The scaffold protein AXIN1: gene ontology, signal network, and physiological function.

AXIN1, has been initially identified as a prominent antagonist within the WNT/ß-catenin signaling pathway, and subsequently unveiled its integral involvement across a diverse spectrum of signaling cascades. These encompass the WNT/ß-catenin, Hippo, TGFß, AMPK, mTOR, MAPK, and antioxidant signaling pathways. The versatile engagement of AXIN1 underscores its pivotal role in the modulation of developmental biological signaling, maintenance of metabolic homeostasis, and coordination of cellular stress responses. The multifaceted functionalities of AXIN1 render it as a compelling candidate for targeted intervention in the realms of degenerative pathologies, systemic metabolic disorders, cancer therapeutics, and anti-aging strategies. This review provides an intricate exploration of the mechanisms governing mammalian AXIN1 gene expression and protein turnover since its initial discovery, while also elucidating its significance in the regulation of signaling pathways, tissue development, and carcinogenesis. Furthermore, we have introduced the innovative concept of the AXIN1-Associated Phosphokinase Complex (AAPC), where the scaffold protein AXIN1 assumes a pivotal role in orchestrating site-specific phosphorylation modifications through interactions with various phosphokinases and their respective substrates.

Peptide vaccine from cancer-testis antigen ODF2 can potentiate the cytotoxic T lymphocyte infiltration through IL-15 in non-MSI-H colorectal cancer.

About 85% of patients with colorectal cancer (CRC) have the non-microsatellite instability-high (non-MSI-H) subtype, and many cannot benefit from immune checkpoint blockade. A potential reason for this is that most non-MSI-H colorectal cancers are immunologically "cold" due to poor CD8+ T cell infiltration. In the present study, we screened for potential cancer-testis antigens (CTAs) by comparing the bioinformatics of CD8+ T effector memory (Tem) cell infiltration between MSI-H and non-MSI-H CRC. Two ODF2-derived epitope peptides, P433 and P609, displayed immunogenicity and increased the proportion of CD8+ T effector memory (Tem) cells in vitro and in vivo. The adoptive transfer of peptide pool-induced CTLs inhibited tumor growth and enhanced CD8+ T cell infiltration in tumor-bearing NOD/SCID mice. The mechanistic study showed that knockdown of ODF2 in CRC cells promoted interleukin-15 expression, which facilitated CD8+ T cell proliferation. In conclusion, ODF2, a CTA, was negatively correlated with CD8+ T cell infiltration in "cold" non-MSI-H CRC and was selected based on the results of bioinformatics analyses. The corresponding HLA-A2 restricted epitope peptide induced antigen-specific CTLs. Immunotherapy targeting ODF2 could improve CTA infiltration via upregulating IL-15 in non-MSI-H CRC. This tumor antigen screening strategy could be exploited to develop therapeutic vaccines targeting non-MSI-H CRC.

Identification of natural product 3, 5-diiodotyrosine as APOBEC3B inhibitor to prevent somatic mutation accumulation and cancer progression.

BACKGROUND: The development of cancer is largely dependent on the accumulation of somatic mutations, indicating the potential to develop cancer chemoprevention agents targeting mutation drivers. However, ideal cancer chemoprevention agents that can effectively inhibit the mutation drivers have not been identified yet. METHODS: The somatic mutation signatures and expression analyses of APOBEC3B were performed in patient with pan-cancer. The computer-aided screening and skeleton-based searching were performed to identify natural products that can inhibit the activity of APOBEC3B. 4-nitroquinoline-1-oxide (4-NQO)-induced spontaneous esophageal squamous cell carcinoma (ESCC) and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced spontaneous colon cancer mouse models were conducted to investigate the influences of APOBEC3B inhibitor on the prevention of somatic mutation accumulation and cancer progression. RESULTS: Here, we discovered that the cytidine deaminase APOBEC3B correlated somatic mutations were widely observed in a variety of cancers, and its overexpression indicated poor survival. SMC247 (3, 5-diiodotyrosine), as a source of kelp iodine without side effects, could strongly bind APOBEC3B (KD=65 nM) and effectively inhibit its deaminase activity (IC50=1.69 µM). Interestingly, 3, 5-diiodotyrosine could significantly reduce the clusters of mutations, prevent the precancerous lesion progression, and prolong the survival in 4-NQO-induced spontaneous ESCC and AOM/DSS-induced spontaneous colon cancer mouse models. Furthermore, 3, 5-diiodotyrosine could reduce colitis, increase the proportion and function of T lymphocytes via IL-15 in tumor microenvironment. The synergistic cancer prevention effects were observed when 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade. CONCLUSIONS: This is the first prove-of-concept study to elucidate that the natural product 3, 5-diiodotyrosine could prevent somatic mutation accumulation and cancer progression through inhibiting the enzymatic activity of APOBEC3B. In addition, 3, 5-diiodotyrosine could reduce the colitis and increase the infiltration and function of T lymphocytes via IL-15 in tumor microenvironment. 3, 5-diiodotyrosine combined with PD-1/PD-L1 blockade could elicit synergistic cancer prevention effects, indicating a novel strategy for both prevent the somatic mutation accumulation and the immune-suppressive microenvironment exacerbation.

Fe/N codoped porous graphitic carbon derived from macadamia shells as an efficient cathode oxygen reduction catalyst in microbial fuel cells.

In this study, Fe/N codoped porous graphitic carbon derived from macadamia shells was prepared at different temperatures as cathodic catalysts for microbial fuel cells (MFCs), with K2FeO4 as a bifunctional catalyst for porosity and graphitization. The catalyst prepared at 750 °C (referred to as MSAC-750) showed a large specific surface area (1670.3 m2 g-1), graphite structure, and high pyridine-N and Fe-N X contents. Through the electrochemical workstation test, MSAC-750 shows excellent oxygen reduction reaction (ORR) activity, with an onset potential of 0.172 V and a half-wave potential of -0.028 V (vs. Ag/AgCl) in a neutral medium, and the ORR electron transfer number is 3.89. When applied to the MFCs as cathodic catalysts, a higher maximum power density and voltage of 378.68 mW m-2 and 0.425 V were achieved with the MSAC-750 catalyst and is superior to that of the Pt/C catalyst (300.85 mW m-2 and 0.402 V). In this case, a promising method is hereby established for the preparation of an excellent electrochemical catalyst for microbial fuel cells using inexpensive and easily available macadamia shells.

Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming.

The antioxidant transcription factor NFE2L1 (also called Nrf1) acts as a core regulator of redox signaling and metabolism homeostasis, and thus, its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism remains elusive. Here, we found that loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation and NFE2L1 deficiency could affect the uptake of glucose. Further experiments revealed that glycosylation of NFE2L1 enabled it to sense the energy state. These results indicated that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. The transcriptome, metabolome, and seahorse data further revealed that disruption of NFE2L1 could reprogram glucose metabolism to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, concomitant with mitochondrial damage. Co-expression and Co-immunoprecipitation experiments demonstrated that NFE2L1 could directly interact and inhibit AMPK. Collectively, NFE2L1 functioned as an energy sensor and negatively regulated AMPK signaling through directly interacting with AMPK. The novel NFE2L1/AMPK signaling pathway delineate the mechanism underlying of NFE2L1-related metabolic diseases and highlight the crosstalk between redox homeostasis and metabolism homeostasis.

Extracellular vesicle IL-32 promotes the M2 macrophage polarization and metastasis of esophageal squamous cell carcinoma via FAK/STAT3 pathway.

BACKGROUND: Metastasis is the leading cause of mortality in human cancers, including esophageal squamous cell carcinoma (ESCC). As a pro-inflammatory cytokine, IL-32 was reported to be a poor prognostic factor in many cancers. However, the role of IL-32 in ESCC metastasis remains unknown. METHODS: ESCC cells with ectopic expression or knockdown of IL-32 were established and their effects on cell motility were detected. Ultracentrifugation, Transmission electron microscopy and Western blot were used to verify the existence of extracellular vesicle IL-32 (EV-IL-32). Coculture assay, immunofluorescence, flow cytometry, and in vivo lung metastasis model were performed to identify how EV-IL-32 regulated the crosstalk between ESCC cells and macrophages. RESULTS: Here, we found that IL-32 was overexpressed and positively correlated to lymph node metastasis of ESCC. IL-32 was significantly higher in the tumor nest compared with the non-cancerous tissue. We found that IL-32ß was the main isoform and loaded in EV derived from ESCC cells. The shuttling of EV-IL-32 derived from ESCC cells into macrophages could promote the polarization of M2 macrophages via FAK-STAT3 pathway. IL-32 overexpression facilitated lung metastasis and was positively correlated with the proportion of M2 macrophages in tumor microenvironment. CONCLUSIONS: Taken together, our results indicated that EV-IL-32 derived from ESCC cell line could be internalized by macrophages and lead to M2 macrophage polarization via FAK-STAT3 pathway, thus promoting the metastasis of ESCC. These findings indicated that IL-32 could serve as a potential therapeutic target in patients with ESCC.

Sulfidised nanoscale zerovalent iron-modified pitaya peel-derived carbon for enrofloxacin degradation and swine wastewater treatment: Combination of electro-Fenton and bio-electro-Fenton process.

In this study, a new Fenton system combining electro-Fenton and bio-electro-Fenton (EF-BEF) processes was proposed for ENR degradation and swine wastewater treatment, and pitaya peel-derived carbon modified with sulfidised nanoscale zerovalent iron (SnZVI) was developed as a catalyst for the system. The as-prepared PPC-800 carbon displayed a hierarchical porous structure (693.5 m2/g), abundant oxygen-containing groups, and carbon defects, which endowed it with a good adsorption capacity, high H2O2 generation capacity (151.9 ± 10.5 mg/L) during the EF period, and good power production performance (194.3 ± 12.50 mW/m2) during the BEF period. When modified with SnZVI, despite the decrease in the adsorption capacity and power output (102.05 ± 4.05 mW/m2), the SnZVI@PPC-2 exhibited the best ENR removal performance with that of 98.9 ± 0.2% in the EF period and 86.2 ± 5.6% during the BEF period. An increase in the current intensity and air flow rate promoted ENR degradation. Finally, swine wastewater was treated using the SnZVI@PPC-2 EF-BEF system, and 97.9 ± 1.3% of the TOC was removed using the combined system.

Feedback regulation of antioxidant transcription factor NFE2L1 and immunostimulatory factor 41BBL mediates the crosstalk between oxidative stress and tumor immunity.

Targeting the immune checkpoint to inhibit tumor immune escape, which is one of the fundamental causes of cancer, has become an important strategy for cancer treatment. The molecular mechanism of tumor immune escape involved in the process of spontaneous hepatocellular carcinoma after specifically knocking out NFE2L1, the core regulator of redox homeostasis, in the mouse liver is still unclear. Transcriptome data showed that the immunostimulatory TNFSF9/41BBL was significantly reduced in NFE2L1 knockdown hepatocarcinoma HepG2 cells, and this suggests that 41BBL may be an oxidative stress-responsive immune checkpoint. The results of the promoter activity experiment showed that NFE2L1 can promote 41BBL gene transcription activation through the ARE element in the promoter region. In addition, cell biology experiments have found that overexpression of 41BBL can inhibit cell proliferation and promote senescence. Importantly, reactive oxygen species in cells significantly increased after overexpression of 41BBL, whereas NFE2L1 was inhibited, indicating that 41BBL has the effect of feedback regulating oxidative stress in cells. In conclusion, in this study, the transcriptional activation effect of NFE2L1 on 41BBL and the feedback inhibition relationship of 41BBL on NFE2L1 was clarified. The NFE2L1/41BBL axis might be an important pathway that mediates the crosstalk between oxidative stress and the tumor immune response.