Potential distribution prediction of Ceracris kiangsu Tsai in China.

Ceracris kiangsu Tsai (C. kiangs) is a kind of forest pest, which can harm nearly 100 kinds of weeds and crops. In this study, based on 314 species distribution points of C. kiangsu which were obtained from Chinese herbaria, literatures and investigation, and data of three future climate scenarios presented by CMIP6, two niche models (Garp, Maxent) were used to predict the suitable area of C. kiangsu in China. The result shows that the main environmental factors affecting the distribution of C. kiangsu are precipitation of driest month (bio14) and min temperature of coldest month (bio6). No matter now and future, the potential distribution areas of C. kiangsu in China are mainly in the south of Qinling-Huaihe River. Under current scenarios, the areas of the total, highly, moderately and poorly suitable of C. kiangsu in China are 160.65 × 104 km2, 31.70 × 104 km2, 60.36 × 104 km2 and 68.59 × 104 km2 respectively. The southern Hubei, western Jiangxi and eastern Hunan are highly-suitable areas. Under SSP1-2.6 and SSP2-4.5 scenarios, both the total suitable area and the highly suitable show a decreasing tread in 2050s. Compared to the 2050s, the total suitable area will coninue to decease in 2090s under SSP1-2.6, while it will increase under SSP2-4.5. The highly suitable area will increase in both scenarios, and the increased percentage under SSP2-4.5 is greater than that under SSP1-2.6. Under SSP5-8.5 scenarios, the total suitable area will increase by 1.83% in the 2050s, and decrease by 1.17% in the 2090s. The highly suitable area in the 2050s and 2090s under this scenarios is larger than under current scenarios. No matter what the scenario, the southern part of Yunnan, the southeast of Sichuan and the southwest of Chongqing will become highly-suitable areas as the climate continues to warm and should be monitored more cosely.

The potential mechanism of Aidi injection against neuroblastoma-an investigation based on network pharmacology analysis.

Background: Aidi injection, a classic traditional Chinese medicine (TCM) formula, has been used on a broader scale in treating a variety of cancers. In this study, we aimed to explore the potential anti-tumor effects of Aidi injection in the treatment of neuroblastoma (NB) using network pharmacology (NP). Methods: To elucidate the anti-NB mechanism of Aidi injection, an NP-based approach and molecular docking validation were employed. The compounds and target genes were collected from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN-TCM) database. The protein-protein interaction network was constructed using the STRING database. clusterProfiler (R package) was utilized to annotate the bioinformatics of hub target genes. The gene survival analysis was performed on R2, a web-based genomic analysis application. iGEMDOCK was used for molecular docking validation, and GROMACS was utilized to validate molecular docking results. Furthermore, we investigated the anticancer effects of gomisin B and ginsenoside Rh2 on human NB cells using a cell viability assay. The Western blot assay was used to validate the protein levels of target genes in gomisin B- and ginsenoside Rh2-treated NB cells. Results: A total of 2 critical compounds with 16 hub target genes were identified for treating NB. All 16 hub genes could potentially influence the survival of NB patients. The top three genes (EGFR, ESR1, and MAPK1) were considered the central hub genes from the drug-compound-hub target gene-pathway network. The endocrine resistance and estrogen signaling pathways were identified as the therapeutic pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Gomisin B and ginsenoside Rh2 showed a good binding ability to the target protein in molecular docking. The results of cell experiments showed the anti-NB effect of gomisin B and ginsenoside Rh2. In addition, the administration of gomisin B over-regulated the expression of ESR1 protein in MYCN-amplified NB cells. Conclusion: In the present study, we investigated the potential pharmacological mechanisms of Aidi against NB and revealed the anti-NB effect of gomisin B, providing clinical evidence of Aidi in treating NB and establishing baselines for further research.

C1Q labels a highly aggressive macrophage-like leukemia population indicating extramedullary infiltration and relapse.

Extramedullary infiltration (EMI) is a concomitant manifestation that may indicate poor outcome of acute myeloid leukemia (AML). The underlying mechanism remains poorly understood and therapeutic options are limited. Here, we employed single-cell RNA sequencing on bone marrow (BM) and EMI samples from a patient with AML presenting pervasive leukemia cutis. A complement C1Q+ macrophage-like leukemia subset, which was enriched within cutis and existed in BM before EMI manifestations, was identified and further verified in multiple patients with AML. Genomic and transcriptional profiling disclosed mutation and gene expression signatures of patients with EMI that expressed high levels of C1Q. RNA sequencing and quantitative proteomic analysis revealed expression dynamics of C1Q from primary to relapse. Univariate and multivariate analysis demonstrated adverse prognosis significance of C1Q expression. Mechanistically, C1Q expression, which was modulated by transcription factor MAF BZIP transcription factor B, endowed leukemia cells with tissue infiltration ability, which could establish prominent cutaneous or gastrointestinal EMI nodules in patient-derived xenograft and cell line-derived xenograft models. Fibroblasts attracted migration of the C1Q+ leukemia cells through C1Q-globular C1Q receptor recognition and subsequent stimulation of transforming growth factor ß1. This cell-to-cell communication also contributed to survival of C1Q+ leukemia cells under chemotherapy stress. Thus, C1Q served as a marker for AML with adverse prognosis, orchestrating cancer infiltration pathways through communicating with fibroblasts and represents a compelling therapeutic target for EMI.

Genome-wide analysis of milk vetch dwarf virus and related alphasatellites from garlic and aphids in Shandong Province, China.

In 2019 and 2020, symptoms of dwarfing, yellowing, and reddening were observed in garlic in open fields in Shandong Province, China. Milk vetch dwarf virus (MDV) was detected in aphids and symptomatic garlic plants using polymerase chain reaction analysis. Furthermore, it was demonstrated using an aphid transmission test that garlic is a natural host of MDV. Rolling-circle amplification was combined with the use of specific primers to amplify the complete genomes of MDV and its related alphasatellites. This is the first report of complete genome sequences of MDV and related alphasatellites from garlic and aphid samples.

Kynurenine derivative 3-HAA is an agonist ligand for transcription factor YY1.

The 3-hydroxyanthranilic acid (3-HAA), a derivative of kynurenine, was reported to suppress tumor growth. However, the function of 3-HAA largely remains unclear. Here, we report that 3-hydroxyanthranilic acid (3-HAA) is lower in tumor cells, while adding exogenous 3-HAA induces apoptosis in hepatocellular carcinoma by binding YY1. This 3-HAA binding of YY1 leads to phosphorylation of YY1 at the Thr 398 by PKCζ, concomitantly enhances YY1 chromatin binding activity to increase expression of target genes. These findings demonstrate that 3-HAA is a ligand of YY1, suggesting it is a promising therapeutic candidate for HCC.

3-hydroxyanthranic acid increases the sensitivity of hepatocellular carcinoma to sorafenib by decreasing tumor cell stemness.

Sorafenib is the FDA-approved first-line target drug for HCC patients. However, sorafenib only confers 3-5 months of survival benefit with <30% of HCC patients. Thus, it is necessary to develop a sensitizer for hepatocellular carcinoma (HCC) to sorafenib. Here, we report that in representative HCC cell lines (SMMC-7721 and PLC8024) that are insensitive to sorafenib, 3-HAA (50 µM) significantly enhances cell sensitivity to sorafenib to an extent that could not be explained by additive effects. In nude mice carrying HCC xenograft, tumor growth is inhibited by sorafenib (10 mg/kg/day) or 3-HAA (100 mg/kg/day) alone. When used in combination, the treatment effectively prevents the xenograft from growing. In a set of mechanistic experiments, we find enhanced AKT activation and increased proportion of CD44+CD133+ cells in sorafenib-resistant HCC cells and tissues. The proportion of CD44+CD133+ cells is reduced upon 3-HAA treatment in both cultured cells and mouse xenografts, suggesting that 3-HAA could decrease the stemness of HCC. We also detect decreased phosphorylation of AKT, a regulator of the GSK3ß/ß-catenin signaling upon 3-HAA treatment. The AKT activator SC79 activates GSK3 ß/ß-catenin signaling while the Wnt inhibitor XAV-939 abolishes 3-HAA inhibition of HCC growth in vitro and in mice. The current study demonstrates that 3-HAA sensitizes HCC cells to sorafenib by reducing tumor stemness, suggesting it is a promising molecule for HCC therapy.

The kynurenine derivative 3-HAA sensitizes hepatocellular carcinoma to sorafenib by upregulating phosphatases.

Objectives: Sorafenib is the only FDA-approved first-line target drug for HCC patients. However, sorafenib merely confers 3-5 months of survival benefit with less than 30% of HCC patients sensitive to sorafenib therapy. Thus, it's necessary to develop a sensitizer for hepatocellular carcinoma (HCC) to sorafenib. Methods: The principal component analysis, gene ontology, and KEGG analysis are utilized following RNA-sequencing. The mass spectrometry analysis following immunoprecipitation is performed to discover the phosphatase targets. Most importantly, both the cell line-derived xenograft (CDX) and the patient-derived xenograft (PDX) mouse model are used to determine the effect of 3-HAA on sorafenib-resistant HCC in vivo. Results: In nude mice carrying HCC xenograft, tumor growth is inhibited by sorafenib or 3-HAA alone. When used in combination, the treatment particularly prevents the xenograft from growing. Combined treatment also suppresses the growth of sorafenib-resistant (≥30mg/kg) PDXs. In a set of mechanistic experiments, we find enhanced AKT activation and decreased apoptotic cells in de novo and acquired sorafenib-resistant HCC cells and tissues. 3-HAA decreases AKT phosphorylation and increases the apoptosis of HCC in both cultured cells and mouse xenografts by upregulation of phosphatases PPP1R15A/DUSP6. PPP1R15A/PPP1α directly reduces Akt phosphorylation while DUSP6 decreases Akt activity through inhibiting PDK1. The AKT activator abolishes 3-HAA inhibition of HCC growth in vitro and in mice. Conclusion: This study demonstrates that 3-HAA sensitizes HCC cells to sorafenib by upregulation of phosphatases, suggesting it as a promising molecule for HCC therapy.

The influence of microenvironment on tumor immunotherapy.

Tumor immunotherapy has achieved remarkable efficacy, with immune-checkpoint inhibitors as especially promising candidates for cancer therapy. However, some issues caused by immunotherapy have raised attention, such as limited efficacy for some patients, narrow antineoplastic spectrum, and adverse reactions, suggesting that using regulators of tumor immune response may prove to be more complicated than anticipated. Current evidence indicates that different factors collectively constituting the unique tumor microenvironment promote immune tolerance, and these include the expression of co-inhibitory molecules, the secretion of lactate, and competition for nutrients between tumor cells and immune cells. Furthermore, cancer-associated fibroblasts, the main cellular components of solid tumors, promote immunosuppression through inhibition of T cell function and extracellular matrix remodeling. Here, we summarize the research advances in tumor immunotherapy and the latest insights into the influence of microenvironment on tumor immunotherapy.

SC1 inhibits the differentiation of F9 embryonic carcinoma cells induced by retinoic acid.

The ability to self-renew is one of the most important properties of embryonic stem (ES) cells. Pluripotin (SC1), a small molecule with high activity and low toxicity, promotes self-renewal in mouse ES cells. SC1 can noticeably change the morphology of retinoic acid (RA)-induced F9 embryonic carcinoma cells (F9 cells). However, in the long term, RA and SC1 together cause cell apoptosis. When being added after 18-24 h of RA-induced F9 cell differentiation, SC1 transitorily activated Nanog and Oct4. Both Nanog and Oct4 were downregulated when SC1 and RA were added simultaneously. On the other hand, Klf4 was continually activated when SC1 was added between 6 and 24 h. Phosphorylated Erk1/2 protein levels were reduced from 6 to 24 h, whereas unphosphorylated Erk1 protein levels remained unchanged. A higher concentration of SC1 promoted cell self-renewal by strengthening the inhibition of Erk1/2 protein phosphorylation in F9 cells. Furthermore, SC1 and RA affect global DNA methylation by influencing the expressions of methylation-associated proteins, including Dnmt3b, Dnmt3l, Tet1, Tet2, and Tet3. In conclusion, SC1 inhibits the differentiation of RA-induced F9 cells mainly by reducing the levels of phosphorylated Erk1/2 and enhancing the expression of Klf4, although it also reduces DNA methylation, which may have an additional effect on ES cell differentiation.

SC1 Promotes MiR124-3p Expression to Maintain the Self-Renewal of Mouse Embryonic Stem Cells by Inhibiting the MEK/ERK Pathway.

BACKGROUND/AIMS: Self-renewal is one of the most important features of embryonic stem (ES) cells. SC1 is a small molecule modulator that effectively maintains the self-renewal of mouse ES cells in the absence of leukemia inhibitory factor (LIF), serum and feeder cells. However, the mechanism by which SC1 maintains the undifferentiated state of mouse ES cells remains unclear. METHODS: In this study, microarray and small RNA deep-sequencing experiments were performed on mouse ES cells treated with or without SC1 to identify the key genes and microRNAs that contributed to self-renewal. RESULTS: SC1 regulates the expressions of pluripotency and differentiation factors, and antagonizes the retinoic acid (RA)-induced differentiation in the presence or absence of LIF. SC1 inhibits the MEK/ERK pathway through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and pathway reporting experiments. Small RNA deep-sequencing revealed that SC1 significantly modulates the expression of multiple microRNAs with crucial functions in ES cells. The expression of miR124-3p is upregulated in SC1-treated ES cells, which significantly inhibits the MEK/ERK pathway by targeting Grb2, Sos2 and Egr1. CONCLUSION: SC1 enhances the self-renewal capacity of mouse ES cells by modulating the expression of key regulatory genes and pluripotency-associated microRNAs. SC1 significantly upregulates miR124-3p expression to further inhibit the MEK/ ERK pathway by targeting Grb2, Sos2 and Egr1.

Comprehensive Proteomic Analysis of PGC7-Interacting Proteins.

Primordial germ cell 7 (PGC7), a maternal factor essential for early development, plays a critical role in the regulation of DNA methylation, transcriptional repression, chromatin condensation, and cell division and the maintenance of cell pluripotentiality. Despite the fundamental roles of PGC7 in these cellular processes, only a few molecular and functional interactions of PGC7 have been reported. Here, a streptavidin-biotin affinity purification technique combined with LC-MS/MS was used to analyze potential proteins that interact with PGC7. In total, 291 potential PGC7-interacting proteins were identified. Through an in-depth bioinformatic analysis of potential interactors, we linked PGC7 to critical cellular processes including translation, RNA processing, cell cycle, and regulation of heterochromatin structure. To better understand the functional interactions of PGC7 with its potential interactors, we constructed a protein-protein interaction network using the STRING database. In addition, we discussed in detail the interactions between PGC7 and some of its newly validated partners. The identification of these potential interactors of PGC7 expands our knowledge on the PGC7 interactome and provides a valuable resource for understanding the diverse functions of this protein.

Effects of Genetically Modified Milk Containing Human Beta-Defensin-3 on Gastrointestinal Health of Mice.

This study was performed to investigate the effects of genetically modified (GM) milk containing human beta-defensin-3 (HBD3) on mice by a 90-day feeding study. The examined parameters included the digestibility of GM milk, general physical examination, gastric emptying function, intestinal permeability, intestinal microflora composition of mice, and the possibility of horizontal gene transfer (HGT). The emphasis was placed on the effects on gastrointestinal (GI) tract due to the fact that GI tract was the first site contacting with food and played crucial roles in metabolic reactions, nutrition absorption and immunity regulation in the host. However, the traditional methods for analyzing the potential toxicological risk of GM product pay little attention on GI health. In this study, the results showed GM milk was easy to be digested in simulated gastric fluid, and it did not have adverse effects on general and GI health compared to conventional milk. And there is little possibility of HGT. This study may enrich the safety assessment of GM product on GI health.