Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 ...macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear. Here, we show that the M2-like tumor-associated macrophages (TAM) have a lower level of Notch pathway activation in mouse tumor models. Forced activation of Notch signaling increased M1 macrophages which produce IL12, no matter whether M1 or M2 inducers were applied. When Notch signaling was blocked, the M1 inducers induced M2 response in the expense of M1. Macrophages deficient in canonical Notch signaling showed TAM phenotypes. Forced activation of Notch signaling in macrophages enhanced their antitumor capacity. We further show that RBP-J-mediated Notch signaling regulates the M1 versus M2 polarization through SOCS3. Therefore, Notch signaling plays critical roles in the determination of M1 versus M2 polarization of macrophages, and compromised Notch pathway activation will lead to the M2-like TAMs. These results provide new insights into the molecular mechanisms of macrophage polarization and shed light on new therapies for cancers through the modulation of macrophage polarization through the Notch signaling.
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Ulcerative colitis (UC) is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment has fueled the search for alternative therapeutic ...strategies. In recent studies, berberine, a plant alkaloid with a long history of medicinal use in Chinese medicine, has shown beneficial effects against animal models of acute UC. However, UC usually presents as a chronic condition with frequent relapse in patients. How berberine will act on chronic UC remains unclear. In the present study, we adopted dextran sulfate sodium (DSS)-induced chronic relapsing colitis model to assess the ameliorating activity of berberine. Colitis was induced by two cycles of 2.0% DSS for five days followed by 14days of drinking water plus a third cycle consisting of DSS only for five days. The colitis mice were orally administered 20mg/kg berberine from day 13 onward for 30days and monitored daily. The body weight, stool consistency, and stool bleeding were recorded for determination of the disease activity index (DAI). At the end of treatment, animals were sacrificed and samples were collected and subjected to histological, RT-qPCR, Western blot, and LC–MS analyses. Lymphocytes were isolated from spleens and mesenteric lymph nodes (MLN) and cultured for flow cytometry analysis of IL-17 secretion from CD4+ cells and the Th17 cell differentiation. Results showed that berberine significantly ameliorated the DAI, colon shortening, colon tissue injury, and reduction of colonic expression of tight junction (TJ) protein ZO-1 and occludin of colitis mice. Notably, berberine treatment pronouncedly reduced DSS-upregulated Th17-related cytokine (IL-17 and ROR-γt) mRNAs in the colon. Furthermore, the mRNA expression of IL-6 and IL-23, and the phosphorylation of STAT3 in colon tissues from DSS-treated mice were pronouncedly inhibited by berberine. Moreover, the up-regulation of IL-17 secretion from CD4+ cells of spleens and MLNs caused by DSS were significantly reversed by berberine treatment. Furthermore, Th17 cell differentiation from naive CD4+ cells isolated from above DSS colitis mice were suppressed by berberine in a concentration-dependent manner. In summary, we demonstrated for the first time that berberine reduced the severity of chronic relapsing DSS-induced colitis by suppressing Th17 responses. The demonstration of activity in this mouse model supports the possibility of clinical efficacy of berberine in treating chronic UC.
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To minimize unwanted reactions with high concentrations of reduced glutathione (GSH) in the tumor microenvironment (TME) during chemodynamic therapy (CDT), a simple and effective ...strategy was developed to fabricate a TME stimuli-responsive theranostic nanomedicine (Fe-CD) for fluorescence imaging-guided GSH depletion and cancer therapy by combining fluorescent imaging carbon dots (CD) and Fe(III). Introducing Fe(III) into Fe-CD not only quenched the fluorescence of CD while reacting with and consuming intracellular GSH for fluorescence imaging of the depletion of GSH but also provided a source of metal ions to generate more abundant hydroxyl radicals (•OH) with hydrogen peroxide (H2O2) through the Fenton reaction to improve CDT. Fe-CD showed promising •OH generation under H2O2 to effectively degrade methylene blue in vitro and obviously activate the green fluorescence of the reactive oxygen species (ROS) probe in cells. Benefiting from the fluorescence enhancement in response to TME stimulation, Fe-CD greatly enhanced CDT cytotoxicity while monitoring successful GSH depletion by fluorescence imaging. Fe-CD has the potential to act as a theranostic nanomedicine for fluorescence imaging-guided GSH depletion to amplify CDT.
Outliers, data points that significantly deviate from the norm, can have a substantial impact on statistical inference and provide valuable insights in data analysis. Multiple methods have been ...developed for outlier detection, however, almost all available approaches fail to consider the spatial dependence and heterogeneity in spatial data. Spatial data has diverse formats and semantics, requiring specialized outlier detection methodology to handle these unique properties. For now, there is limited research exists on robust spatial outlier detection methods designed specifically under the spatial error model (SEM) structure.
We propose the Spatial-Θ-Iterative Procedure for Outlier Detection (Spatial-Θ-IPOD), which utilizes a mean-shift vector to identify outliers within the SEM. Our method enables an effective detection of spatial outliers while also providing robust coefficient estimates. To assess the performance of our approach, we conducted extensive simulations and applied it to a real-world empirical study using life expectancy data from multiple countries.
Simulation results showed that the masking and JD (Joint Detection) indicators of our Spatial-Θ-IPOD method outperformed several commonly used methods, even in high-dimensional scenarios, demonstrating stable performance. Conversely, the Θ-IPOD method proved to be ineffective in detecting outliers when spatial correlation was present. Moreover, our model successfully provided reliable coefficient estimation alongside outlier detection. The proposed method consistently outperformed other models (both robust and non-robust) in most cases. In the empirical study, our proposed model successfully detected outliers and provided valuable insights in the modeling process.
Our proposed Spatial-Θ-IPOD offers an effective solution for detecting spatial outliers for SEM while providing robust coefficient estimates. Notably, our approach showcases its relative superiority even in the presence of high leverage points. By successfully identifying outliers, our method enhances the overall understanding of the data and provides valuable insights for further analysis.
As a signaling molecule, hydrogen sulfide (H
2
S) plays an indispensable role in the modulation of ripening and senescence in fruits and vegetables. To explore the role of H
2
S in regulating ...metabolism of postharvest tomato, ripening-related physiological parameters, activities of antioxidant enzymes and gene expression were analyzed in H
2
S-fumigated tomato fruits. These results show that H
2
S significantly delayed the color transition and softening of tomato fruit, and maintained higher level of flavonoids and lower level of anthocyanin during storage. Besides, H
2
S could maintain higher level of nutritional-related metabolites, such as reducing sugar, ascorbic acid during postharvest storage. Moreover, H
2
S decreased the rate of O
2
−
production, inhibited the production of H
2
O
2
and malondialdehyde (MDA), enhanced the activities of antioxidant enzymes including ascorbate peroxidase (APX), superoxide dismutase (SOD), catalase (CAT) and guaiacol peroxidase (POD) in tomato fruits, while reduced the activities of phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO) and lipoxygenase (LOX). Besides, the expression of the antioxidant-encoding genes
SlCAT2
,
SlPOD12
was generally upregulated with H
2
S fumigation. Principal component analysis (PCA) suggests that H
2
S induced significant discrepancy mainly to the differences in firmness, anthocyanin, flavonoid and the activity of guaiacol peroxidase (POD), and the correlation analysis further shows that H
2
S affected pigment metabolism and nutritional quality. In conclusion, H
2
S could maintain better appearance and nutritional quality, and prolong the storage period of postharvest tomato fruits through activating the antioxidative system.
Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) play critical roles in tumorigenesis. However, the mechanisms underlying MDSC and TAM development and function remain ...unclear. In this study, we find that myeloid-specific activation of Notch/RBP-J signaling downregulates lactate transporter MCT2 transcription via its downstream molecule Hes1, leading to reduced intracellular lactate levels, blunted granulocytic MDSC (G-MDSC) differentiation, and enhanced TAM maturation. We identify c-Jun as a novel intracellular sensor of lactate in myeloid cells using liquid-chromatography-mass spectrometry (LC-MS) followed by CRISPR-Cas9-mediated gene disruption. Meanwhile, lactate interacts with c-Jun to protect from FBW7 ubiquitin-ligase-mediated degradation. Activation of Notch signaling and blockade of lactate import repress tumor progression by remodeling myeloid development. Consistently, the relationship between the Notch-MCT2/lactate-c-Jun axis in myeloid cells and tumorigenesis is also confirmed in clinical lung cancer biopsies. Taken together, our current study shows that lactate metabolism regulated by activated Notch signaling might participate in MDSC differentiation and TAM maturation.
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•Notch signaling represses MCT2-mediated lactate transport in myeloid cells•Lactate promotes M-MDSC differentiation into G-MDSCs rather than mature macrophages•Lactate interacts with intracellular c-Jun to protect from FBW7-mediated degradation•Combining Notch activation and MCT2 inhibition in myeloid cells represses tumor growth
Zhao et al. show that Notch-signaling-mediated lactate metabolism in tumor-associated myeloid cells blunts G-MDSC differentiation and enhances TAM maturation. Lactate interacts with intracellular c-Jun to protect from its degradation, leading to COX2 expression. Notch-MCT2/lactate-c-Jun axis in myeloid cells should be targets for tumor therapy.
Background and Objectives
This study aimed to compare outcomes between neoadjuvant imatinib and upfront surgery in patients with localized rectal gastrointestinal stromal tumors (GIST) patients.
...Methods
Eighty‐five patients with localized rectal GIST were divided into two groups: upfront surgery ± adjuvant imatinib (Group A, n = 33) and the neoadjuvant imatinib + surgery + adjuvant imatinib (Group B, n = 52). Baseline characteristics between groups were controlled for with inverse probability of treatment weighting (IPTW) adjusted analysis.
Results
The response rate to neoadjuvant imatinib was 65.9%. After the IPTW‐adjusted analysis, patients who underwent neoadjuvant therapy had better distant recurrence‐free survival (DRFS) and disease‐specific survival (DSS) compared with those who underwent upfront surgery (5‐year DRFS 97.8 vs. 71.9%, hazard ratio HR, 0.15; 95% CI, 0.03–0.87; p = 0.03; 5‐year DSS 100 vs. 77.1%; HR, 0.11; 95% CI, 0.01–0.92; p = 0.04). While no significant association was found between overall survival (OS) and treatment groups (p = 0.07), 5‐year OS was higher for the neoadjuvant group than upfront surgery group (97.8% vs. 71.9%; HR, 0.2; 95% CI, 0.03–1.15).
Conclusions
In patients with localized rectal GIST, neoadjuvant imatinib not only shrunk the tumor size but also decreased the risk of metastasis and tumor‐related deaths when compared to upfront surgery and adjuvant imatinib alone.
Phenazine compounds are widely used in agricultural control and the medicine industry due to their high inhibitory activity against pathogens and antitumor activity. The green and sustainable method ...of synthesizing phenazine compounds through microbial fermentation often requires a complex culture medium containing tryptone and yeast extract, and its cost is relatively high, which greatly limits the large-scale industrial production of phenazine compounds by fermentation. The aim of this study was to develop a cost-effective minimal medium for the efficient synthesis of phenazine compounds by Pseudomonas chlororaphis. Through testing the minimum medium commonly used by Pseudomonas, an ME medium for P. chlororaphis with a high production of phenazine compounds was obtained. Then, the components of the ME medium and the other medium were compared and replaced to verify the beneficial promoting effect of Fe2+ and NH4+ on phenazine compounds. A cost-effective general defined medium (GDM) using glycerol as the sole carbon source was obtained by optimizing the composition of the ME medium. Using the GDM, the production of phenazine compounds by P. chlororaphis reached 1073.5 mg/L, which was 1.3 times that achieved using a complex medium, while the cost of the GDM was only 10% that of a complex medium (e.g., the KB medium). Finally, by engineering the glycerol metabolic pathway, the titer of phenazine-1-carboxylic acid reached the highest level achieved using a minimum medium so far. This work demonstrates how we systematically analyzed and optimized the composition of the medium and integrated a metabolic engineering method to obtain the most cost-effective fermentation strategy.
Minimizing precious metal loading into electrocatalysts for water splitting is vital to promoting hydrogen energy technology toward practical applications. Low-content loading of precious-metal ...electrocatalysts is achieved by decorating precious metal nanostructures on co-electrocatalysts typically via surface confinement. Here, an electrocatalyst of ultralow-content Pt nanodots (0.71 wt%)/Ni3Fe nanoparticles on reduced oxidation graphene (Pt/Ni3Fe/rGO) is constructed for overall water splitting by pyrolyzing a single-source precursor PtCl63− guest-intercalated MgNiFe-layered double hydroxide (MgNiFe-LDH) host via a distinctive interlayer confinement. Consequently, Pt/Ni3Fe/rGO demonstrates attractive overpotentials of 240 and 76 mV at 10 mA cm−2 for the oxygen and hydrogen evolution reactions (OER and HER), respectively, outperforming those of its /Ni3Fe/rGO counterpart. Moreover, the Pt/Ni3Fe/rGO∥Pt/Ni3Fe/rGO electrolyzer generates a current density of 10 mA cm−2 at 1.55 V, with a retention of 92.4% after 50 h. Furthermore, the measured specific activity and low transfer resistance, as well as the density functional theory (DFT) calculations, indicate that the active Pt/Ni3Fe in Pt/Ni3Fe/rGO can optimize the adsorption/desorption of reaction intermediates and thus boost OER/HER kinetics, all of which lead to enhanced performance. The results demonstrate that such an interlayer confinement-based synthesis strategy can allow for the design of cost-effective precious nanodots as potential electrocatalysts.
Aspergillus niger, a saprophytic fungus, is widely distributed in soil, air and cereals, and can cause postharvest diseases in fruit. Polygalacturonase (PG) is one of the main enzymes in fungal ...pathogens to degrade plant cell wall. To evaluate whether the deletion of an exo-polygalacturonase gene pgxB would influence fungal pathogenicity to fruit, pgxB gene was deleted in Aspergillus niger MA 70.15 (wild type) via homologous recombination. The ΔpgxB mutant showed similar growth behavior compared with the wild type. Pectin medium induced significant higher expression of all pectinase genes in both wild type and ΔpgxB in comparison to potato dextrose agar medium. However, the ΔpgxB mutant was less virulent on apple fruits as the necrosis diameter caused by ΔpgxB mutant was significantly smaller than that of wild type. Results of quantitive-PCR showed that, in the process of infection in apple fruit, gene expressions of polygalacturonase genes pgaI, pgaII, pgaA, pgaC, pgaD and pgaE were enhanced in ΔpgxB mutant in comparison to wild type. These results prove that, despite the increased gene expression of other polygalacturonase genes in ΔpgxB mutant, the lack of pgxB gene significantly reduced the virulence of A. niger on apple fruit, suggesting that pgxB plays an important role in the infection process on the apple fruit.
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