Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8 T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8 T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8 T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.

Materials with multifunctionality or multiresponsiveness, especially polymers derived from green, renewable precursors, have recently attracted significant attention resulting from their technological impact. Nowadays, vegetable‐oil‐based waterborne polyurethanes (WPUs) are widely used in various fields, while strategies for simultaneous realization of their self‐healing, reprocessing, shape memory as well as high mechanical properties are still highly anticipated. We report development of a multifunctional castor‐oil‐based waterborne polyurethane with high strength using controlled amounts of dithiodiphenylamine. The polymer networks possessed high tensile strength up to 38 MPa as well as excellent self‐healing efficiency. Moreover, the WPU film exhibited a maximum recovery of 100 % of the original mechanical properties after reprocessing four times. The broad glass‐transition temperature of the samples endowed the films with a versatile shape‐memory effect, including a dual‐to‐quadruple shape‐memory effect.

Evodiamine, a naturally occurring indole alkaloid, is one of the main bioactive ingredients of Evodiae fructus. With respect to the pharmacological actions of evodiamine, more attention has been paid to beneficial effects in insults involving cancer, obesity, nociception, inflammation, cardiovascular diseases, Alzheimer's disease, infectious diseases and themoregulative effects. evodiamine has evolved a superior ability to bind various proteins, so we also argue that it is good starting point for multi-target drugs. This review is primarily addressed to the description of the recent advances in the biological activity studies of evodiamine, with a focus on pharmacological mechanism. The present review also includes the pharmacokinetics and the detailed exploration of target-binding properties of evodiamine in an attempt to provide a direction for further multi-target drug design.

Stromal cell-derived factor-1 (SDF-1) is a potent chemokine for bone marrow-derived stromal stem cells (BMSCs) that express CXCR4, the receptor for SDF-1. SDF-1 is considered to play an important role in the trafficking of BMSCs. We investigated the contribution of SDF-1 to the recruitment of BMSCs to the wound area and its promotion of wound repair and neovascularization. BMSCs were pretreated with or without anti-CXCR4 blocking antibody and combined with CM-DiI label, and injected via the tail vein into mice with full-thickness skin wounds on the dorsum. Simultaneously, anti-SDF-1 antibody was injected into local wounds in another group of mice. The results show that blockade of CXCR4 on either infused BMSCs or SDF-1 in the host wounds (1) dramatically impaired the number of infused BMSCs being recruited to the injured tissue, (2) reduced the expression of growth factors involved in the repair of injured tissue such as vascular endothelial growth factor, basic fibroblast growth factor and transforming growth factor beta 1, (3) decreased the resultant neovascularization, and (4) retarded wound healing. Taken together, the findings indicate that the SDF-1/CXCR4 signal pathway facilitates wound healing through augmenting BMSC recruitment to wound tissues, responsive secretion of growth factors by BMSCs and neovascularization in the wound area.

BackgroundDynamic contrast-enhanced MRI (DCE-MRI) estimates vascular permeability of brain tumors, and susceptibility-weighted imaging (SWI) may demonstrate tumor vascularity by intratumoral susceptibility signals (ITSS). This study assessed volume transfer constant (Ktrans) accuracy, the volume of extravascular extracellular space (EES) per unit volume of tissue (Ve) derived from DCE-MRI, and the degree of ITSS in glioma grading.MethodsThirty-two patients with different glioma grades were enrolled in this retrospective study. Patients underwent DCE-MRI and non-contrast enhanced SWI by three-tesla scanning. Ktrans values, Ve, and the degree of ITSS in glioma were compared. Receiver operating characteristic (ROC) curve analysis determined diagnostic performances of Ktrans and Ve in glioma grading, and Spearman’s correlation analysis determined the associations between Ktrans, Ve, ITSS, and tumor grade.ResultsKtrans and Ve values were significantly different between low grade gliomas (LGGs) and both high grade gliomas (HGGs) and grade II, III and IV gliomas (P < 0.01). The degree of ITSS of LGGs was lower than HGGs (P < 0.01), and the ITSS of grade II gliomas was lower than grade III or IV gliomas. Ktrans and Ve were correlated with glioma grade (P < 0.01), while ITSS was moderately correlated (P < 0.01). Ktrans values were moderately correlated with ITSS in the same segments (P < 0.01).ConclusionKtrans and Ve values, and ITSS helped distinguish the differences between LGGs and HGGs and between grade II, III and IV gliomas. There was a moderate correlation between Ktrans and ITSS in the same tumor segments.

Adhesion of circulating tumor cells (CTCs) to vascular endothelial bed becomes a crucial starting point in metastatic cascade. We hypothesized that nitric oxide (NO) may prevent cancer metastasis from happening by its direct vasodilation and inhibition of cell adhesion molecules (CAMs). Here we show that S-nitrosocaptopril (CAP-NO, a typical NO donor) produced direct vasorelaxation that can be antagonized by typical NO scavenger hemoglobin and guanylate cyclase inhibitor. Cytokines significantly stimulated production of typical CAMs by the highly-purified human umbilical vein endothelial cells (HUVECs). CAP-NO inhibited expression of the stimulated CAMs (particularly VCAM-1) and the resultant hetero-adhesion of human colorectal cancer cells HT-29 to the HUVECs in a concentration-dependent manner. The same concentration of CAP-NO, however, did not significantly affect cell viability, cell cycle and mitochondrial membrane potential of HT-29, thus excluding the possibility that inhibition of the hetero-adhesion was caused by cytotoxicity by CAP-NO on HT-29. Hemoglobin reversed the inhibition of CAP-NO on both the hetero-adhesion between HT-29 and HUVECs and VCAM-1 expression. These data demonstrate that CAP-NO, by directly releasing NO, produces vasorelaxation and interferes with hetero-adhesion of cancer cells to vascular endothelium via down-regulating expression of CAMs. The study highlights the importance of NO in cancer metastatic prevention.

The aryl hydrocarbon receptor (AhR) is an important immune regulator with a role in inflammatory response. However, the role of AhR in IL-10 production by inflammatory macrophages is currently unknown. In this study, we investigated LPS-induced IL-10 expression in macrophages from AhR-KO mice and AhR-overexpressing RAW264.7 cells. AhR was highly expressed after LPS stimulation through NF-κB pathway. Loss of AhR resulted in reduced IL-10 expression in LPS-induced macrophages. Moreover, the IL-10 expression was elevated in LPS-induced AhR-overexpressing RAW264.7 cells. Maximal IL-10 expression was dependent on an AhR non-genomic pathway closely related to Src and STAT3. Furthermore, AhR-associated Src activity was responsible for tyrosine phosphorylation of STAT3 and IL-10 expression by inflammatory macrophages. Adoptive transfer of AhR-expressing macrophages protected mice against LPS-induced peritonitis associated with high IL-10 production. In conclusion, we identified the AhR-Src-STAT3-IL-10 signaling pathway as a critical pathway in the immune regulation of inflammatory macrophages, It suggests that AhR may be a potential therapeutic target in immune response.

The ternary and tandem strategies are effective methods for improving the photovoltaic performance of organic solar cells (OSCs). Here an asymmetric wide-bandgap nonfullerene acceptor named AITC is synthesized. AITC with...