Atrachinenins D-S, novel meroterpenoids with geranyl hydroquinone moiety from Atractylodes chinensis by the LC/MS-based molecular decoy and targeted isolation.

To mine fascinating molecules from the rhizomes of Atractylodes chinensis, the known molecular formula of atrachinenin A was used as a bait to search LC-HRMS data in different subfractions. Sixteen new meroterpenoids, atrachinenins D-S (1-16) including three unprecedented carbon skeletons (1-5) and eleven new oxygen-bridged hybrids (6-16) were obtained by the targeted isolation. Their structures and absolute configurations were elucidated by the spectroscopic data and electronic circular dichroism (ECD) calculations. The isolated compounds were evaluated for their inhibitory activity of NO production and compounds 1, 4, 8, and 13 showed moderate anti-inflammatory activity. The proposed biosynthetic pathways of 1-5 were also discussed.

The PSCA rs2294008 (C/T) Polymorphism Increases the Risk of Gastric and Bladder Cancer: A Meta-Analysis.

Background: It has been reported that prostate stem cell antigen (PSCA) is overexpressed in certain cancer types and confers poor prognoses. The rs2294008 (C/T) polymorphism of PSCA is considered to be associated with risk for gastric, bladder, and colorectal cancers; however, these studies have produced inconsistent results, so we performed this meta-analysis to verify the association between the PSCA rs2294008 (C/T) polymorphism and cancer risk. Methods: A systematic literature search was performed using PubMed, EMBASE, and the Chinese National Knowledge Infrastructure, through October 20, 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association between the PSCA rs2294008 (C/T) polymorphism and cancer risk. In addition, we explored PSCA mRNA expression in cancers through online databases. Results: In total, 45 articles met our inclusion criteria and were analyzed, including 37,586 cancer cases and 51,197 non-cancer controls. Except in the recessive model, the pooled effect indicated the PSCA rs2294008 T allele was associated with an increased overall cancer risk (T vs. C: OR = 1.120, 95% CI = 1.056-1.188, p < 0.01; TT vs. CC: OR = 1.206, 95% CI = 1.066-1.364, p = 0.03; CT vs. CC: OR = 1.249, 95% CI = 1.151-1.356, p < 0.01; [CT+TT] vs. CC: OR = 1.248, 95% CI = 1.147-1.359, p < 0.01; TT vs. [CT+CC]: OR = 1.051, 95% CI = 0.954-1.156, p = 0.314). In the subgroup analysis, there were significant associations between the rs2294008 T allele and increased risk of bladder and gastric cancer. Two different online tools were used to explore the PSCA mRNA levels in cancer and the corresponding normal adjacent tissues. We found that expression of PSCA was significantly lower in gastric cancer patients. Conclusions: The PSCA rs2294008 T polymorphism is related to increased cancer susceptibility, especially for gastric and bladder cancers. This polymorphism results in a decreased PSCA expression level in gastric cancer.

Ferroptosis Regulator Modification Patterns and Tumor Microenvironment Immune Infiltration Characterization in Hepatocellular Carcinoma.

Accumulating studies have highlighted the biologic significances of ferroptosis modification in tumor progression, but little is known whether ferroptosis modification patterns have potential roles in tumor microenvironment (TME) immune cell infiltration of hepatocellular carcinoma (HCC). In this study, we evaluated 51 ferroptosis regulators and performed consensus clustering algorithm to determine ferroptosis modification patterns and the ferroptosis related gene signature in HCC. Gene set variation analysis (GSVA) was employed to explore biological molecular variations in distinct ferroptosis modification patterns. Single sample gene set enrichment analysis (ssGSEA) algorithm was performed to quantify the relative infiltration levels of various immune cell subsets. Principal component analysis (PCA) algorithm was used to construct the ferroptosisSig score to quantify ferroptosis modification patterns of individual tumors with immune responses. Three distinct ferroptosis modification patterns were identified. GSVA enrichment analysis indicated that three ferroptosis modification subgroups were enriched in different metabolic pathways. ssGSEA analysis determined that 19 of 24 immune infiltrating cells had significant differences in three distinct ferroptosis patterns. A 91-ferroptosis gene signature was constructed to stratify patients into two ferroptosisSig score groups. Patients in the higher ferroptosisSig score were characterized by significantly prolonged survival time compared with patients in the lower ferroptosisSig score group (p < .0001). An immunotherapy cohort confirmed patients with higher ferroptosisSig score determined significant therapeutic advantages and clinical benefits. Receiver operating characteristic (ROC) curve analysis confirmed the predictive capacity of anti-PD/L1 immunotherapy by ferroptosisSig score. Our study indicated the ferroptosis modification played a significant role in TME heterogeneity and complexity. Evaluating the ferroptosis modification pattern of individual tumor could strengthen our cognition of TME infiltration characteristics and guide more effective clinic immunotherapy strategies.

Correction to: MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming.

An amendment to this paper has been published and can be accessed via the original article.

miR-17-5p and miR-20a-5p suppress postoperative metastasis of hepatocellular carcinoma via blocking HGF/ERBB3-NF-κB positive feedback loop.

Dysregulation of microRNA (miRNA) is a frequent event in hepatocellular carcinoma (HCC), but little is known whether it is a bystander or an actual player on residual HCC metastasis during liver microenvironment remodeling initiated by hepatectomy. Methods: The differently expressed miRNAs and mRNAs were identified from RNA-seq data. Western blot, qRT-PCR, fluorescence in situ hybridization, immunofluorescence and immunohistochemical were used to detect the expression of miRNA and mRNA in cell lines and patient tissues. The biological functions were investigated in vitro and in vivo. Chromatin immunoprecipitation, proximity ligation and luciferase reporter assay were used to explore the specific binding of target genes. The expression of HGF/ERBB3 signaling was detected by Western blot. Results: In this study, HGF induced by hepatectomy was shown to promote metastasis of residual HCC cells. miR-17-5p and miR-20a-5p were confirmed to play inhibitory roles on HCC metastasis. And ERBB3 was found to be the common target of miR-17-5p and miR-20a-5p. HCC cells with lower levels of miR-17-5p and miR-20a-5p or higher level of ERBB3 were often more sensitive to response HGF stimuli and to facilitate metastatic colonization both in vitro and in vivo experimental systems. Furthermore, HGF reinforced ERBB3 expression by NF-κB transcriptional activity in a positive feedback loop. Of particular importance, HCC patients with lower levels of miR-17-5p and miR-20a-5p or higher level of ERBB3 had significantly shorter OS and PFS survivals after surgical resection. Conclusion: miR-17-5p and miR-20a-5p could suppress postoperative metastasis of hepatocellular carcinoma via blocking HGF/ERBB3-NF-κB positive feedback loop and offer a new probable strategy for metastasis prevention after HCC resection.

MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming.

BACKGROUND: MicroRNA-612 (miR-612) has been proven to suppress EMT, stemness, and tumor metastasis of hepatocellular carcinoma (HCC) via PI3K/AKT2 and Sp1/Nanog signaling. However, its biological roles on HCC progression are far from elucidated. METHODS: We found direct downstream target of miR-612, hadha by RNA immunoprecipitation and sequencing. To explore its biological characteristic, potential molecular mechanism, and clinical relevance in HCC patients, we performed several in-vitro and in-vivo models, as well as human tissue chip. RESULTS: Ectopic expression of miR-612 could partially reverse the level of HADHA, then suppress function of pseudopods, and diminish metastatic and invasive potential of HCC by lipid reprogramming. In detail, miR-612 might reduce invadopodia formation via HADHA-mediated cell membrane cholesterol alteration and accompanied with the inhibition of Wnt/ß-catenin regulated EMT occurrence. Our results showed that the maximum oxygen consumption rates (OCR) of HCCLM3miR-612-OE and HCCLM3hadha-KD cells were decreased nearly by 40% and 60% of their counterparts (p < 0.05). The levels of acetyl CoA were significantly decreased, about 1/3 (p > 0.05) or 1/2 (p < 0.05) of their controls, in exogenous miR-612 or hadha-shRNA transfected HCCLM3 cell lines. Besides, overexpression of hadha cell lines had a high expression level of total cholesterol, especially 27-hydroxycholesterol (p < 0.005). SREBP2 protein expression level as well as its downstream targets, HMGCS1, HMGCR, MVD, SQLE were all deregulated by HADHA. Meanwhile, the ATP levels were reduced to 1/2 and 1/4 in HCCLM3miR-612-OE (p < 0.05) and HCCLM3hadha-KD (p < 0.01) respectively. Moreover, patients with low miR-612 levels and high HADHA levels had a poor prognosis with shorter overall survival. CONCLUSION: miR-612 can suppress the formation of invadopodia, EMT, and HCC metastasis and by HADHA-mediated lipid programming, which may provide a new insight of miR-612 on tumor metastasis and progression.

Bioactive triterpenoids from Sambucus javanica Blume.

A new triterpene, javablumine A (1) along with six known ones were isolated from the aerial parts of Sambucus javanica Blume. They were identified as 3ß,23-dihydroxy-11α,12α-epoxy-urs-20(30)-en-28,13ß-olide (1), ursolic acid (2), pomolic acid (3), oleanic acid (4), 2α-hydroxy-oleanolic acid (5), α-amyrin (6), and lupeol palmitate (7), respectively. Compounds 1 and 3 exhibited inhibitory effect against nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 macrophage cell lines with IC50 values of 17.4 and 26.2 µM, respectively.

A hybrid variable selection strategy based on continuous shrinkage of variable space in multivariate calibration.

When analyzing high-dimensional near-infrared (NIR) spectral datasets, variable selection is critical to improving models' predictive abilities. However, some methods have many limitations, such as a high risk of overfitting, time-intensiveness, or large computation demands, when dealing with a high number of variables. In this study, we propose a hybrid variable selection strategy based on the continuous shrinkage of variable space which is the core idea of variable combination population analysis (VCPA). The VCPA-based hybrid strategy continuously shrinks the variable space from big to small and optimizes it based on modified VCPA in the first step. It then employs iteratively retaining informative variables (IRIV) and a genetic algorithm (GA) to carry out further optimization in the second step. It takes full advantage of VCPA, GA, and IRIV, and makes up for their drawbacks in the face of high numbers of variables. Three NIR datasets and three variable selection methods including two widely-used methods (competitive adaptive reweighted sampling, CARS and genetic algorithm-interval partial least squares, GA-iPLS) and one hybrid method (variable importance in projection coupled with genetic algorithm, VIP-GA) were used to investigate the improvement of VCPA-based hybrid strategy. The results show that VCPA-GA and VCPA-IRIV significantly improve model's prediction performance when compared with other methods, indicating that the modified VCPA step is a very efficient way to filter the uninformative variables and VCPA-based hybrid strategy is a good and promising strategy for variable selection in NIR. The MATLAB source codes of VCPA-GA and VCPA-IRIV can be freely downloaded in the website: https://cn.mathworks.com/matlabcentral/profile/authors/5526470-yonghuan-yun.

Genetic source tracking of an anthrax outbreak in Shaanxi province, China.

BACKGROUND: Anthrax is an acute zoonotic infectious disease caused by the bacterium known as Bacillus anthracis. From 26 July to 8 August 2015, an outbreak with 20 suspected cutaneous anthrax cases was reported in Ganquan County, Shaanxi province in China. The genetic source tracking analysis of the anthrax outbreak was performed by molecular epidemiological methods in this study. METHODS: Three molecular typing methods, namely canonical single nucleotide polymorphisms (canSNP), multiple-locus variable-number tandem repeat analysis (MLVA), and single nucleotide repeat (SNR) analysis, were used to investigate the possible source of transmission and identify the genetic relationship among the strains isolated from human cases and diseased animals during the outbreak. RESULTS: Five strains isolated from diseased mules were clustered together with patients' isolates using canSNP typing and MLVA. The causative B. anthracis lineages in this outbreak belonged to the A.Br.001/002 canSNP subgroup and the MLVA15-31 genotype (the 31 genotype in MLVA15 scheme). Because nine isolates from another four provinces in China were clustered together with outbreak-related strains by the canSNP (A.Br.001/002 subgroup) and MLVA15 method (MLVA15-31 genotype), still another SNR analysis (CL10, CL12, CL33, and CL35) was used to source track the outbreak, and the results suggesting that these patients in the anthrax outbreak were probably infected by the same pathogen clone. CONCLUSIONS: It was deduced that the anthrax outbreak occurred in Shaanxi province, China in 2015 was a local occurrence.

miR-612 suppresses stem cell-like property of hepatocellular carcinoma cells by modulating Sp1/Nanog signaling.

In our previous study we found that miR-612 negatively regulated stem cell-like property and tumor metastasis of hepatocellular carcinoma cells (HCC). In this study, we try to elucidate underlying mechanism of the regulation, and find that miR-612 inversely modulate the mRNA and protein level of epithelial cell adhesion molecule as well as CD133, negatively regulate the numbers and sizes of tumor spheres, directly inhibit the protein level of Sp1, and subsequently reduce transcription activity of Nanog. Of importance, the higher levels of Sp1 and Nanog in biopsies are the more unfavorable prognoses of HCC patients are found after tumor resection. Taken together, miR-612 has a suppressive role on HCC stemness via Sp1/Nanog signaling pathway.

MiR-612 suppresses the stemness of liver cancer via Wnt/ß-catenin signaling.

Previous research showed that microRNA-612 (miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial-mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/ß-catenin signaling is required in the regulation of EMT-associated stem cell-like traits by miR-612.