YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling.

The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer. Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis (YTE-17), attributing these effects to the regulation of multiple signaling pathways. However, knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited. In this study, we conducted isobaric tags for relative and absolute quantification (iTRAQ) analysis on intestinal epithelial cells (IECs) exposed YTE-17, both in vitro and invivo, revealing a significant inhibition of the Wnt family member 5a (Wnt5a)/c-Jun N-terminal kinase (JNK) signaling pathway. Subsequently, we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment (TME), specifically focusing on macrophage-mediated T helper 17 (Th17) cell induction in a colitis-associated cancer (CAC) model with Wnt5a deletion. Additionally, we performed the single-cell RNA sequencing (scRNA-seq) on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition, lineage, and functional status of immune mesenchymal cells during different stages of colorectal cancer (CRC) progression. Remarkably, our findings demonstrate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17, leading to the restoration of regulatory T (Treg)/Th17 cell balance in azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Furthermore, we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages. Notably, our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical ß-catenin oncogenic pathway in vivo. Specifically, we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with ß-catenin activity within the TME, involving macrophages and T cells. In summary, our study undergoes the potential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment, thereby mitigating the risk of malignancies.

Latent profiles of academic resilience in undergraduate nursing students and their association with resilience and self-efficacy.

AIM: This study aimed to investigate the heterogeneity of academic resilience among nursing students using latent profile analysis and its associated influencing factors. BACKGROUND: Nursing students experience higher levels of stress compared to their peers in other professions, and the cultivation of academic resilience plays a pivotal role in their ability to effectively cope with this stress. Academic resilience not only facilitates success in the face of academic adversity but also contributes to the promotion of mental well-being among nursing students. However, the current research on the academic resilience of nursing students has predominantly focused on a scale-centered total score approach, disregarding individual variability, and hindering the development to inform personalized interventions for enhancing academic resilience. DESIGN: A cross-sectional study. METHODS: A convenience sampling method was used to collect a total of 644 nursing students from two medical schools in Guangzhou City. The participants were recruited through an online survey conducted from January to March 2023. The questionnaires consisted of a general information form, the Chinese version of the Academic Resilience Scale-30 (C-ARS-30), the 10-item Connor Davidson Resilience Scale (CD-RISC-10), and the General Self-Efficacy Scale (GSES). Latent profile analysis was used to identify distinct categories of academic resilience among nursing students, and influencing factors were examined through ordinal logistic regression analysis. RESULTS: The academic resilience levels of nursing students can be divided into three potential categories: 'low academic resilience' (13.0%), 'moderate academic resilience' (70.0%), and 'high academic resilience' (17.0%). Level of grade, GPA, self-reported physical health level, resilience and self-efficacy were significantly influenced the different categories of academic resilience of nursing students (P<0.05). CONCLUSIONS: The majority of undergraduate nursing students were placed in the moderate academic resilience group, however, educational institutions should pay special attention to nursing students demonstrating low levels. Regular assessments of academic resilience are recommended, and personalized interventions should be tailored to address specific academic resilience characteristics across different grades of nursing students. Strategies aimed at enhancing academic resilience among nursing students may include improvements in GPA performance, attention to physical health, and the reinforcement of resilience and self-efficacy.

Potential pharmacological mechanisms of tanshinone IIA in the treatment of human neuroblastoma based on network pharmacological and molecular docking Technology.

Tanshinone IIA (Tan-IIA) is the main bioactive component of Chinese herbal medicine salvia miltiorrhiza (Danshen). Sodium sulfonate of Tan-IIA is widely used in the treatment of cardiovascular and cerebrovascular diseases. Tan-IIA also has inhibitory effects on tumor cells such as gastric cancer, but its therapeutic effect and mechanism on human neuroblastoma have not been evaluated, so its pharmacological mechanism is systematically evaluated by the combined method of network pharmacology and molecular docking. PharmMapper and SwissTargetPrediction predicted 331 potential Tan-IIA-related targets, and 1,152 potential neuroblastoma-related targets were obtained from GeneCards, DisGeNET, DrugBank, OMIM and Therapeutic Target databases (TTD), 107 common targets for Tan-IIA and neuroblastoma. Through gene ontology (GO) functional annotation, Kyoto Encyclopedia of Genes and Genomesa (KEGG) pathway enrichment, protein-protein interaction (PPI) network and cytoHubba plug-in, 10 related signal pathways (Pathways in cancer, PI3K-Akt signaling pathway, Prostate cancer, etc.) and 10 hub genes were identified. The results of molecular docking showed that Tan-IIA could interact with 10 targets: GRB2, SRC, EGFR, PTPN1, ESR1, IGF1, MAPK1, PIK3R1, AKT1 and IGF1R. This study analyzed the related pathways and targets of Tan-IIA in the treatment of human neuroblastoma, as well as the potential anticancer and anti-tumor targets and related signaling pathways of Tan-IIA, which provides a reference for us to find and explore effective drugs for the treatment of human neuroblastoma.

Recent advances in the involvement of epigenetics in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease that manifests as skin rash, arthritis, lymphadenopathy, and multiple organ lesions. Epigenetics, including DNA methylation, histone modification, and non-coding RNA regulation, mainly affect the function and characteristics of cells through the regulation of gene transcription or translation. Increasing evidence indicates that there are a variety of complex epigenetic effects in patients with SLE, which interfere with the differentiation and function of T, and B lymphocytes, monocytes, and neutrophils, and enhance the expression of SLE-associated pathogenic genes. This paper summarizes our currently knowledge regarding pathogenesis of SLE, and introduces current advances in the epigenetic regulation of SLE from three aspects: immune function, inflammatory response, and lupus complications. We propose that epigenetic changes could be used as potential biomarkers and therapeutic targets of SLE.

Akkermansia muciniphila inhibits tryptophan metabolism via the AhR/ß-catenin signaling pathway to counter the progression of colorectal cancer.

Akkermansia muciniphila (A. muciniphila), a gram-negative anaerobic bacterium, is selectively decreased in the fecal microbiota of patients with colorectal cancer (CRC), but its molecular mechanism in CRC development remains inconclusive. In this study, we first confirmed the inhibitory effect of A. muciniphila on CRC formation and analyzed the metabolic role of intestinal flora in human Polyps, A-CRA (advanced colorectal adenoma) and CRC samples. To better clarify the role of A. muciniphila in CRC development, a pseudo-germ-free (GF) azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model was established, followed by infection with or without A. muciniphila. Metabolomic analysis and RNA-seq analysis showed tryptophan-mediated aryl hydrocarbon receptor (AhR) was significantly down-regulated in A. muciniphila-infected CRC mice. Then, mice with intestinal specific AhR deficiency (AhRfl/fl Cre) were generated and were used in 2 murine models: AOM/DSS treatment as a model of carcinogen-induced colon cancer and a genetically induced model using ApcMin/+ mice. Notably, AhR deficiency inhibited CRC growth in the AOM/DSS and ApcMin/+ mouse model. Moreover, AhR deficiency inhibited, rather than enhanced, tumor formation and tumor-derived organoids in Apc-deficient cells both in vivo and in vitro by activating Wnt/ß-catenin signaling and TCF4/LEF1-dependent transcription. Furthermore, the antitumor effectiveness of A. muciniphila was abolished either in a human colon cancer tumor model induced by subcutaneous transplantation of AhR-silenced CRC cells, or AhR-deficienty spontaneous colorectal cancer model. In conclusion, supplementation with A. muciniphila. protected mice from CRC development by specifically inhibiting tryptophan-mediated AhR/ß-catenin signaling.

[Identifying Driving Factors and Their Interacting Effects on Sources of Heavy Metal in Farmland Soils with Geodetector and Multi-source Data].

The identification of heavy metal sources in farmland soils is essential for the rational health condition management and sustainable development of soil. Using source resolution results(source component spectrum and source contribution)of a positive matrix factorization(PMF)model, historical survey data, and time-series remote sensing data, integrating a geodetector(GD), an optimal parameters-based geographical detector(OPGD), a spatial association detector(SPADE), and an interactive detector for spatial associations(IDSA)model, this study explored the modifiable areal unit problem(MAUP) of spatial heterogeneity of soil heavy metal sources and identified the driving factors and their interacting effects on the spatial heterogeneity of soil heavy metal sources in categorical and continuous variables, respectively. The results showed that the spatial heterogeneity of soil heavy metal sources at small and medium scales was affected by the spatial scale, and the optional spatial unit was 0.08 km2 for detecting spatial heterogeneity of soil heavy metal sources in the study region. Considering spatial correlation and discretization level, the combination of the quantile method and discretization parameters with an interruption number of 10 could be implied to reduce the partitioning effects on continuous variables in the detection of spatial heterogeneity of soil heavy metal sources. Within categorical variables, strata(PD 0.12-0.48) controlled the spatial heterogeneity of soil heavy metal sources, the interaction between strata and watersheds explained 27.28%-60.61% of each source, and the high-risk areas of each source were distributed in the lower sinian system, upper cretaceous in strata, mining land in land use, and haplic acrisols in soil types. Within continuous variables, population (PSD 0.40-0.82) controlled the spatial variation in soil heavy metal sources, and the explanatory power of spatial combinations of continuous variables for each source ranged from 61.77% to 78.46%. The high-risk areas of each source were distributed in evapotranspiration (41.2-43 kg·m-2), distance from the river (315-398 m), enhanced vegetation index (0.796-0.995), and distance from the river (499-605 m). The results of this study provide a reference for the research of the drivers of heavy metal sources and their interactions in arable soils and provide an important scientific basis for the management of arable soil and its sustainable development in karst areas.

Exosomes derived from MDR cells induce cetuximab resistance in CRC via PI3K/AKT signaling­mediated Sox2 and PD­L1 expression.

The anti-EGFR antibody cetuximab is used as a first-line targeted therapeutic drug in colorectal cancer. It has previously been reported that the efficacy of the EGFR antibody cetuximab is limited by the emergence of acquired drug resistance. In our previous study the transmissibility effect of exosomes from drug resistant tumor cells to sensitive tumor cells was identified. It can therefore be hypothesized that drug resistant cells might affect neighboring and distant cells via regulation of exosome composition and behavior. However, the mechanism of exosomes in KRAS-wild-type colorectal cancer (CRC) remains unknown. In the present study, functional analysis of overall survival post-diagnosis in patients with KRAS wild-type and those with mutant CRC was performed using human CRC specimens. Furthermore, it was demonstrated that multidrug resistance (MDR) cancer cell-derived exosomes were potentially a key factor, which promoted cetuximab-resistance in CRC cells and reduced the inhibitory effect of cetuximab in CRC xenograft models. The Cell Counting Kit-8 and colony formation assays were performed to assess the effects of exosomes derived from CRC/MDR cells on cetuximab resistance. Sphere formation assay results demonstrated that exosomes derived from CRC/MDR cells altered the self-renewal and multipotential ability of stem-cell-associated markers and facilitated resistance to cetuximab in cetuximab-sensitive cells. Furthermore, exosomes derived from CRC/MDR cells decreased sensitivity to cetuximab via the activation of PI3K/AKT signaling, which promoted Sox2 and programmed death-ligand 1 (PD-L1) mRNA and protein expression according to reverse transcription-quantitative PCR, western blotting and immunohistochemistry analyses, as well as apoptosis resistance both in vitro and in vivo according to a TUNEL assay. In conclusion, the results of the present study demonstrated that exosomes derived from CRC/MDR cells may promote cetuximab resistance in KRAS wild-type cells via activation of the PI3K/AKT signaling pathway-mediated expression of Sox2 and PD-L1, which will be useful for investigating a potential clinical target in predicting cetuximab resistance.

ZiBuPiYin recipe ameliorates diabetes-associated cognitive decline by improving neuronal mitochondrial function in chronic psychologically stressed zucker diabetic fatty rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Zibu Piyin Recipe (ZBPYR) is a traditional Chinese medicine compound composed of 12 kinds of Chinese herbal medicines including red ginseng and yam. Long-term basic and clinical applications have proved that ZBPYR can prevent and treat cognitive dysfunction. Previous studies showed that chronic psychological stress can increase the risk of type 2 diabetes mellitus (T2DM), and lead to cognitive decline. Mitochondrial dysfunction plays a key role in chronic psychological stress-induced diabetes mellitus. While the mechanism of mitochondrial dysfunction and insulin resistance in diabetes-associated cognitive decline (DACD) is unclear. AIM OF THE STUDY: Our previous research found that a ZiBuPiYin recipe (ZBPYR) has significant pharmacological effects against DACD. The present study investigated changes in mitochondrial dysfunction in the brain and the mechanism of insulin resistance and mitochondrial damage to explore the relationship between neuronal mitochondrial dysfunction and insulin resistance in chronic psychologically stressed DACD rats. MATERIALS AND METHODS: Zucker diabetic fatty (ZDF) rats with spontaneous T2DM and rats with diabetic cognitive impairment that was induced by chronic psychological stress were used in in vivo experiments. PC12 cells that were damaged by rotenone were used for the in vitro experiment. RESULTS: The findings indicated that the number of mitochondria decreased, morphology and membrane potential were damaged, and reactive oxygen species increased in the cortex and hippocampus in psychologically stressed DACD rats. Protein kinase Cß2 (PKCß2) activation and insulin resistance were markedly induced by chronic psychological stress, together with decreases in peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial fusion protein 2 (Mfn2). Furthermore, ZBPYR exerted protective effects both in in vivo and in vitro. CONCLUSION: Mitochondrial damage and insulin resistance were observed in the brain in chronic psychologically stressed DACD rats. The ZBPYR significantly improved brain mitochondrial damage and insulin resistance in chronic psychologically stressed DACD rats. These results provide novel insights for the development of ZBPYR as a traditional Chinese medicine for the treatment of chronic psychological stress and DACD.

Deciphering the species differences in CES1A-mediated hydrolytic metabolism by using a bioluminescence substrate.

Carboxylesterases 1A (CES1A) is a key enzyme responsible for the hydrolytic metabolism of a great deal of endogenous and exogenous substrates bearing ester- or amide-bond(s). This study aimed to decipher the species difference in CES1A-mediated hydrolytic metabolism by using a newly developed bioluminescence CES1A sensor (termed NLMe) as the probe substrate, while the liver microsomes from six different mammalian species (human, cynomolgus monkey, dog, minipig, rat and mouse) were used as the enzyme sources. Metabolite profiling demonstrated that all tested liver microsomes from various species could catalyze NLMe hydrolysis, but significant difference in hydrolytic rate was observed. Kinetic plots of NLMe hydrolysis in liver microsomes from different species showed that the inherent clearance rates (Clint) of NLMe in human liver microsomes (HLM), cynomolgus monkey liver microsomes (CyLM), and pig liver microsome (PLM) were comparable, while the Clint values of NLMe in dog liver microsomes (DLM), mouse liver microsomes (MLM), and rat liver microsomes (RLM) were relatively small. Moreover, chemical inhibition assays showed that NLMe hydrolysis in all tested liver microsomes could be competently inhibited by BNPP (a potent broad-spectrum inhibitor of CES), but CUA (a selective inhibitor of human CES1A) only inhibited NLMe hydrolysis in human liver microsomes and dog liver microsomes. In summary, the species differences in CES1A-catalyzed NLMe hydrolysis were carefully investigated from the views of the similarities in metabolite profile, hydrolytic kinetics and inhibitor response. All these findings provide new insights into the species differences in CES1A-mediated hydrolytic metabolism and suggest that it is necessary for the pharmacologists to choose appropriate animal models to replace humans for evaluating the in vivo effects of CES1A inhibitors.

Optimal Growth Conditions for Forming c-Axis (002) Aluminum Nitride Thin Films as a Buffer Layer for Hexagonal Gallium Nitride Thin Films Produced with In Situ Continual Radio Frequency Sputtering.

Aluminum nitride (AlN) thin-film materials possess a wide energy gap; thus, they are suitable for use in various optoelectronic devices. In this study, AlN thin films were deposited using radio frequency magnetron sputtering with an Al sputtering target and N2 as the reactive gas. The N2 working gas flow rate was varied among 20, 30, and 40 sccm to optimize the AlN thin film growth. The optimal AlN thin film was produced with 40 sccm N2 flow at 500 W under 100% N2 gas and at 600 °C. The films were studied using X-ray diffraction and had (002) phase orientation. X-ray photoelectron spectroscopy was used to determine the atomic content of the optimal film to be Al, 32%; N, 52%; and O, 12% at 100 nm beneath the surface of the thin film. The film was also investigated through atomic force microscopy and had a root mean square roughness of 2.57 nm and a hardness of 76.21 GPa. Finally, in situ continual sputtering was used to produce a gallium nitride (GaN) layer on Si with the AlN thin film as a buffer layer. The AlN thin films investigated in this study have excellent material properties, and the proposed process could be a less expensive method of growing high-quality GaN thin films for various applications in GaN-based power transistors and Si integrated circuits.

Corrigendum: Tanshinone IIA Inhibits Epithelial-to-Mesenchymal Transition Through Hindering ß-Arrestin1 Mediated ß-Catenin Signaling Pathway in Colorectal Cancer.

[This corrects the article DOI: 10.3389/fphar.2020.586616.].

Moxibustion attenuates inflammation in intestinal mucosal by regulating RAGE-mediated TLR4-NF-κBp65 signaling pathway in vivo and in vitro.

This study was performed to investigate the effect of moxibustion on the RAGE/TLR4-NF-κBp65 pathways and mucosal damage in rat model of 5-fluorouracil (5-Fu)-induced intestinal mucositis (IM) and the underlying mechanisms. 5-Fu treatment significantly increased the expression of the receptor for advanced glycation end products (RAGE) and its ligand, thehigh-mobility group box 1 protein (HMGB1), in the rat intestinal tissue. The inhibition of RAGE could induce the repair of intestinal mucosal damage and downregulate the expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-B (NF-κB) p65 in intestinal tissues of 5-Fu-treated rats. Moxibustion treatment significantly improved the physical symptoms and repaired the intestinal mucosal damage of IM rats and increased the expression of tight junction proteins in these rats. The expression of RAGE, HMGB1, TLR4, NF-κBp65, and related downstream inflammatory factors, namely, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1ß, were significantly decreased after moxibustion treatment. A moxibustion dose of 15 min/day exerted a better therapeutic effect than a dose of 30 min/day. The phosphorylation of NF-κBp65 and IκBa is involved in reducing inflammation by regulating the RAGE signaling pathway. Moxibustion can reduce intestinal mucosal damage and inflammation in 5-Fu-induced IM rats via modulation of the RAGE/TLR4-NF-κBp65 signaling pathways.

Hotspots and Frontiers in Inflammatory Tumor Microenvironment Research: A Scientometric and Visualization Analysis.

Methods: Articles on inflammatory tumor microenvironment were retrieved from the Web of Science Core Collection, and the characteristics of the articles were analyzed by CiteSpace software. Background: The inflammatory tumor microenvironment is an essential feature of the tumor microenvironment. The way in which it promotes or inhibits tumor progression plays an important role in the outcome of a tumor treatment. This research aims to explore a scientific collaboration network, describe evolution of hotspots, and predict future trends through bibliometric analysis. Results: A total of 3,534 papers published by 390 institutions in 81 countries/regions were screened, and the annual quantity has been increasing rapidly in the past decades. United States was the leading country and has the most productive institutions in this field. The research topics were mainly focused on inflammation and immunity mediated by crucial factors as well as the mechanisms of angiogenesis. Additionally, the development and application of nanoparticles is currently a novel research frontier with bright prospect. Conclusion: The present scientometric study provides an overview of inflammatory tumor microenvironment research over the previous decades using quantitative and qualitative methods, and the findings of this study can provide references for researchers focusing on tumor treatment.

Identification of hub genes associated with COVID-19 and idiopathic pulmonary fibrosis by integrated bioinformatics analysis.

INTRODUCTION: The coronavirus disease 2019 (COVID-19), emerged in late 2019, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The risk factors for idiopathic pulmonary fibrosis (IPF) and COVID-19 are reported to be common. This study aimed to determine the potential role of differentially expressed genes (DEGs) common in IPF and COVID-19. MATERIALS AND METHODS: Based on GEO database, we obtained DEGs from one SARS-CoV-2 dataset and five IPF datasets. A series of enrichment analysis were performed to identify the function of upregulated and downregulated DEGs, respectively. Two plugins in Cytoscape, Cytohubba and MCODE, were utilized to identify hub genes after a protein-protein interaction (PPI) network. Finally, candidate drugs were predicted to target the upregulated DEGs. RESULTS: A total of 188 DEGs were found between COVID-19 and IPF, out of which 117 were upregulated and 71 were downregulated. The upregulated DEGs were involved in cytokine function, while downregulated DEGs were associated with extracellular matrix disassembly. Twenty-two hub genes were upregulated in COVID-19 and IPF, for which 155 candidate drugs were predicted (adj.P.value < 0.01). CONCLUSION: Identifying the hub genes aberrantly regulated in both COVID-19 and IPF may enable development of molecules, encoded by those genes, as therapeutic targets for preventing IPF progression and SARS-CoV-2 infections.

YYFZBJS inhibits colorectal tumorigenesis by enhancing Tregs-induced immunosuppression through HIF-1α mediated hypoxia in vivo and in vitro.

BACKGROUND AND PURPOSE: The occurrence of colorectal cancer (CRC) is associated with a variety of factors. Accumulating evidence shows that peripheral differentiation of regulatory T cells (Tregs) is critical in controlling tumorigenesis. Our previous studies demonstrated that the Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) extract exerted potent anticancer activities by significantly enhancing immunosuppression in ApcMin/+ mice. However, there is limited knowledge on the effect of YYFZBJS in the prevention of colorectal cancer and the underlying mechanisms of action. METHODS: In this study, we investigated the effect of oral administration of YYFZBJS in preventing azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis. We found that YYFZBJS treatment decreased tumor load, tumor number, histology, and the severity of disease activity index (DAI) scores. To investigate if YYFZBJS inhibited tumorigenesis by regulating regulatory T cells, we depleted Tregs in AOM/DSS mice. We then analyzed the effect of intragastric administration of YYFZBJS on tumorigenesis and the regulation of tumor microenvironment. RESULTS: As expected, intragastric administration of YYFZBJS in AOM/DSS mice model significantly increased immune responses in the tumor microenvironment through its hypoxia-associated anti-cancer activities. Additionally, YYFZBJS regulated the polarization of peripheral Treg (pTreg) to suppress CRC cell proliferation and infiltration. This was demonstrated by the decrease in tumor proliferation-related proteins including p-STAT3, p-NF-κB and MMPs in a dose-dependent manner. Clinically, the increase in the levels of Tregs in human tissues during CRC progression was associated with low expression of HIF-1α in the stroma, and correlated with CRC survival and prognosis. CONCLUSION: Altogether, we demonstrated that HIF-1α may promote pTreg -induced carcinogenesis and progression of CRC cells, indicating that YYFZBJS is a promising protective agent against HIF-1α-mediated Treg activation in colorectal cancer. This study is the first to imply a novel clinical significance of a traditional Chinese herbal medicine from Synopsis of Golden Chamber in the cancer treatment and clarify the important role of tumor microenvironment in preventing tumorigenesis.

Structure-guided engineering of a flavin-containing monooxygenase for the efficient production of indirubin.

Indirubin is a bisindole compound for the treatment of chronic myelocytic leukemia. Here, we presented a structure-guided method to improve the activity of a flavin-containing monooxygenase (bFMO) for the efficient production of indirubin in Escherichia coli. A flexible loop interlocked with the active pocket through a helix and the substrate tunnel rather than the active pocket in bFMO were identified to be two reconfigurable structures to improve its activity, resulting in K223R and N291T mutants with enhanced catalytic activity by 2.5- and 2.0-fold, respectively. A combined modification at the two regions (K223R/D317S) achieved a 6.6-fold improvement in catalytic efficiency (kcat/Km) due to enhancing π-π stacking interactions stabilization. Finally, an engineered E. coli strain was constructed by metabolic engineering, which could produce 860.7 mg/L (18 mg/L/h) indirubin, the highest yield ever reported. This work provides new insight into the redesign of FMOs to boost their activities and an efficient approach to produce indirubin.

YYFZBJS inhibits colorectal tumorigenesis by remodeling gut microbiota and influence on M2 macrophage polarization in vivo and in vitro.

Our previous studies indicated that the extract of Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) had potent anticancer activities by significantly inhibiting intestinal tumor development in ApcMin/+ mice. However, knowledge regarding the mechanism and effect of YYFZBJS in the prevention of colorectal cancer is limited. In this study, we aim to investigate the preventive effects of YYFZBJS in enterotoxigenic Bacteroides fragilis (ETBF)-colonized mice with azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis. First, the colonic tissues of the AOM/DSS mouse models were collected for biomedical analysis, and gut microbiota profiling was detected post YYFZBJS treatment using a 16S rRNA gene sequencing. Then, antibiotic solution (Abx) mice were acclimated with AOM/DSS treatment and then fed with ETBF with or without YYFZBJS for three cycles. As expected, the intragastric administration of YYFZBJS in the AOM/DSS mouse model significantly decreased the tumor load, the severity of disease activity index (DAI) scores, and the level of M2 macrophage markers such as CD206, Arg-1 and IL-10. Notably, the reverse of polarized macrophages induced by YYFZBJS could suppress CRC cell proliferation and infiltration, as demonstrated by the decrease of some tumor proliferation-related proteins in a dose-dependent manner. Importantly, ETBF dysbiosis can contribute to colon tumor development by stimulating p-STAT3 mediated M2 macrophages polarization to promote chronic inflammation and adenoma malignant transformation, which YYFZBJS can effectively limit. Altogether, we demonstrate that ETBF dysbiosis may contribute to M2 macrophages-promoted colon carcinogenesis and progression of CRC cells, while YYFZBJS could be a promising protective agent against ETBF-mediated colorectal cancer.

The Impact of Inflammatory Immune Reactions of the Vascular Niche on Organ Fibrosis.

Inflammation is a type of defense response against tissue damage, and can be mediated by lymphocytes and macrophages. Fibrosis is induced by tissue injury and inflammation, which leads to an increase in fibrous connective tissue in organs and a decrease in organ parenchyma cells, finally leading to organ dysfunction or even failure. The vascular niche is composed of endothelial cells, pericytes, macrophages, and hematopoietic stem cells. It forms a guiding microenvironment for the behavior of adjacent cells, and mainly exists in the microcirculation, including capillaries. When an organ is damaged, the vascular niche regulates inflammation and affects the repair of organ damage in a variety of ways, such as via its angiocrine function and transformation of myofibroblasts. In this paper, the main roles of vascular niche in the process of organ fibrosis and its mechanism of promoting the progress of fibrosis through inflammatory immunoregulation are summarized. It was proposed that the vascular niche should be regarded as a new therapeutic target for organ fibrosis, suggesting that antifibrotic effects could be achieved by regulating macrophages, inhibiting endothelial-mesenchymal transition, interfering with the angiocrine function of endothelial cells, and inhibiting the transformation of pericytes into myofibroblasts, thus providing new ideas for antifibrosis drug research.

ß-Arrestin1 Promotes Colorectal Cancer Metastasis Through GSK-3ß/ß-Catenin Signaling- Mediated Epithelial-to-Mesenchymal Transition.

Recurrence and metastasis seriously affects the prognosis of patients with tumors, and the epithelial-to-mesenchymal transition (EMT) plays a key role in promoting tumor invasion and metastasis. Previous studies have showed that ß-arrestin1 acted as a tumor-promoting factor in multiple types of tumor. However, the exact role and mechanism of ß-arrestin1 in colorectal cancer (CRC) progression remains to be elucidated. Our research aimed to explore the potential mechanism underlying the role of ß-arrestin1 in CRC metastasis. The expression of ß-arrestin1 was investigated in both primary and metastatic CRC tissues using the GSE41258 database, and it was revealed that CRC patients with liver/lung metastasis had a higher expression level of ß-arrestin1, and the expression level of ß-arrestin1 was inversely correlated with the prognosis of CRC patients. Further in vitro mechanism studies indicated that ß-arrestin1 had the ability to promote the migration of CRC cells through regulating the EMT process by activating Wingless/integration-1 (Wnt)/ß-catenin signaling pathways. Blocking Wnt/ß-catenin signaling with inhibitor ICG001 decreased the promoting effect of ß-arrestin1 on EMT in CRC. In vivo imaging experiments further demonstrated the promoting effect of ß-arrestin1 on the lung metastasis of CRC cells by tail vein injection in mice. The results of this paper suggest that ß-arrestin1 promotes EMT via Wnt/ß-catenin signaling pathway in CRC metastasis, and provides a novel therapeutic target for CRC metastasis.