Angeliticin B, a new chromone isolated from Angelica polymorpha Maxim.

A new chromone, angeliticin B (1) together with nine known compounds, psoralene (2), isoimperatorin (3), (S)-(-)-2'-methoxypeucedanin hydrate (4), (S)-(-)-oxypeucedanin (5), xanthotoxin (6), isopimpinellin (7), 1'-O-ß-D-glucopyranosyl-(2'S, 3'R)-3'-hydroxymarmesin (8), sec-O-glucosylhamaudol (9) and vanillin (10) were isolated from the methanol extract of Angelica polymorpha Maxim. The structures of these compounds were elucidated through a comprehensive analysis of standard spectral data (MS, IR, and NMR). Compound 1 exhibited antioxidant activity with IC50 = 198.57 µM in DPPH experiment and 31.71 µM in ABTS experiment. Compound 2, 6, 7 exhibited ABTS radical scavenging activity with IC50 ranging from 105.96 µM to 167.67 µM. Compound 3 demonstrated a synergistic induction effect on nigericin-activated NLRP3 inflammasome in THP-1 cell by LDH release method.

Eomesodermin spatiotemporally orchestrates the early and late stages of NK cell development by targeting KLF2 and T-bet, respectively.

Eomesodermin (Eomes) is a critical factor in the development of natural killer (NK) cells, but its precise role in temporal and spatial coordination during this process remains unclear. Our study revealed that Eomes plays distinct roles during the early and late stages of NK cell development. Specifically, the early deletion of Eomes via the CD122-Cre transgene resulted in significant blockade at the progenitor stage due to the downregulation of KLF2, another important transcription factor. ChIP-seq revealed direct binding of Eomes to the conserved noncoding sequence (CNS) of Klf2. Utilizing the CHimeric IMmune Editing (CHIME) technique, we found that deletion of the CNS region of Klf2 via CRISPRi led to a reduction in the NK cell population and developmental arrest. Moreover, constitutive activation of this specific CNS region through CRISPRa significantly reversed the severe defects in NK cell development caused by Eomes deficiency. Conversely, Ncr1-Cre-mediated terminal deletion of Eomes expedited the transition of NK cell subsets from the CD27+CD11b+ phenotype to the CD27-CD11b+ phenotype. Late-stage deficiency of Eomes led to a significant increase in T-bet expression, which subsequently increased the expression of the transcription factor Zeb2. Genetic deletion of one allele of Tbx21, encoding T-bet, effectively reversed the aberrant differentiation of Eomes-deficient NK cells. In summary, we utilized two innovative genetic models to elucidate the intricate mechanisms underlying Eomes-mediated NK cell commitment and differentiation.

A single-cell analysis of the NK-cell landscape reveals that dietary restriction boosts NK cell antitumor immunity via Eomesdermin.

Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cell, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. Natural killer (NK) cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. Herein, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. Firstly, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through non-tumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.