Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus.

In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett's oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63+KRT5+KRT7+) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett's metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett's oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+KRT5+KRT7+ basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett's oesophagus.

Research and practice of the BOPPPS teaching model based on the OBE concept in clinical basic laboratory experiment teaching.

"Clinical basic inspection technology" is one of the essential courses in the medical laboratory profession. Combining the characteristics of the discipline itself, the research and practice of the BOPPPS model based on the OBE concept in clinical basic laboratory experiment teaching are discussed, and the reform of in teaching objectives, teaching contents, and teaching design path is implemented. The "student-centered" teaching process is divided into six stages: before, during, and after class, and the teaching process is continuously improved to achieve the desired teaching effect. Results of the experiment teaching show that the model has improved students' active participation and developed their clinical thinking skills, and more than 95% of students are satisfied with this teaching model.

CRNDE mediates the viability and epithelial-mesenchymal transition of renal cell carcinoma via miR-136-5p.

Long non-coding RNAs (lncRNAs) regulate epithelial-mesenchymal transition (EMT) and the mutual adhesion and development of renal cell carcinoma (RCC). The underlying molecular mechanism of EMT and RCC cells in the treatment of RCC was less reported. In this study, the related functional lncRNA and miRNA in RCC tissues were predicted by bioinformatics analysis and verified by quantitative real-time PCR (qRT-PCR). The RNA interference technology was applied to measure the effects of the predicted lncRNAs and miRNAs on RCC cells. The expressions of EMT-related mRNAs and proteins were determined using qRT-PCR and Western-blot experiments. CRNDE was overexpressed and miR-136-5p was low-expressed in RCC. Upregulation of CRNDE could promote the viability, migration, invasion of RCC, while downregulation of CRNDE produced the opposite effects. Both the upregulation and downregulation of CRNDE alternated the protein expressions related to EMT, while miR-136-5p resulted in the opposite effects on CRNDE. Moreover, the promotive effect of overexpressed CRNDE on RCC cells could be blocked by miR-136-5p mimic. CRNDE can mediate miR-136-5p, promote the development of EMT and RCC cells, showing the potential to serve as a novel biomarker and therapeutic target in RCC treatment.

Targeting SOX2 Protein with Peptide Aptamers for Therapeutic Gains against Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a predominant cancer type in developing countries such as China, where ESCC accounts for approximately 90% of esophageal malignancies. Lacking effective and targeted therapy contributes to the poor 5-year survival rate. Recent studies showed that about 30% of ESCC cases have high levels of SOX2. Herein, we aim to target this transcription factor with aptamer. We established a peptide aptamer library and then performed an unbiased screening to identify several peptide aptamers including P42 that can bind and inhibit SOX2 downstream target genes. We further found that P42 overexpression or incubation with a synthetic peptide 42 inhibited the proliferation, migration, and invasion of ESCC cells. Moreover, peptide 42 treatment inhibited the growth and metastasis of ESCC xenografts in mouse and zebrafish. Further analysis revealed that P42 overexpression led to alternations in the levels of proteins that are important for the proliferation and migration of ESCC cells. Taken together, our study identified the peptide 42 as a key inhibitor of SOX2 function, reducing the proliferation and migration of ESCC cells in vitro and in vivo, and thereby offering a potential therapy against ESCC.

LC-MS/MS method for the determination of erianin in rat plasma: Application to a pharmacokinetic study.

Erianin is one of the bibenzyl ingredients isolated from Dctidrobium chrysotoxum Lindl. In recent years, erianin has attracted attention owing to its antitumor activity. In this study, an LC-MS/MS method was established to measure erianin in rat plasma. Gigantol was used as the internal standard. A Waters Acquity UPLC BEH C18 column was employed for chromatographic separation. The mobile phase consisted of water containing 0.1% formic acid and acetonitrile with a gradient elution at the flow rate of 0.4 ml/min. Selective reaction monitoring mode was used for quantitative analysis of erianin in positive electrospray ionization. In the concentration range of 0.1-1200 ng/ml, erianin in rat plasma was linear with correlation coefficient >0.999. The lowest limit of quantification was 0.1 ng/ml. The intra- and inter-day RSDs were <9.69%, while the RE was in the range of -8.59-11.24%. The mean recovery was >85.37%. Erianin was stable in rat plasma after storage under certain conditions. The validated method was demonstrated to be selective, sensitive and reliable, and has been successfully applied to pharmacokinetic study of erianin in rat plasma. Erianin was rapidly eliminated from rat plasma with a short half-life (〜1.5 h) and low oral bioavailability (8.7%).

Development and stem cells of the esophagus.

The esophagus is derived from the anterior portion of the developmental intermediate foregut, a structure that also gives rise to other organs including the trachea, lung, and stomach. Genetic studies have shown that multiple signaling pathways (e.g. Bmp) and transcription factors (e.g. SOX2) are required for the separation of the esophagus from the neighboring respiratory system. Notably, some of these signaling pathways and transcription factors continue to play essential roles in the subsequent morphogenesis of the esophageal epithelium which undergoes a simple columnar-to-stratified squamous conversion. Reactivation of the relevant signaling pathways has also been associated with pathogenesis of esophageal diseases that affect the epithelium and its stem cells in adults. In this review we will summarize these findings. We will also discuss new data regarding the cell-of-origin for the striated and smooth muscles surrounding the esophagus and how they are differentiated from the mesenchyme during development.

Development of a novel ssDNA aptamer targeting neutrophil gelatinase-associated lipocalin and its application in clinical trials.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker of early diagnosis and prediction for acute kidney injury (AKI). However, the current program for NGAL detection is not extensively applied in clinics due to the high expense of antibodies. Nucleic acid aptamers are single-strand DNAs or RNAs which could bind to targets with high specificity and affinity, and they have been widely used in the diagnosis and therapy for multiple diseases. It is valuable for us to develop a new method for NGAL detection using aptamers instead of antibodies to achieve increased efficiency and decreased cost. METHODS: Nucleic acid aptamers against NGAL were obtained after SELEX process using magnetic beads, and an enzyme-linked aptamer analysis (ELAA), which can be widely used in clinical diagnosis at low cost, were successfully established. The feasibility of ELAA was further validated with urine samples harvested from 43 AKI patients and 30 healthy people. RESULTS: Three candidate aptamers, including NA36, NA42 and NA53, were obtained after 8 rounds of SELEX process with magnetic beads and verified by quantitative polymerase chain reaction (qPCR), and the Kd value of each aptamer was 43.59, 66.55 and 32.52 nM, respectively. Moreover, the linear relationship was consistent at the range of 125-4000 ng/mL, and the detection limit of ELAA assay was 30.45 ng/mL. We also found that NGAL could be exclusively detected with NA53, and no cross-reaction between NA53 and human albumin or globulin occurred, the coefficient of variation (CV) between inner-plate and inter-plate was less than 15%, and the recovery rate was between 80 and 110%. Moreover, the sensitivity and specificity of ELAA assay in this study are 100% and 90%, respectively. Consistently, these results could also diagnose whether the occurrence of AKI in lots of patients, which has been demonstrated with the ELAA method we established after using NA53. CONCLUSIONS: Taken together, NA53, the best candidate aptamer targeting NGAL protein, can be applied in clinical testing.

Mesenchymal stem cells drive paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells via paracrine of neuregulin 1.

We had previously demonstrated that increased expression of ErbB3 is required for ErbB2-mediated paclitaxel resistance in breast cancer cells. In the present study, we have explored the possible role of mesenchymal stem cells (MSCs) in regulating the paclitaxel-sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. We show that human umbilical cord-derived MSCs express significantly higher level of neuregulin-1 as compared with ErbB2/ErbB3-coexpressing breast cancer cells themselves. Coculture or treatment with conditioned medium of MSCs not only decreases the anti-proliferation effect of paclitaxel on ErbB2/ErbB3-coexpressing breast cancer cells, but also significantly inhibits paclitaxel-induced apoptosis. We further demonstrate that this MSCs-drived paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells could be attributed to upregulation of Survivin via paracrine effect of NRG-1/ErbB3/PI-3K/Akt signaling, as either specific knockdown expression of ErbB3, or blocking of downstream PI-3K/Akt signaling, or specific inhibition of Survivin can completely reverse this effect. Moreover, targeted knockdown of NRG-1 expression in MSCs abrogates theirs effect on paclitaxel sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. Taken together, our study indicate that paracrine of NRG-1 by MSCs induces paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells through PI-3K/Akt signaling-dependent upregulation of Survivin. Our findings suggest that simultaneously targeting mesenchymal stem cells in tumor microenvironment may be a novel strategy to overcome paclitaxel resistance in patients with ErbB2/ErbB3-coexpressing breast cancer.

Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal.

BACKGROUND: Metformin (Met) is a widely available diabetic drug and shows suppressed effects on renal cell carcinoma (RCC) metabolism and proliferation. Laboratory studies in RCC suggested that metformin has remarkable antitumor activities and seems to be a potential antitumor drug. But the facts that metformin may be not effective in reducing the risk of RCC in cancer clinical trials made it difficult to determine the benefits of metformin in RCC prevention and treatment. The mechanisms underlying the different conclusions between laboratory experiments and clinical analysis remains unclear. The goal of the present study was to determine whether long-term metformin use can induce resistance in RCC, whether metformin resistance could be used to explain the disaccord in laboratory and clinical studies, and whether the drug valproic acid (VPA), which inhibits histone deacetylase, exhibits synergistic cytotoxicity with metformin and can counteract the resistance of metformin in RCC. METHODS: We performed CCK8, transwell, wound healing assay, flow cytometry and western blotting to detect the regulations of proliferation, migration, cell cycle and apoptosis in 786-O, ACHN and metformin resistance 786-O (786-M-R) cells treated with VPA, metformin or a combination of two drugs. We used TGF-ß, SC79, LY294002, Rapamycin, protein kinase B (AKT) inhibitor to treat the 786-O or 786-M-R cells and detected the regulations in TGF-ß /pSMAD3 and AMPK/AKT pathways. RESULTS: 786-M-R was refractory to metformin-induced antitumor effects on proliferation, migration, cell cycle and cell apoptosis. AMPK/AKT pathways and TGF-ß/SMAD3 pathways showed low sensibilities in 786-M-R. The histone H3 acetylation diminished in the 786-M-R cells. However, the addition of VPA dramatically upregulated histone H3 acetylation, increased the sensibility of AKT and inhibited pSMAD3/SMAD4, letting the combination of VPA and metformin remarkably reappear the anti-tumour effects of metformin in 786-M-R cells. CONCLUSIONS: VPA not only exhibits synergistic cytotoxicity with metformin but also counteracts resistance to metformin in renal cell carcinoma cell. The re-sensitization to metformin induced by VPA in metformin-resistant cells may help treat renal cell carcinoma patients.

SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis.

BACKGROUND: High levels of SOX2 protein are correlated with increased dissemination of breast cancer. However, the underlying molecular mechanisms are not fully understood. METHODS: In this study we investigate the role of SOX2 in breast cancer metastasis using multiple in vitro and in vivo assays including cell culture, shRNA-mediated knockdown, wound healing, colony formation, transwell chamber, xenograft and tail vein injection. Moreover, western blot, immunostaining, microarray and real-time PCR were used to determine the change of protein and miRNA levels. Luciferase assays were also used to evaluate activity which TUSC3 is a target of miR-181a-5p and miR-30e-5p, and the clinical survival relevance was analyzed by Kaplan-Meier analysis. RESULTS: We identified a novel pathway involving SOX2 regulation of microRNAs to control the proliferation and migration of breast cancer cells. shRNA-mediated knockdown of SOX2 inhibits breast cancer cell expansion and migration. More importantly, we found that these changes are accompanied by significant reduction in the levels of two microRNAs, miR-181a-5p and miR-30e-5p. Overexpression of these two microRNAs leads to reduced protein levels of Tumor Suppressor Candidate 3 (TUSC3) in breast cancer cells; mutations of the potential binding sites in the 3'-UTR of TUSC3 abrogate the inhibitory effects of the microRNAs. We further found that upregulation of TUSC3 expression leads to reduced proliferation and migration of breast cancer cells. In human breast cancer samples the levels of TUSC3 protein are inversely correlated with those of SOX2 protein. CONCLUSIONS: Taken together, our work reveals a novel SOX2-mediated regulatory axis that plays critical roles in the proliferation, migration and invasiveness of breast cancer cells. Targeting this axis may provide beneficial effect in the treatment of breast cancer.

Repression of PES1 expression inhibits growth of gastric cancer.

Gastric cancer is one of the leading causes of cancer death worldwide. However, precise molecular mechanisms underlining its development are far from clear. We recently reported that PES1 promoted development of breast cancer and ovarian cancer as an oncogene. In this study, we reported that ablation of endogenous PES1 resulted in significant suppression of cell proliferation and growth and led to cell cycle arrest in G2 or G1 phase, respectively, in two gastric cancer cell lines (AGS and N87) in vitro. Meanwhile, silencing of PES1 obviously decreased expressions of cyclin D1, HIF-1α, and vascular endothelial growth factor (VEGF) expressions and increased p21WAF1 expression. Re-expression of PES1 in these two kinds of PES1 knockdown cells rescued these effects. In vivo, repression of endogenous PES1 expression suppressed gastric tumor growth in nude mice. In addition, 40.7 % (24/59) of gastric cancer tissues showed PES1 expression via immunohistochemical (IHC) staining. However, there were not any positive PES1 stainings in matched adjacent tissues. Our results demonstrated that repression of PES1 changed expressions of some cell proliferation- and angiogenesis-related genes and inhibited gastric cancer growth, and PES1 expression increased in gastric cancer tissues. These results suggest that PES1 may play an important role in development of gastric cancer. PES1 may be a potential target for gastric cancer therapy.

Neutralization of staphylococcal enterotoxin B by an aptamer antagonist.

Staphylococcal enterotoxin B (SEB) is a major virulence factor for staphylococcal toxic shock syndrome (TSS). SEB activates a large subset of the T lymphocytic population, releasing proinflammatory cytokines. Blocking SEB-initiated toxicity may be an effective strategy for treating TSS. Using a process known as systematic evolution of ligands by exponential enrichment (SELEX), we identified an aptamer that can antagonize SEB with nanomolar binding affinity (Kd = 64 nM). The aptamer antagonist effectively inhibits SEB-mediated proliferation and cytokine secretion in human peripheral blood mononuclear cells. Moreover, a PEGylated aptamer antagonist significantly reduced mortality in a "double-hit" mouse model of SEB-induced TSS, established via sensitization with d-galactosamine followed by SEB challenge. Therefore, our novel aptamer antagonist may offer potential therapeutic efficacy against SEB-mediated TSS.

A 23-year bibliometric analysis of the development of global research on hereditary renal carcinoma.

Objectives: Medical research continues to be extensively devoted to investigating the pathogenesis and treatment approaches of hereditary renal cancer. By aspect including researchers, institutions, countries, journals, and keywords, we conduct a bibliometric analysis of the literature pertaining to hereditary renal cancer over the last 23 years. Methods: From the Web of Science Core Collection, we conducted a search for publications published between January 1, 2000 and November 28, 2023. Reviews and original articles were included. Results: A cumulative count of 2,194 publications met the specified criteria for inclusion. The studies of the included articles involved a collective of 2,402 institutions representing 80 countries. Notably, the United States exhibited the highest number of published documents, constituting approximately 45.49% of the total. The preeminent institution in this discipline is the National Cancer Institute (NCI), which maintains a publication volume of 8.98%. In addition to being the most prolific author (125 publications), Linehan WM's works received the highest number of citations (11,985). In a comprehensive count, 803 journals have published related articles. In the top 10 most recent occurrences were the terms "hereditary leiomyomatosis" and "fumarate hydratase." Conclusion: This is the first bibliometric analysis of the literature on hereditary renal cancer. This article offers a thorough examination of the present status of investigations concerning hereditary renal cancer during the previous 23 years.

Treponema pallidum recombinant protein Tp0768 enhances the ability of HUVECs to promote neutrophil chemotaxis through TLR2/ER stress signaling pathway.

Neutrophils are essential cells involved in inflammation. However, the specific mechanism of neutrophil chemotaxis induced by Treponema Pallidum (T. pallidum) remains unknow. In this study, human umbilical vein endothelial cells (HUVECs) were utilized as target cells to investigate the expression levels of chemokines when stimulated with different concentrations of Tp0768(also known as TpN44.5 or TmpA, a T. pallidum infection dependent antigen). The results indicated that Tp0768 treatment enhanced neutrophil chemotaxis in HUVECs, which was closely associated with the expression levels of CXCL1(C-X-C Motif Chemokine Ligand 1), CXCL2(C-X-C Motif Chemokine Ligand 2), and CXCL8(C-X-C Motif Chemokine Ligand 8, also known as interleukin-8). At the same time, the results show that Toll Like Receptor 2 (TLR2) signaling pathway is activated and endoplasmic reticulum stress (ER stress) occurs. Furthermore, the findings revealed that the use of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and Immunoglobulin-Regulated Enhancer 1 (IRE1) inhibitors reduced the expression levels of CXCL1, CXCL2, and CXCL8. Additionally, inhibiting TLR2 significantly decreased the expression levels of ER stress-related proteins (PERK and IRE1), CXCL1, CXCL2, and CXCL8. Consequently, neutrophil chemotaxis was significantly inhibited after treatment with TLR2, PERK, and IRE1 inhibitors. These findings shed light on the role of Tp0768 in enhancing neutrophil chemotaxis in endothelial cells, providing a foundation for further exploration of syphilis pathogenesis and offering a new direction for the diagnosis and treatment of T. pallidum infection.

Aptamers: a promising tool for cancer imaging, diagnosis, and therapy.

Aptamers are a group of molecules, which can specifically bind, track, and inhibit target molecules, comprising DNA aptamers, RNA aptamers, and peptide aptamers. So far, there are much progress about developing novel aptamers and their expansile applications. This prospect systematically introduces the composition and technological evolution of aptamers, and then focuses on the application of aptamers in cancer diagnosis, imaging, and therapy. Following this, we discuss the potential to harness aptamers in discovering the biomarker of stem cells, which is favorable for us to study the normal developmental or abnormal pathological process of tissue and to deliver drugs into target cells or tissues in the future.

PES1 differentially regulates the expression of ERα and ERß in ovarian cancer.

Estrogen exhibits mitogenic activity in early ovarian carcinogenesis and plays an important role in ovarian tumorigenesis. Due to the increased expression of ERα and decreased expression of the ERß, the ratio of ERα and ERß is markedly increased in ovarian cancer. We have recently reported that PES1 regulates the balance of ERα and ERß at the post-transcriptional level in breast cancer. Here, we report that PES1 inversely regulates the expression of ERα and ERß in addition to their transcriptional activities in epithelial ovarian cancer. We found that the ablation of PES1 resulted in the significant downregulation of ERα and estrogen-responsive genes such as cylin D1, HIF-1α and VEGF and the up-regulation of ERß and p21WAF1. Cell proliferation in both tested ovarian cell lines was markedly inhibited and cells were arrested in G2 after PES1 was ablated. Further analysis of clinical samples showed that expression of PES1 correlated positively with ERα expression and negatively with ERß expression. Our results demonstrate that PES1 may play important role in the progression of ovarian cancer by inversely regulating the ERα and ERß expression. PES1 may be a new target for ovarian cancer therapy.

A new labdane diterpene from Vitex negundo.

CONTEXT: Vitex negundo Linn. (Verbenaceae) seeds are pepper substitute and occasionally used as a condiment for edible purposes. The seeds also find use for analgesia, sedation, rheumatism and joint inflammation in folk medicine. OBJECTIVE: To isolate and characterize bioactive constituents from V. negundo seeds. MATERIALS AND METHODS: The ethanol extract of V. negundo seeds was subjected to repeated column chromatography. Chemical structures were elucidated by detailed spectroscopic analyses on the basis of NMR, IR, and MS data. Several pathogenic fungi isolates were employed to evaluate the antifungal activity of the isolated compound. RESULTS: Chemical investigations of the seed extract afforded a new labdane diterpenoid, named negundol (1a + 1b), as an inseparable mixture of two diastereoisomers in a 5:4 ratio. Their structures were identified as (rel 3S, 5S, 8R, 9R, 10S, 13S, 16S)-3-acetoxy-9, 13-epoxy-16-hydroxy-labda-15, 16-olide (1a), and (rel 3S, 5S, 8R, 9R, 10S, 13S, 16R)-3-acetoxy-9, 13-epoxy-16-hydroxy-labda-15, 16-olide (1b). Compound 1 was active as an antifungal agent with MIC80 values in the range of 16-64 µg/mL. DISCUSSION AND CONCLUSION: The presence of compound 1 in V. negundo is of chemotaxonomic significance, since plants under the genus Vitex are chemically characterized with labdane diterpenoids. Compound 1 exhibited potential antifungal activity and may be considered a lead compound for promising antifungal agent.

Applied research on serum protein fingerprints for prediction of Qi deficiency syndrome and phlegm and blood stasis in patients with non-small cell lung cancer.

OBJECTIVE: This study screened serum tumor biomarkers by surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to establish a subset which could be used for the prediction of Qi deficiency syndrome and phlegm and blood stasis in patients with non-small cell lung cancer; and as diagnostic model of Chinese medicine. METHODS: Serum samples from 63 lung cancer patients with Qi deficiency syndrome and phlegm and blood stasis, and 28 lung cancer patients with non-Qi deficiency syndrome and phlegm and blood stasis were analyzed using SELDI-TOF-MS with a PBS II-C protein chip reader. Protein profiles were generated using immobilized metal affinity capture (IMAC3) protein chips. Differentially-expressed proteins were screened. Protein peak clustering and classification analyses were performed using Biomarker Wizard and Biomarker Pattern software packages, respectively. RESULTS: A total of 268 effective protein peaks were detected in the 1,000-10,000 Da molecular range for the 15 serum proteins screened (P<0.05). The decision tree model was M 2284.97, with a sensitivity of 96.2% and a specificity of 66.7%. CONCLUSION: SELDI-TOF-MS techniques, combined with a decision tree model, can help identify serum proteomic biomarkers related to Qi deficiency syndrome and phlegm and blood stasis in lung cancer patients; and the predictive model can be used to discriminate between Chinese medicine diagnostic models of disease.

Supramolecular catalytic nanomedicines based on coordination self-assembly of amino acids for cascade-activated and -amplified synergetic cancer therapy.

Simple biomolecule-based supramolecular nanomedicines hold great promise in cancer therapy, but their clinical translation is greatly hindered by low tumor-specificity and unsatisfactory antitumor performance. Herein, we developed an amino acid basedsupramolecular nanomedicine that could be co-activated by multiple stimuli in tumor tissue to trigger cascade catalytic reactions in situ for synergetic therapy. The supramolecular nanomedicine was developed based on a combination of coordination and hydrophobic noncovalent interactions among amphiphilic amino acids, glucose oxidase (GOx), copper ions, as well as doxorubicin (DOX)-camptothecin (CPT) prodrugs. The cascade reactions including the catalytic oxidation of glucose to generate H2O2, GSH reducing Cu2+ to Cu+, a Fenton-like reaction between H2O2 and Cu+ to produce hydroxyl radicals (˙OH), and ˙OH-triggered rapid release of dual parent drugs were specifically activated in tumor cells. With these cascade reactions, the catalytic-chemo synergetic therapy was realized for high-efficiency tumor suppression.