treatment-naïve CML cells was associated with TKI resistance. We have also identified PAK6 as a target gene of miR-185 that was upregulated in CD34 + TKI-nonresponder cells. However,its role in regulating TKI resistance remains largely unknown. In this study,we specifically targeted PAK6 in imatinib (IM)-resistant cells and CD34 + stem/progenitor cells from IM-nonresponders using a lentiviral-mediated PAK6 knockdown strategy. Interestingly,the genetic and pharmacological suppression of PAK6 significantly reduced proliferation and increased apoptosis in TKI-resistant cells. Cell survivability was further diminished when IM was combined with PAK6 knockdown. Importantly,PAK6 inhibition in TKI-resistant cells induced cell cycle arrest in the G2-M phase and cellular senescence,accompanied by increased levels of DNA damage-associated senescence markers. Mechanically,we identified a PAK6-mediated MDM2-p21 axis that regulates cell cycle arrest and senescence. Thus,PAK6 plays a critical role in determining alternative cell fates in leukemic cells,and targeting PAK6 may offer a therapeutic strategy to selectively eradicate TKI-resistant cells. View Publication