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 regu-lation 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 in vivo,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 demon-strate 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 b-catenin oncogenic pathway in vivo.Specifically,we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with b-catenin activity within the TME,involving macrophages and T cells.In summary,our study undergoes the po-tential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment,thereby mitigating the risk of malignancies.

Circumferential variation in mechanical characteristics of porcine descending aorta

Arterial characterization of healthy descending thoracic aorta(DTA)is indispensable in determining stress distributions across wall thickness and different regions that may be responsible for aorta inhomogeneous dilation,rupture,and dissection when aneurysm occurs.Few studies have shown the inhomogeneity of DTA along the aorta tree considering changes in circumferential direction.The present study aims to clarify the circumferential regional characterization of DTA.Porcine DTA tissues were tested according to region and orientation using uniaxial tension.For axial test,results show that the difference in circumferential direction was mainly in collagen fiber modulus,where the anterior collagen fiber modulus was significantly lower than the posterior quadrant.For circumferential test,the difference in circumferential direction was mainly in the recruitment parameter,where the circumferential stiffness is significantly higher in the posterior region at physiological maximum stress.The proximal posterior quadrant and left quadrant showed significantly lower axial collagen fiber stiffness than the right and anterior quadrants,which may be a factor in aneurysm development.Furthermore,the constitutive parameters for similar detailed regions can be used by biomedical engineers to investigate improved therapies and thoroughly understand the initial stage of aneurysm development.The regional collagen fiber modulus can help improve our understanding of the mechanisms of arterial dilation and aortic dissection.