Although immune checkpoint therapy has significantly improved the prognosis of melanoma patients, urgent attention still needs to be paid on the low patient response rates and inability to precisely identify before treatment. Therefore, it is crucial to investigate the novel immunosuppressive mechanisms and targets in the tumor microenvironment in order to reverse tumor immune escape. In this study, we found that the cell cycle checkpoint AURKB suppressed the anti-tumor immune response, and its inhibitor Tozasertib, effectively activated T lymphocytes cytokine release in vitro and anti-tumor immunity in vivo. Tozasertib significantly inhibited the melanoma xenograft tumor growth by decreasing the number of inhibitory CD4+ Treg cells in the tumors, which in turn activated CD8+ T cells. Single-cell analysis revealed that the mechanism by which AURKB suppressed antitumor immunity may be through increasing MIF-CD74/CXCR4 signal communication between tumor cells and lymphocytes. Our study suggests that AURKB is a new identified anti-tumor immunity suppressor whose inhibitors may develop as novel anti-tumor immunity drugs, and may have synergistic anti-melanoma effects with immune checkpoint therapies.
Nicotine is regarded as the main active addictive ingredient in tobacco products driving continued tobacco abuse behavior (smoking) to the addiction behavior, whereas nicotinic acetylcholine receptors (nAChR) is the crucial effective apparatus or molecular effector of nicotine and acetylcholine and other similar ligands.Many nAChR subunits have been revealed to bind to either neurotransmitters or exogenous ligands, such as nicotine and acetylcholine, being involved in the nicotinic receptor signal transduction.Therefore, the nicotinic receptor signalling molecules and the receptor-ligand molecular interactions between nAChRs and their ligands are universally regarded as crucial mediators of cellular functions and drug targets in medical treatment and clinical diagnosis.Given numerous endeavours have been made in defining the roles of nAChRs in response to nicotine and other addictive drugs, this review focuses on studies and reports in recent years on the receptor-ligand interactions between nAChR receptors and ligands, including lipid-nAChR and protein-nAChR molecular interactions, relevant signal transduction pathways and their molecular mechanisms in the nicotinic receptor signalling systems.All the references were carefully retrieved from the PubMed database by searching key words "nicotine", "acetylcholine", "nicotinic acetylcholine receptor(s)", "nAChR*", "protein and nAChR", "lipid and nAChR", "smok*" and "tobacco".All the relevant referred papers and reports retrieved were fully reviewed for manual inspection.This effort intend to get a quick insight and understanding of the nicotinic receptor signalling and their molecular interactions mechanisms.Understanding the cellular receptor-ligand interactions and molecular mechanisms between nAChRs and ligands will lead to a better translational and therapeutic operations and outcomes for the prevention and treatment of nicotine addiction and other chronic drug addictions in the brainʼs reward circuitry.
Abstract IR ‐783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR ‐783 has not been well demonstrated. In this study, we showed that IR ‐783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA ‐ MB ‐231 cells to IR ‐783 resulted in the loss of mitochondrial membrane potential ( MMP ), adenosine triphosphate ( ATP ) depletion, mitochondrial permeability transition pore ( mPTP ) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR ‐783 induced dynamin‐related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor ( MFF ) and fission‐1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 ( OPA 1). Moreover, knockdown of Drp1 markedly blocked IR ‐783‐mediated mitochondrial fission, loss of MMP , ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR ‐783 markedly inhibited tumour growth and induced apoptosis in an MDA ‐ MB ‐231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR ‐783 induces apoptosis in human breast cancer cells by increasing Drp1‐mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti‐breast cancer effects of IR ‐783 and provided novel perspectives for the application of IR ‐783 in the treatment of breast cancer.
Contemporary agricultural science and technology is under great scrutiny. Understanding the past and current trends of Agricultural science and technology is crucial. Fuyang city is one of the Chinese traditional big agricultural cities and the largest city in terms of population in Anhui province, China. In the study, an index system for the development and innovation levels of agricultural science and technology was established and the regional innovation of current agricultural science and technology in Fuyang city was empirically evaluated and analyzed by using the index system based on the existing annual data available. The purpose of this study was to make an objective analysis and evaluation of the sub-area innovation levels among urban districts and counties in Fuyang city. All the data was processed and transformed simultaneously based on the same scales of social-economic index and next analyzed based on the methods of factor analysis in view of dimension reduction. Finally, the comprehensive evaluation was carried out and the scores was ranked as followed by Linquan county, Yingshang county, Funan county, Taihe county, Jieshou county, Yingzhou district, Yingquan district and Yingdong district. It is concluded that the innovation level of Fuyang city is unbalanced with two main features. Firstly, on the whole, the city’s innovation is rather active with supports from subordinate districts and counties, but the innovation levels of subordinate counties are better than those of urban districts in view of the quantities and activities of agricultural science and technology innovation. Higher levels of agricultural science and technology innovation are seen in the natural growing zones. Secondly, in consideration of agricultural science and technology innovation, the different indicators of counties and districts in Fuyang city have shown their own advantages and disadvantages, especially on specific negative principal component score which shows that the corresponding defects on specific principal components. That is, the district or county are relatively backward in corresponding index of agricultural science and technology innovation and even some of the principal component factor have become the bottleneck of these districts or counties for innovation and sustainable development.
Artesunate (ART), a natural product isolated from traditional Chinese plant Artemisia annua, has not been extensively explored for its anti-melanoma properties. In our study, we found that ART inhibited melanoma cell proliferation and induced melanoma cell ferroptosis. Mechanistic study revealed that ART directly targets Ido1, thereby suppressing Hic1-mediated transcription suppression of Hmox1, resulting in melanoma cell ferroptosis. In CD8+ T cells, ART does not cause cell ferroptosis due to the low expression of Hmox1. It also targets Ido1, elevating tryptophan levels, which inhibits NFATc1-mediated PD1 transcription, consequently activating CD8+ T cells. Our study uncovered a potent and synergistic anti-melanoma efficacy arising from ART-induced melanoma cell ferroptosis and concurrently enhancing CD8+ T cell-mediated immune response both in vivo and in vitro through directly targeting Ido1. Our study provides a novel mechanistic basis for the utilization of ART as an Ido1 inhibitor and application in clinical melanoma treatment.
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