Natural Product Quercetin-3-methyl ether Promotes Colorectal Cancer Cell Apoptosis by Downregulating Intracellular Polyamine Signaling.

Dysregulation of cellular metabolism is a key marker of cancer, and it is suggested that metabolism should be considered as a targeted weakness of colorectal cancer. Increased polyamine metabolism is a common metabolic change in tumors. Thus, targeting polyamine metabolism for anticancer therapy, particularly polyamine blockade therapy, has gradually become a hot topic. Quercetin-3-methyl ether is a natural compound existed in various plants with diverse biological activities like antioxidant and antiaging. Here, we reported that Quercetin-3-methyl ether inhibits colorectal cancer cell viability, and promotes apoptosis in a dose-dependent and time-dependent manner. Intriguingly, the polyamine levels, including spermidine and spermine, in colorectal cancer cells were reduced upon treatment of Quercetin-3-methyl ether. This is likely resulted from the downregulation of SMOX, a key enzyme in polyamine metabolism that catalyzes the oxidation of spermine to spermidine. These findings suggest Quercetin-3-methyl ether decreases cellular polyamine level by suppressing SMOX expression, thereby inducing colorectal cancer cell apoptosis. Our results also reveal a correlation between the anti-tumor activity of Quercetin-3-methyl ether and the polyamine metabolism modulation, which may provide new insights into a better understanding of the pharmacological activity of Quercetin-3-methyl ether and how it reprograms cellular polyamine metabolism.

The upregulation of peripheral blood polyamine metabolites spermidine and spermine in children with hand, foot, mouth disease is related to enterovirus 71 capsid protein VP1, but not VP4.

Background: Hand, foot, and mouth disease (HFMD) is a common viral childhood illness caused most commonly by enterovirus 71 (EV71) and coxsackievirus A16. The pathogenesis of EV71 has been extensively studied, and the regulation of the host immune response is suspected to aggravate the serious complications induced by EV71. Our previous research showed that EV71 infection significantly increased the release of circulating interleukin (IL)-6, IL-10, IL-13, and IL-27. Notably, these cytokines are related to the EV71 infection risk and clinical stage. Polyamines are compounds that are ubiquitous in mammalian cells and play a key role in various cellular processes. Several studies have shown that targeting polyamine metabolic pathways can reduce infections caused by viruses. However, the significance of polyamine metabolism in EV71 infection remains largely unknown. Methods: Serum samples from 82 children with HFMD and 70 healthy volunteers (HVs) were collected to determine the polyamine metabolites spermidine (SPD) and spermine (SPM), and IL-6 levels. In addition, peripheral blood mononuclear cells (PBMCs) were treated with EV71 viral protein 1 (VP1) and EV71 VP4, and the cells and supernatant were then collected to analyze the expression of polyamine metabolism-related enzymes by western blot. The data were analyzed using GraphPad Prism 7.0 software (USA). Results: The serum polyamine metabolites SPD and SPM were elevated in the HFMD patients, especially in the EV71-infected children. Further, a positive correlation was found between serum SPD and IL-6 levels in the EV71-infected children. We also found that the upregulation of peripheral blood polyamine metabolites in the EV71-infected HFMD children was related to EV71 capsid protein VP1, but not VP4. VP1 may promote the expression of polyamine metabolism-related enzymes and promote the production of polyamine metabolites, thereby upregulating the SPD/nuclear factor kappa B/IL-6 signaling pathway. However, VP4 has the opposite effect in this process. Conclusions: Our results suggest that EV71 capsid protein may regulate the polyamine metabolic pathways of infected cells in a variety of ways. This study provides insights into the mechanism of EV71 infection and polyamine metabolism and has good reference value for the development of EV71 vaccine.

The role of polyamine metabolism in remodeling immune responses and blocking therapy within the tumor immune microenvironment.

The study of metabolism provides important information for understanding the biological basis of cancer cells and the defects of cancer treatment. Disorders of polyamine metabolism is a common metabolic change in cancer. With the deepening of understanding of polyamine metabolism, including molecular functions and changes in cancer, polyamine metabolism as a new anti-cancer strategy has become the focus of attention. There are many kinds of polyamine biosynthesis inhibitors and transport inhibitors, but not many drugs have been put into clinical application. Recent evidence shows that polyamine metabolism plays essential roles in remodeling the tumor immune microenvironment (TIME), particularly treatment of DFMO, an inhibitor of ODC, alters the immune cell population in the tumor microenvironment. Tumor immunosuppression is a major problem in cancer treatment. More and more studies have shown that the immunosuppressive effect of polyamines can help cancer cells to evade immune surveillance and promote tumor development and progression. Therefore, targeting polyamine metabolic pathways is expected to become a new avenue for immunotherapy for cancer.

Gingiva-Derived Mesenchymal Stem Cells Attenuate Imiquimod- (IMQ-) Induced Murine Psoriasis-Like Skin Inflammation.

Human gingiva-derived mesenchymal stem cells (GMSCs) are isolated from the gingival propria with promising regenerative, immunomodulatory, and anti-inflammatory properties. Recently, several studies, including ours, have found that GMSCs have the therapeutic potentials of nerve regeneration and skin disorders in various types such as the cell itself, cell-free conditioned medium, or extracellular vesicles (EVs). However, the mechanobiological behavior of GMSCs is closely related to the culture conditions. Therefore, the purpose of this study was to evaluate the function of human GMSCs on imiquimod- (IMQ-) induced murine psoriasis-like skin inflammation in two-dimensional (2D) and three-dimensional (3D) culture conditions. Here, we isolated and characterized GMSCs in 2D and 3D culture conditions and found that GMSCs in 2D and 3D infusion can significantly ameliorate the IMQ-induced murine psoriasis-like skin inflammation, reduce the levels of Th1- and Th17-related cytokines IFN-γ, TNF-α, IL-6, IL-17A, IL-17F, IL-21, and IL-22, and upregulate the percentage of spleen CD25+CD3+ T cells while downregulate the percentage of spleen IL-17+CD3+ T cells. In summary, our novel findings reveal that GMSCs in 2D and 3D infusion may possess therapeutic effects in the treatment of psoriasis.

Beta-1 syntrophin (SNTB1) regulates colorectal cancer progression and stemness via regulation of the Wnt/ß-catenin signaling pathway.

BACKGROUND: Beta-1 syntrophin (SNTB1) is an intracellular scaffold protein that provides a platform for the formation of signal transduction complexes, thereby modulating and coordinating various intracellular signaling events and crucial cellular processes. However, the physiological role of SNTB1 is poorly understood. This study aims to explore the role of SNTB1 in colorectal cancer (CRC) tumorigenesis and progression, with particular focus on SNTB1's expression pattern, clinical relevance, and possible molecular mechanism in CRC development. METHODS: SNTB1 expression was analyzed in both clinical tissues and The Cancer Genome Atlas (TCGA) database. Real-time polymerase chain reaction (PCR), Western blot, and immunohistochemical assays were used to detect the relative mRNA and protein levels of SNTB1. Statistical analysis was performed to examine the correlation between SNTB1 expression and the clinicopathological characteristics of patients with CRC. Bioinformatics gene set enrichment analysis (GSEA), Western blot, luciferase assay, and agonist recovery assays were conducted to evaluate the relevance of SNTB1 and the ß-catenin signaling pathway in CRC. A flow cytometry-based Hoechst 33342 efflux assay was applied to assess the proportion of the side population (SP) within total CRC cells. RESULTS: Elevated levels of SNTB1 were identified in CRC tissues and cell lines. The elevation of SNTB1 was positively correlated with the degree of malignancy and poor prognosis in CRC. We further revealed that, by modulating the ß-catenin signaling pathway, silencing SNTB1 expression suppressed tumor growth and cancer stemness in vitro, as well as tumorigenesis in vivo. CONCLUSIONS: These findings suggest that SNTB1 plays a crucial role in colorectal tumorigenesis and progression by modulating ß-catenin signaling and the stemness maintenance of cancer cells.

ALKAL1 gene silencing prevents colorectal cancer progression via suppressing Sonic Hedgehog (SHH) signaling pathway.

Anaplastic lymphoma kinase (ALK) has been described in a range of human cancers and is involved in cancer initiation and progression via activating multiple signaling pathways, such as the PI3K-AKT, CRKL-C3G, MEKK2/3-MEK5-ERK5, JAK-STAT and MAPK signal pathways. Recently ALK and LTK ligand 1 (ALKAL1) also named "augmentor-ß" or "FAM150A" is identified as a potent activating ligands for human ALK that bind to the extracellular domain of ALK. However, due to its poor stability, the mechanisms of ALKAL1 underlying the tumor progression in the human cancers including colorectal cancer have not been well documented. Herein, ALKAL1 expression was evaluated by RNA sequencing datasets from The Cancer Genome Atlas (TCGA) of 625 cases colorectal cancer, immunohistochemical analysis of 377 cases colorectal cancer tissues, and Western blotting even Real-time PCR of 10 pairs of colorectal cancer tissues and adjacent normal tissues, as well as 8 colorectal cancer cell lines. Statistical analysis was performed to explore the correlation between ALKAL1 expression and clinicopathological features in colorectal cancer. Univariate and multivariate Cox regression analysis were performed to examine the association between ALKAL1 expression and overall survival. In vitro and in vivo assays were performed to assess the biological roles of ALKAL1 in colorectal cancer. Gene set enrichment analysis (GSEA), Western blotting and luciferase assays were used to identify the underlying signal pathway involved in the tumor progression role of ALKAL1. As a result, we showed that ALKAL1 was upregulated in colorectal cancer tissues and cell lines. Upregulation of ALKAL1 correlated with tumor malignancy and poor prognosis in colorectal cancer. ALKAL1 silencing inhibited tumorigenesis, metastasis and invasion of colorectal cancer cells, and inhibited SHH signaling pathway, which is essential for ALKAL1 induced migration. Our findings reveal a new mechanism by which ALKAL1 participates in colorectal cancer migration and invasion via activating the SHH signaling pathway.

Association between ADAMTS7 TagSNPs and the risk of myocardialinfarction.

PURPOSE OF THE STUDY: Genome-wide association studies have revealed an association of ADAMTS7 polymorphisms with the risk of cardiovascular diseases. Nonetheless, the role of ADAMTS7 polymorphisms on myocardial infarction (MI) risk remains poorly understood. Here, we aim to evaluate the effect of ADAMTS7 tag single nucleotide polymorphisms (SNPs) on individual susceptibility to MI. STUDY DESIGN: Genotyping of the four tagSNPs (rs1994016, rs3825807, rs4380028 and rs7173743) was performed in 232 MI cases and 661 control subjects using PCR-ligase detection reaction (LDR) method. The association of these four tagSNPs with MI risk was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that ADAMTS7 tagSNP rs3825807 exhibited a significant effect on MI risk. Compared with the TT homozygotes, the CT genotype (OR1.93, 95% CI1.30to 2.85, Pc=0.004) and the combined CC/CT genotypes (OR1.70, 95% CI1.16 to 2.50, Pc=0.028) were statistically significantly associated with the increased risk for MI. Further stratified analysis revealed a more significant association with MI risk among older subjects, hypertensives, non-diabetics and patients with hyperlipidaemia. Consistently, the haplotype rs1994016T-rs3825807C containing rs3825807 C allele exhibited increased MI risk (OR1.52, 95% CI1.10 to 2.10, p=0.010). However, we did not detect any association of the other three tagSNPs with MI risk. CONCLUSIONS: Our finding suggest that ADAMTS7 tagSNP rs3825807 contributes to MI susceptibility in the Chinese Han population. Further studies are necessary to confirm the general validity of our findings and to clarify the underlying mechanism for this association.