Plant growth regulators and Axl and immune checkpoint inhibitors from the edible mushroom Leucopaxillus giganteus

ABSTRACT

A novel compound, (R)-4-ethoxy-2-hydroxy-4-oxobutanoic acid (1), and six known compounds (2–7) were isolated from the fruiting bodies of the wild edible mushroom Leucopaxillus giganteus. The planar structure of 1 was determined by the interpretation of spectroscopic data analysis. The absolute configuration of 1 was determined by comparing specific rotation of the synthetic compounds. In the plant regulatory assay, the isolated compounds (1–7) and the chemically prepared compounds (8–10) were evaluated their biological activity against the lettuce (Lactuca sativa) growth. Compounds 1 and 3–10 showed the significant regulatory activity of lettuce growth. 1 showed the strongest inhibition activity among the all the compounds tested. In the lung cancer assay, all the compounds were assessed the mRNA expression of Axl and immune checkpoints (PD-L1, PD-L2) in the human A549 alveolar epithelial cell line by RT-PCR. Compounds 1–10 showed significant inhibition activity against Axl and/or immune checkpoint.     

Positive selection and convergent evolution shape molecular phenotypic traits of innate immunity receptors in tits (Paridae)

Despite widespread variability and redundancy abounding animal immunity, little is currently known about the rate of evolutionary convergence (functionally analogous traits not inherited from a common ancestor) in host molecular adaptations to parasite selective pressures. Toll‐like receptors (TLRs) provide the molecular interface allowing hosts to recognize pathogenic structures and trigger early danger signals initiating an immune response. Using a novel combination of bioinformatic approaches, here we explore genetic variation in ligand‐binding regions of bacteria‐sensing TLR4 and TLR5 in 29 species belonging to the tit family of passerine birds (Aves: Paridae). Three out of the four consensual positively selected sites in TLR4 and six out of 14 positively selected positions in TLR5 were located on the receptor surface near the functionally important sites, and based on the phylogenetic pattern evolved in a convergent (parallel) manner. This type of evolution was also seen at one N‐glycosylation site and two positively selected phosphorylation sites, providing the first evidence of convergence in post‐translational modifications in evolutionary immunology. Finally, the overall mismatch between phylogeny and the clustering of surface charge distribution demonstrates that convergence is common in overall TLR4 and TLR5 molecular phenotypes involved in ligand binding. Our analysis did not reveal any broad ecological traits explaining the convergence observed in electrostatic potentials, suggesting that information on microbial symbionts may be needed to explain TLR evolution. Adopting state‐of‐the‐art predictive structural bionformatics, we have outlined a new broadly applicable methodological approach to estimate the functional significance of positively selected variation and test for the adaptive molecular convergence in protein‐coding polymorphisms.     

Balancing selection in Pattern Recognition Receptor signalling pathways is associated with gene function and pleiotropy in a wild rodent

Pathogen‐mediated balancing selection is commonly considered to play an important role in the maintenance of genetic diversity, in particular in immune genes. However, the factors that may influence which immune genes are the targets of such selection are largely unknown. To address this, here we focus on Pattern Recognition Receptor (PRR) signalling pathways, which play a key role in innate immunity. We used whole‐genome resequencing data from a population of bank voles (Myodes glareolus) to test for associations between balancing selection, pleiotropy and gene function in a set of 123 PRR signalling pathway genes. To investigate the effect of gene function, we compared genes encoding (a) receptors for microbial ligands versus downstream signalling proteins, and (b) receptors recognizing components of microbial cell walls, flagella and capsids versus receptors recognizing features of microbial nucleic acids. Analyses based on the nucleotide diversity of full coding sequences showed that balancing selection primarily targeted receptor genes with a low degree of pleiotropy. Moreover, genes encoding receptors recognizing components of microbial cell walls etc. were more important targets of balancing selection than receptors recognizing nucleic acids. Tests for localized signatures of balancing selection in coding and noncoding sequences showed that such signatures were mostly located in introns, and more evenly distributed among different functional categories of PRR pathway genes. The finding that signatures of balancing selection in full coding sequences primarily occur in receptor genes, in particular those encoding receptors for components of microbial cell walls etc., is consistent with the idea that coevolution between hosts and pathogens is an important cause of balancing selection on immune genes.     

The landscape and prognostic value of immune characteristics in uterine corpus endometrial cancer

In the present study, we explored the clinical and immunological characteristics of 575 uterine corpus endometrial carcinoma (UCEC) samples obtained from The Cancer Genome Atlas (TCGA) using the ESTIMATE and CIBERSORT algorithms. First, Kaplan–Meier and univariate Cox regression analyses indicated that the immune cell score was a prognostic factor for overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox regression analysis further revealed that the immune cell score was an independent prognostic factor for UCEC patients. Second, we investigated the correlation between the infiltration levels of 22 types of immune cells and the immune score. Survival analysis based on the 22 immune cell types showed that higher levels of regulatory T cell, activated NK cell, and follicular helper T-cell infiltration were associated with longer OS, while higher levels of CD8+ T cell and naive B-cell infiltration were associated with longer RFS. Next, we performed differential expression and prognosis analyses on 1534 immune-related genes and selected five from 14 candidate genes to construct a prognostic prediction model. The area under the receiver-operating characteristic (ROC) curve (AUC) for 3- and 5-year survival were 0.711 and 0.728, respectively. Further validation using a stage I–II subgroup showed similar results, presenting AUC values for 3- and five-year survival of 0.677 and 0.692, respectively. Taken together, the present study provides not only a deeper understanding of the relationship between UCEC and the immune landscape but also guidance for the future development of UCEC immunotherapy.     

Correlations between glycolysis with clinical traits and immune function in bladder urothelial carcinoma

Background: Glycolysis was a representative hallmark in the tumor microenvironment (TME), and we aimed to explore the correlations between glycolysis with immune activity and clinical traits in bladder urothelial carcinoma (BLCA).Methods: Our study obtained glycolysis scores for each BLCA samples from TCGA by a single-sample gene set enrichment analysis (ssGSEA) algorithm, based on a glycolytic gene set. The relationship between glycolysis with prognosis, clinical characteristics, and immune function were investigated subsequently.Results: We found that enhanced glycolysis was associated with poor prognosis and metastasis in BLCA. Moreover, glycolysis had a close correlation with immune function, and enhanced glycolysis increased immune activities. In other words, glycolysis had a positive correlation with immune activities. Immune checkpoints such as IDO1, CD274, were up-regulated in high-glycolysis group as well.Conclusion: We speculated that in BLCA, elevated glycolysis enhanced immune function, which caused tumor cells to overexpress immune checkpoints to evade immune surveillance. Inhibition of glycolysis might be a promising assistant for immunotherapy in bladder cancer.     

Kunitz型丝氨酸蛋白酶抑制剂研究进展

Kunitz型丝氨酸蛋白酶抑制剂是一类普遍存在的蛋白酶抑制剂,在体内各项生命活动中扮演着重要角色。这类抑制剂结构稳定且富有特色,通常具有一个或几个串联存在的Kunitz结构域,能够以类似底物的方式与丝氨酸蛋白酶结合,从而抑制酶的活性。在功能方面,Kunitz型丝氨酸蛋白酶抑制剂参与凝血和纤维蛋白溶解、肿瘤免疫、炎症调节以及抵抗细菌、真菌感染等过程。文中就Kunitz型丝氨酸蛋白酶抑制剂研究进展作一综述,为新型Kunitz型丝氨酸蛋白酶抑制剂的开发提供研究思路。     

Innate lymphoid cells and gastrointestinal disease

Innate lymphoid cells (ILCs) are a group of innate immune cells, which constitute the first line of defense in the immune system, together with skin and mucous membrane. ILCs also play an important role in maintaining the homeostasis of the body, particularly in the complex and diverse environment of the intestine. ILCs respond to different microenvironments, maintaining homeostasis directly or indirectly through cytokines. As a result, ILCs, with complex and pleiotropic characteristics, are associated with many gastrointestinal diseases. Their ability of transition among those subgroups makes them function as both promoting and inhibiting cells, thus affecting homeostasis and disease progressing to either alleviation or deterioration. With these special characteristics, ILCs theoretically can be used in the new generation of immunotherapy as an alternative and supplement to current tumor therapy. Our review summarizes the characteristics of ILCs with respect to category, function, and the relationship with intestinal homeostasis and gastrointestinal diseases. In addition, potential tumor immunotherapies involving ILCs are also discussed to shed light on the perspectives of immunotherapy.     

鳞翅目昆虫抗病毒免疫反应的研究进展

鳞翅目昆虫种类繁多,对农业生产和人类生活产生重大影响,宿主昆虫与病毒相互关系的研究对于利用病毒杀虫剂进行害虫治理和益虫病毒性疾病的预防具有重要意义.因此,鳞翅目昆虫与病毒的互作研究显得尤为重要,宿主昆虫的免疫系统在抗病毒感染过程中发挥着关键作用,对病毒产生不同程度的免疫反应.本文综述了昆虫围食膜和中肠对病毒入侵的防御作用,病毒进入体腔后昆虫所产生的细胞免疫和体液免疫反应,以及RNAi、细胞的自噬与凋亡、Toll、Imd、JAK-STAT和STING信号通路等相关的抗病毒免疫途径,并对昆虫抗病毒免疫研究的制约因素和未来鳞翅目昆虫抗病毒免疫的研究重点进行了讨论,以期为害虫的生物防治和益虫疾病的防控提供理论依据.     

Regulation of the innate immune cells during pregnancy: An immune checkpoint perspective

The foetus can be regarded as a half-allograft implanted into the maternal body. In a successful pregnancy, the mother does not reject the foetus because of the immune tolerance mechanism at the maternal-foetal interface. The innate immune cells are a large part of the decidual leukocytes contributing significantly to a successful pregnancy. Although the contributions have been recognized, their role in human pregnancy has not been completely elucidated. Additionally, the accumulated evidence demonstrates that the immune checkpoint molecules expressed on the immune cells are co-inhibitory receptors regulating their activation and biological function. Therefore, it is critical to understand the immune microenvironment and explore the function of the innate immune cells during pregnancy. This review summarizes the classic immune checkpoints such as PD-1, CTLA-4 and some novel molecules recently identified, including TIM-3, CD200, TIGIT and the Siglecs family on the decidual and peripheral innate immune cells during pregnancy. Furthermore, it emphasizes the role of the immune checkpoint molecules in pregnancy-associated complications and reproductive immunotherapy.