Search

Abstract The interaction between glioblastoma cells and glioblastoma-associated macrophages (GAMs) influences the immunosuppressive tumor microenvironment, leading to ineffective immunotherapies. We hypothesized that disrupting the communication between tumors and macrophages would enhance the efficacy of immunotherapies. Transcriptomic analysis of recurrent glioblastoma specimens indicated an enhanced neuroinflammatory pathway, with CXCL12 emerging as the top-ranked gene in secretory molecules. Single-cell transcriptome profiling of naïve glioblastoma specimens revealed CXCL12 expression in tumor and myeloid clusters. An analysis of public glioblastoma datasets has confirmed the association of CXCL12 with disease and PD-L1 expression. In vitro studies have demonstrated that exogenous CXCL12 induces pro-tumorigenic characteristics in macrophage-like cells and upregulated PD-L1 expression through NF-κB signaling. We identified CXCR7, an atypical receptor for CXCL12 predominantly present in tumor cells, as a negative regulator of CXCL12 expression by interfering with extracellular signal-regulated kinase activation. CXCR7 knockdown in a glioblastoma mouse model resulted in worse survival outcomes, increased PD-L1 expression in GAMs, and reduced CD8+ T-cell infiltration compared with the control group. Ex vivo T-cell experiments demonstrated enhanced cytotoxicity against tumor cells with a selective CXCR7 agonist, VUF11207, reversing GAM-induced immunosuppression in a glioblastoma cell-macrophage-T-cell co-culture system. Notably, VUF11207 prolonged survival and potentiated the anti-tumor effect of the anti-PD-L1 antibody in glioblastoma-bearing mice. This effect was mitigated by an anti-CD8β antibody, indicating the synergistic effect of VUF11207. In conclusion, CXCL12 conferred immunosuppression mediated by pro-tumorigenic and PD-L1-expressing GAMs in glioblastoma. Targeted activation of glioblastoma-derived CXCR7 inhibits CXCL12, thereby eliciting anti-tumor immunity and enhancing the efficacy of anti-PD-L1 antibodies.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic syndrome characterized by chronic inflammation, insulin resistance, and islet cell damage. The prevention of T2DM and its associated complications is an urgent public health issue that affects hundreds of millions of people globally. Numerous studies suggest that disturbances in gut metabolites are important driving forces for the pathogenesis of diabetes. However, the functions and mechanisms of action of most commensal bacteria in T2DM remain largely unknown. Methods: The quantification of bile acids (BAs) in fecal samples was performed using ultra-performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS). The anti-diabetic effects of Bacteroides uniformis (B. uniformis) and its metabolites cholic acid (CA) and chenodeoxycholic acid (CDCA) were assessed in T2DM mice induced by streptozocin (STZ) plus high-fat diet (HFD). Results: We found that the abundance of B. uniformis in the feces and the contents of CA and CDCA were significantly downregulated in T2DM mice. B. uniformis was diminished in diabetic individuals and this bacterium was sufficient to promote the production of BAs. Colonization of B. uniformis and intragastric gavage of CA and CDCA effectively improved the disorder of glucose and lipid metabolism in T2DM mice by inhibiting gluconeogenesis and lipolysis in the liver. CA and CDCA improved hepatic glucose and lipid metabolism by acting on the Takeda G protein-coupled receptor 5 (TGR5)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway since knockdown of TGR5 minimized the benefit of CA and CDCA. Furthermore, we screened a natural product—vaccarin (VAC)—that exhibited anti-diabetic effects by promoting the growth of B. uniformis in vitro and in vivo. Gut microbiota pre-depletion abolished the favorable effects of VAC in diabetic mice. Conclusions: These data suggest that supplementation of B. uniformis may be a promising avenue to ameliorate T2DM by linking the gut and liver.

BACKGROUND: Zanthoxylum seed, as a low‐cost and easily accessible plant protein resource, has good potential in the food industry. But protein and its hydrolysates from Zanthoxylum seed are underutilized due to the dearth of studies on them. This study aimed to investigate the structure and physicochemical and biological activities of Zanthoxylum seed protein (ZSP) hydrolysates prepared using Protamex®, Alcalase®, Neutrase®, trypsin, or pepsin. RESULTS: Hydrolysis using each of the five enzymes diminished average particle size and molecular weight of ZSP but increased random coil content. ZSP hydrolysate prepared using pepsin had the highest degree of hydrolysis (24.07%) and the smallest molecular weight (<13 kDa) and average particle size (129.80 nm) with the highest solubility (98.9%). In contrast, ZSP hydrolysate prepared using Alcalase had the highest surface hydrophobicity and foaming capacity (88.89%), as well as the lowest foam stability (45.00%). Moreover, ZSP hydrolysate prepared using Alcalase exhibited the best hydroxyl‐radical scavenging (half maximal inhibitory concentration (IC50) 1.94 mg mL−1) and ferrous‐ion chelating (IC50 0.61 mg mL−1) activities. Additionally, ZSP hydrolysate prepared using pepsin displayed the highest angiotensin‐converting enzyme inhibition activity (IC50 0.54 mg mL−1). CONCLUSION: These data showed that enzyme hydrolysis improved the physicochemical properties of ZSP, and enzymatic hydrolysates of ZSP exhibited significant biological activity. These results provided validation for application of ZSP enzymatic hydrolysates as antioxidants and antihypertensive agents in the food or medicinal industries. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

BACKGROUND: The limited physicochemical properties (such as low foaming and emulsifying capacity) of mung bean protein hydrolysate restrict its application in the food industry. Ultrasound treatment could change the structures of protein hydrolysate to accordingly affect its physicochemical properties. The aim of this study was to investigate the effects of ultrasound treatment on the structural and physicochemical properties of mung bean protein hydrolysate of protamex (MBHP). The structural characteristics of MBHP were evaluated using tricine sodium dodecylsulfate–polyacrylamide gel electrophoresis, laser scattering, fluorescence spectrometry, etc. Solubility, fat absorption capacity and foaming, emulsifying and thermal properties were determined to characterize the physicochemical properties of MBHP. RESULTS: MBHP and ultrasonicated‐MBHPs (UT‐MBHPs) all contained five main bands of 25.8, 12.1, 5.6, 4.8 and 3.9 kDa, illustrating that ultrasound did not change the subunits of MBHP. Ultrasound treatment increased the contents of α‐helix, β‐sheet and random coil and enhanced the intrinsic fluorescence intensity of MBHP, but decreased the content of β‐turn, which demonstrated that ultrasound modified the secondary and tertiary structures of MBHP. UT‐MBHPs exhibited higher solubility, foaming capacity and emulsifying properties than MBHP, among which MBHP‐330 W had the highest solubility (97.32%), foaming capacity (200%), emulsification activity index (306.96 m2 g−1) and emulsion stability index (94.80%) at pH 9.0. CONCLUSION: Ultrasound treatment enhanced the physicochemical properties of MBHP, which could broaden its application as a vital ingredient in the food industry. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Cancer vaccines represent among the most promising strategies in the battle against cancers. However, the clinical efficacy of current cancer vaccines is largely limited by the lack of optimized delivery systems to generate strong and persistent antitumor immune responses. Moreover, most cancer vaccines require multiple injections to boost the immune responses, leading to poor patient compliance. Controlled-release drug delivery systems are able to address these issues by presenting drugs in a controlled spatiotemporal manner, which allows co-delivery of multiple drugs, reduction of dosing frequency and avoidance of significant systemic toxicities. In this review, we outline the recent progress in cancer vaccines including subunit vaccines, genetic vaccines, dendritic cell-based vaccines, tumor cell-based vaccines and in situ vaccines. Furthermore, we highlight the efforts and challenges of controlled or sustained release drug delivery systems (e.g., microparticles, scaffolds, injectable gels, and microneedles) in ameliorating the safety, effectiveness and operability of cancer vaccines. Finally, we briefly discuss the correlations of vaccine release kinetics and the immune responses to enlighten the rational design of the next-generation platforms for cancer therapy.

Deep learning is the major technique used to identify objects in images captured by the synthetic aperture radar (SAR). While SAR images can be used to identify ships in general, detecting multiple ships or small vessels in these images in complex contexts remains an outstanding challenge. This study proposes a model of detection based on the improved PP-YOLO deep convolutional neural network that can identify multiple ships as well as small vessels in complex scenarios from SAR images. The histogram equalization algorithm is first used to preprocess the SAR images, and then the initial anchor box is optimized by using the shape similarity distance-based K-means clustering algorithm. Following this, the accuracy of the training network is improved based on the feature pyramid network and an attention mechanism. The experimental results show that the average accuracy (average precision) of the model was 94.25% at 41.63 frames per second on the GF-3 and the Sentinel-1 SAR datasets, superior to those of YOLOv3 (Darknet), YOLOv7, FPN (VGG), SSD, Faster R-CNN, and PP-YOLO (RestNet50-vd). The model also satisfies the demands of real-time detection. [ABSTRACT FROM AUTHOR]

Cancer-related fatigue (CRF) is one of the most common and serious complications in cancer patients, which greatly reduces the quality of life. The mechanism induced fatigue may be diverse. In this study, we tried to investigate the effect of 1,25(OH)2D3, the active metabolite of vitamin D on CRF in Lewis lung cancer-bearing mice. Network pharmacological analysis, behavioral testing, western blotting, ELISA and flow cytometry were used. We found that there was an interaction between proteins related to the role of 1,25(OH)2D3 and CRF-related proteins. The results of animal model experiments showed that 1,25(OH)2D3 could mitigate the CRF behavior of tumor-bearing mice, and the treatment of 1,25(OH)2D3 reduced the levels of inflammatory factors, changed the tryptophan metabolism direction, and caused changes in immune cells. Collectively, 1,25(OH)2D3 might improve CRF in tumor-bearing mice by changing the direction of tryptophan metabolism and inflammatory factor levels. This study provided a possible solution for patients with clinical CRF.

Let (Zn) be a supercritical bisexual branching process in a random environment ξ. We study the almost sure (a.s.) convergence rate of the submartingale to its limit , where (In) is an usually used norming sequence. We prove that under a moment condition of order p ∈ (1, 2), a.s. for some a > 0 that we find explicitly; assuming the logarithmic moment condition holds, we have a.s.. In order to obtain these results, we provide the Lp — convergence of (); similar conclusions hold for a bisexual branching process in a varying environment. [ABSTRACT FROM AUTHOR]