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Lung cancer ranks the top of malignancies that cause cancer-related deaths worldwide. The leaves of Morus alba L are traditional Chinese medicine widely applied in respiratory diseases. Our previous work has demonstrated the anti-lung cancer effect of secondary metabolites of mulberry leaf, but their mechanism of action has still not fully elucidated. We synthesized Moracin N (MAN)-Probe conjugated with alkyne to label lung cancer cells and identified protein targets by chemical proteomic analysis. MAN and its probe exerted similar growth-inhibitory effect on human lung cancer cells. Chemical proteomic results showed that MAN targeted the programmed death ligand 1 (PD-L1) checkpoint pathway and T cell receptor (TCR) signaling pathway, indicating its immune-regulatory function. Cell-free surface plasmon resonance (SPR) results showed the direct interaction of MAN with PD-L1 protein. Molecular docking analysis demonstrated that MAN bound to E158 residue of PD-L1 protein. MAN downregulated the expression levels of PD-L1 in a time- and dose-dependent manner and disrupted the PD-L1/programmed death 1 (PD-1) binding, including other secondary metabolites of mulberry leaves Guangsangon E (GSE) and Chalcomoracin (CMR). Human peripheral blood mononuclear cells (PBMCs) co-cultured with MAN-treated A549 cells, resulting in the increase of CD8+ GZMB+ T cells and the decrease of CD8+ PD-1+ T cells. It suggested that MAN exerts anti-cancer effect through blocking the PD-L1/PD-1 signaling. In vivo, MAN combined with anti-PD-1 antibody significantly inhibited lung cancer development and metastasis, indicating their synergistic effect. Taken together, secondary metabolites of mulberry leaves target the PD-L1/PD-1 signaling, enhance T cell-mediated immunity and inhibit the tumorigenesis of lung cancer. Their modulatory effect on tumor microenvironment makes them able to enhance the therapeutic efficacy of immune checkpoint inhibitors in lung cancer.

Abstract The colour‐enhanced point cloud map is increasingly being employed in fields such as robotics, 3D reconstruction and virtual reality. The authors propose ER‐Mapping (Extrinsic Robust coloured Mapping system using residual evaluation and selection). ER‐Mapping consists of two components: the simultaneous localisation and mapping (SLAM) subsystem and the colouring subsystem. The SLAM subsystem reconstructs the geometric structure, where it employs a dynamic threshold‐based residual selection in LiDAR‐inertial odometry to improve mapping accuracy. On the other hand, the colouring subsystem focuses on recovering texture information from input images and innovatively utilises 3D–2D feature selection and optimisation methods, eliminating the need for strict hardware time synchronisation and highly accurate extrinsic parameters. Experiments were conducted in both indoor and outdoor environments. The results demonstrate that our system can enhance accuracy, reduce computational costs and achieve extrinsic robustness.

Colon cancer, the third most frequent occurred cancer, has high mortality and extremely poor prognosis. Ginsenoside, the active components of traditional Chinese herbal medicine Panax ginseng, exerts antitumor effect in various cancers, including colon cancer. However, the detailed molecular mechanism of Ginsenoside in the tumor suppression have not been fully elucidated. Here, we chose the representative ginsenoside Rg3 and reported for the first time that Rg3 induces mitophagy in human colon cancer cells, which is responsible for its anticancer effect. Rg3 treatment leads to mitochondria damage and the formation of mitophagosome; when autophagy is inhibited, the clearance of damaged mitochondria can be reversed. Next, our results showed that Rg3 treatment activates the PINK1-Parkin signaling pathway and recruits Parkin and ubiquitin proteins to mitochondria to induce mitophagy. GO analysis of Parkin targets showed that Parkin interacts with a large number of mitochondrial proteins and regulates the molecular function of mitochondria. The cellular energy metabolism enzyme GAPDH is validated as a novel substrate of Parkin, which is ubiquitinated by Parkin. Moreover, GAPDH participates in the Rg3-induced mitophagy and regulates the translocation of Parkin to mitochondria. Functionally, Rg3 exerts the inhibitory effect through regulating the nonglycolytic activity of GAPDH, which could be associated with the cellular oxidative stress. Thus, our results revealed GAPDH ubiquitination by Parkin as a crucial mechanism for mitophagy induction that contributes to the tumor-suppressive function of ginsenoside, which could be a novel treatment strategy for colon cancer.

Parkin, an E3 ubiquitin ligase, plays a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Accumulating evidence suggests that the acetylation modification of the key mitophagy machinery influences mitophagy level, but the underlying mechanism is poorly understood. Here, our study demonstrated that inhibition of histone deacetylase (HDAC) by treatment of HDACis activates mitophagy through mediating Parkin acetylation, leading to inhibition of cervical cancer cell proliferation. Bioinformatics analysis shows that Parkin expression is inversely correlated with HDAC2 expression in human cervical cancer, indicating the low acetylation level of Parkin. Using mass spectrometry, Parkin is identified to interact with two upstream molecules, acetylase acetyl-CoA acetyltransferase 1 (ACAT1) and deacetylase HDAC2. Under treatment of suberoylanilide hydroxamic acid (SAHA), Parkin is acetylated at lysine residues 129, 220 and 349, located in different domains of Parkin protein. In in vitro experiments, combined mutation of Parkin largely attenuate the interaction of Parkin with PTEN induced putative kinase 1 (PINK1) and the function of Parkin in mitophagy induction and tumor suppression. In tumor xenografts, the expression of mutant Parkin impairs the tumor suppressive effect of Parkin and decreases the anticancer activity of SAHA. Our results reveal an acetylation-dependent regulatory mechanism governing Parkin in mitophagy and cervical carcinogenesis, which offers a new mitophagy modulation strategy for cancer therapy.

Abstract Head and neck cancer (HNC) tumorigenesis involves a combination of multiple genetic alteration processes. Tumour necrosis factor-alpha-induced proteins (TNFAIPs) are involved in tumour development and progression, but few studies have been conducted on these factors in HNC. We aimed to analyse TNFAIPs and assess their potential as prognostic biomarkers and therapeutic targets using the Oncomine, UALCAN, Human Protein Atlas, LinkedOmics, cBioPortal, GeneMANIA, Enrichr, and Tumor IMmune Estimation Resource databases. We found that the transcript levels of TNFAIP1, TNFAIP3, EFNA1, TNFAIP6 and TNFAIP8 were increased, while those of TNFAIP8L3 and STEAP4 were reduced in HNC tissues versus normal tissues. The EFNA1, TNFAIP8 and TNFAIP8L3 expression levels were significantly correlated with the pathological stage. In HNC patients, high PTX3 and TNFAIP6 transcript levels were significantly associated with shorter overall survival (OS). Moreover, genetic alterations in TNFAIP1, TNFAIP6, and STEAP4 resulted in poorer disease-free survival, progression-free survival, and OS, respectively. TNFAIPs may mediate HNC tumorigenesis by regulating PI3K-Akt, Ras and other signalling pathways. TNFAIPs are also closely correlated with the infiltration of immune cells, including B cells, CD8+ T cells, CD4+ T cells, etc. The data above indicate that TNFAIPs may be potential biomarkers and therapeutic targets for HNC.

Simultaneous localization and mapping (SLAM) is one of the crucial techniques applied in autonomous robot navigation. The majority of present popular SLAM algorithms are built within probabilistic optimization frameworks, achieving high accuracy performance at the expense of high power consumption and latency. In contrast to robots, animals are born with the capability to efficiently and robustly navigate in nature, and bionic SLAM algorithms have received increasing attention recently. Current bionic SLAM algorithms, including RatSLAM, with relatively low accuracy and robustness, tend to fail in certain challenging environments. In order to design a bionic SLAM system with a novel framework and relatively high practicality, and to facilitate the development of bionic SLAM research, in this paper we present LFVB-BioSLAM, a bionic SLAM system with a light-weight LiDAR-based front end and a bio-inspired vision-based back end. We adopt a range flow-based LiDAR odometry as the front end of the SLAM system, providing the odometry estimation for the back end, and we propose a biologically-inspired back end processing algorithm based on the monocular RGB camera, performing loop closure detection and path integration. Our method is verified through real-world experiments, and the results show that LFVB-BioSLAM outperforms RatSLAM, a vision-based bionic SLAM algorithm, and RF2O, a laser-based horizontal planar odometry algorithm, in terms of accuracy and robustness.

As a heterogeneous group of clonal disorders, acute myeloid leukemia with internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation usually shows an inferior prognosis. In the present study, we found that homoharringtonine (HHT), a protein translation inhibitor of plant alkaloid in China, exhibited potent cytotoxic effect against FLT3-ITD (+) cell lines and primary leukemia cells, and a remarkable synergistic anti-leukemia action was demonstrated in vitro and in vivo in xenograft mouse models when co-treated with the heat shock protein 90 inhibitor IPI504. Mechanistically, HHT combined with IPI504 synergistically inhibited the growth of leukemia cells by inducing apoptosis and G1 phase arrest. This synergistic action resulted in a prominent reduction of total and phosphorylated FLT3 (p-FLT3) as well as inhibition of its downstream signaling molecules such as STAT5, AKT, ERK and 4E-BP1. Furthermore, co-treatment of HHT and IPI504 led to a synergistic or additive effect on 55.56%(10/18) of acute myeloid leukemia cases tested, including three relapsed/refractory patients. In conclusion, our findings indicate that the combination of HHT and HSP90 inhibitor provides an alternative way for the treatment of FLT3-ITD positive acute myeloid leukemia, especially for relapsed/refractory AML.

Background Currently, acute myelocytic leukemia (AML) still has a poor prognosis. As a result, gene markers for predicting AML prognosis must be identified through systemic analysis of multi-omics data. Methods First of all, the copy number variation (CNV), mutation, RNA-Seq, and single nucleotide polymorphism (SNP) data, as well as those clinical follow-up data, were obtained based on The Cancer Genome Atlas (TCGA) database. Thereafter, all samples (n = 229) were randomized as test set and training set, respectively. Of them, the training set was used to screen for genes related to prognosis, and genes with mutation, SNP or CNV. Then, shrinkage estimate was used for feature selection of all the as-screened genes, to select those stable biomarkers. Eventually, a prognosis model related to those genes was established, and validated within the GEO verification (n = 124 and 72) and test set (n = 127). Moreover, it was compared with the AML prognosis prediction model reported in literature. Results Altogether 832 genes related to prognosis, 23 related to copy amplification, 774 associated with copy deletion, and 189 with significant genomic variations were acquired in this study. Later, genes with genomic variations and those related to prognosis were integrated to obtain 38 candidate genes; eventually, a shrinkage estimate was adopted to obtain 10 feature genes (including FAT2, CAMK2A, TCERG1, GDF9, PTGIS, DOC2B, DNTTIP1, PREX1, CRISPLD1 and C22orf42). Further, a signature was established using these 10 genes based on Cox regression analysis, and it served as an independent factor to predict AML prognosis. More importantly, it was able to stratify those external verification, test and training set samples with regard to the risk (P

IntroductionThe leaves of Morus alba L is a traditional Chinese medicine widely applied in lung diseases. Moracin N (MAN), a secondary metabolite extracted form the leaves of Morus alba L, is a potent anticancer agent. But its molecular mechanism remains unveiled.ObjectiveIn this study, we aimed to examine the effect of MAN on human lung cancer and reveal the underlying molecular mechanism.MethodsMTT assay was conducted to measure cell viability. Annexin V-FITC/PI staining was used to detect cell apoptosis. Confocal microscope was performed to determine the formation of autophagosomes and autolysosomes. Flow cytometry was performed to quantify cell death. Western blotting was used to determine the related-signaling pathway.ResultsIn the present study, we demonstrated for the first time that MAN inhibitd cell proliferation and induced cell apoptosis in human non-small-cell lung carcinoma (NSCLC) cells. We found that MAN treatment dysregulated mitochondrial function and led to mitochondrial apoptosis in A549 and PC9 cells. Meanwhile, MAN enhanced autophagy flux by the increase of autophagosome formation, the fusion of autophagsomes and lysosomes and lysosomal function. Moreover, mTOR signaling pathway, a classical pathway regualting autophagy, was inhibited by MAN in a time- and dose-dependent mannner, resulting in autophagy induction. Interestingly, autophagy inhibition by CQ or Atg5 knockdown attenuated cell apoptosis by MAN, indicating that autophagy serves as cell death. Furthermore, autophagy-mediated cell death by MAN can be blocked by reactive oxygen species (ROS) scavenger NAC, indicating that ROS accumulation is the inducing factor of apoptosis and autophagy. In summary, we revealed the molecular mechanism of MAN against lung cancer through apoptosis and autophagy, suggesting that MAN might be a novel therapeutic agent for NSCLC treatment.