Isolation, Identification, Anti-Inflammatory, and In Silico Analysis of New Lignans from the Resin of Ferula sinkiangensis.

Ferula sinkiangensis K. M. Shen (Apiaceae) is distributed in arid desert areas of Xinjiang, and its resin is a traditional Chinese medicine to treat gastrointestinal digestive diseases. To explore bioactive components from F. sinkiangensis, three new lignans and thirteen known components were isolated. The structural elucidation of the components was established utilizing spectroscopic analyses together with ECD calculations. Griess reaction results indicated new compounds 1 and 2 significantly decreased NO production in LPS-stimulated RAW 264.7 macrophages, and ELISA results indicated that they effectively attenuated LPS-induced inflammation by inhibiting TNF-α, IL-1ß, and IL-6 expressions. The in silico approach confirmed that compound 1 docked into the receptors with strong binding energies of -5.84~-10.79 kcal/mol. In addition, compound 6 inhibited the proliferation of AGS gastric cancer cells with IC50 values of 15.2 µM by suppressing the cell migration and invasion. This study disclosed that F. sinkiangensis might be a promising potential resource for bioactive components.

Chemical Constituents, Biological Activities, and Proposed Biosynthetic Pathways of Steroidal Saponins from Healthy Nutritious Vegetable-Allium.

Allium is a common functional vegetable with edible and medicinal value. Allium plants have a special spicy taste, so they are often used as food and seasoning in people's diets. As a functional food, Allium also has abundant biological activities, some of which are used as drugs to treat diseases. By consuming Allium on a daily basis, people can receive active compounds of natural origin, thereby improving their health status and reducing the likelihood of disease. Steroidal saponins are important secondary metabolites of Allium, which are formed by the steroidal aglycone group and sugar. Steroidal saponins have various physiological activities, such as hypoglycemic, antiplatelet aggregation, anti-inflammatory, antitumor, antimicrobial, and enzyme activity inhibition, which is one of the key reasons why Allium has such significant health benefits. The structural diversity and rich biological activities of steroidal saponins make Allium important plants for both food and medicine. In this paper, the chemical structures, biological activities, and structure-activity relationships of steroidal saponins isolated from Allium are reviewed, and the biosynthetic pathways of some key compounds are proposed as well, to provide a molecular reference basis based on secondary metabolites for the health value of Allium.

A spliceosome-associated gene signature aids in predicting prognosis and tumor microenvironment of hepatocellular carcinoma.

Splicing alterations have been shown to be key tumorigenesis drivers. In this study, we identified a novel spliceosome-related genes (SRGs) signature to predict the overall survival (OS) of patients with hepatocellular carcinoma (HCC). A total of 25 SRGs were identified from the GSE14520 dataset (training set). Univariate and least absolute shrinkage and selection operator (LASSO) regression analyses were utilized to construct the signature using genes with predictive significance. We then constructed a risk model using six SRGs (BUB3, IGF2BP3, RBM3, ILF3, ZC3H13, and CCT3). The reliability and predictive power of the gene signature were validated in two validation sets (TCGA and GSE76427 dataset). Patients in training and validation sets were divided into high and low-risk groups based on the gene signature. Patients in high-risk groups exhibited a poorer OS than in low-risk groups both in the training set and two validation sets. Next, risk score, BCLC staging, TNM staging, and multinodular were combined in a nomogram for OS prediction, and the decision curve analysis (DCA) curve exhibited the excellent prediction performance of the nomogram. The functional enrichment analyses demonstrated high-risk score patients were closely related to multiple oncology characteristics and invasive-related pathways, such as Cell cycle, DNA replication, and Spliceosome. Different compositions of the tumor microenvironment and immunocyte infiltration ratio might contribute to the prognostic difference between high and low-risk score groups. In conclusion, a spliceosome-related six-gene signature exhibited good performance for predicting the OS of patients with HCC, which may aid in clinical decision-making for individual treatment.

SNRPD1 inhibition suppresses the proliferation of hepatocellular carcinoma and promotes autophagy through the PI3K/AKT/mTOR/4EBP1 pathway.

BACKGROUND: Small nuclear ribonucleoprotein Sm D1 (SNRPD1) has been reported as an oncogene in some solid cancers. Our previous study suggested that SNRPD1 has diagnostic and prognostic value in hepatocellular carcinoma (HCC), but its role in tumor growth and biological behavior remains unknown. In this study, we aimed to unravel the role and mechanism of SNRPD1 in HCC. METHODS: We investigated the SNRPD1 mRNA level in adjacent normal liver tissues and HCC tissues with different tumor stages in the UALCAN database. The associations between SNRPD1 mRNA expression and HCC prognosis were investigated in TCGA database. Then, 52 pairs of frozen HCC tissues and corresponding adjacent normal liver tissues were collected to perform qPCR and immunohistochemistry assay. Next, we carried out a series of experiments in vitro and in vivo to investigate the effects of SNRPD1 expression on cell invasion, migration, proliferation, autophagy, and the PI3K/AKT/mTOR pathway. RESULTS: The bioinformatics analysis and qPCR in our patient cohort demonstrated that the SNRPD1 mRNA level in HCC tissues was higher than in adjacent normal tissues. In addition, the immunohistochemistry assay exhibited an increased SNRPD1 protein level with the tumor stage increase. Survival analysis suggested that higher expression of SNRPD1 was significantly associated with unfavorable prognosis of patients with HCC. The functional experiments in vitro indicated that SNRPD1 knockdown suppressed the cellular proliferation, migration, and invasion capacities. Furthermore, SNRPD1 inhibition induced cellular apoptosis and arrested the HCC cells at the G0/G1 phase of the cell cycle. Mechanistic analyses demonstrated that SNRPD1 knockdown induced the increase of autophagic vacuoles and the expression of autophagy-related genes (ATG5, ATG7, and ATG12) and blocked the PI3K/AKT/mTOR/4EBP1 pathway in vitro. Moreover, SNRPD1 inhibition suppressed tumor growth and expression of the Ki67 protein in vivo. CONCLUSIONS: SNRPD1 may serve as an oncogene in HCC and promote tumor proliferation via inhibiting autophagy induced through the PI3K/Akt/mTOR/4EBP1 pathway.

Upregulation of HCFC1 expression promoted hepatocellular carcinoma progression through inhibiting cell cycle arrest and correlated with immune infiltration.

Background: Host cell factor 1 (HCFC1) was reported associated with the progression of a variety of cancers. However, its role in the prognosis and immunological characteristics of hepatocellular carcinoma (HCC) patients has not been revealed. Methods: The expression and prognostic value of HCFC1 in HCC were investigated from the Cancer Genome Atlas (TCGA) dataset and a cohort of 150 HCC patients. The associations between HCFC1 expression with somatic mutational signature, tumor mutational burden (TMB), and microsatellite instability (MSI) were investigated. Next, the correlation of HCFC1 expression with immune cell infiltration was investigated. In vitro, cytological experiments were conducted to verify the role of HCFC1 in HCC. Results: HCFC1 mRNA and protein upregulated in HCC tissues and correlated to poor prognosis. Multivariate regression analysis based on a cohort of 150 HCC patients revealed that high HCFC1 protein expression was an independent risk factor for prognosis. Upregulation of HCFC1 expression was associated with TMB, MSI, and tumor purity. HCFC1 expression showed a significant positive association with B cell memory, T cell CD4 memory, macrophage M0, and a significant positive association with immune checkpoint-related gene expression in the tumor microenvironment. HCFC1 expression negatively correlated to ImmuneScore, EstimateScore, and StromalScore. The single-cell RNA sequencing analysis demonstrated that the malignant cells and immune cells (B cells, T cells, and macrophages) represented high HCFC1 expression in HCC tissues. Functional analysis revealed that HCFC1 was remarkably correlated with cell cycle signaling. HCFC1 knockdown inhibited the proliferation, migration, and invasion capacity while promoting the apoptosis of HCC cells. At the same time, the cell-cycle-related proteins such as Cyclin D1 (CCND1), Cyclin A2 (CCNA2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) were downregulated. Conclusion: Upregulation of HCFC1 predicted undesirable prognosis of HCC patients and promoted tumor progression through inhibiting cell cycle arrest.

Pre- to postoperative alpha-fetoprotein ratio-based nomogram to predict tumor recurrence in patients with hepatocellular carcinoma.

Background: This study aimed to investigate the role of the alpha fetoprotein (AFP) ratio before and after curative resection in the prognosis of patients with hepatocellular carcinoma (HCC) and to develop a novel pre- to postoperative AFP ratio nomogram to predict recurrence free survival (RFS) for HCC patients after curative resection. Methods: A total of 485 pathologically confirmed HCC patients who underwent radical hepatectomy from January 2010 to December 2018 were retrospectively analyzed. The independent prognostic factors of hepatocellular carcinoma were identified by multivariate COX proportional model analysis, and the nomogram model was constructed. The receiver operating characteristic and the C-index were used to evaluate the accuracy and efficacy of the model prediction, the correction curve was used to assess the calibration of the prediction model, and decision curve analysis was used to evaluate the clinical application value of the nomogram model. Results: A total of 485 HCC patients were divided into the training cohort (n = 340) and the validation cohort (n = 145) by random sampling at a ratio of 7:3. Using X-tile software, it was found that the optimal cut-off value of the AFP ratio in the training cohort was 0.8. In both cohorts, the relapse-free survival of patients with an AFP ratio <0.8 (high-risk group) was significantly shorter than in those with an AFP ratio ≥0.8 (low-risk group) (P < 0.05). An AFP ratio <0.8 was an independent risk factor for recurrence of HCC after curative resection. Based on the AFP ratio, BCLC stage and cirrhosis diagnosis, a satisfactory nomogram was developed. The AUC of our nomogram for predicting 1-, 3-, and 5-year RFS was 0.719, 0.690, and 0.708 in the training cohort and 0.721, 0.682, and 0.681 in the validation cohort, respectively. Furthermore, our model demonstrated excellent stratification as well as clinical applicability. Conclusion: The AFP ratio was a reliable biomarker for tumor recurrence. This easy-to-use AFP ratio-based nomogram precisely predicted tumor recurrence in HCC patients after curative resection.

Bioinformatics analysis and experimental validation of a novel autophagy-related signature relevant to immune infiltration for recurrence prediction after curative hepatectomy.

Hepatocellular carcinoma (HCC) remains imposing an enormous economic and healthcare burden worldwide. In this present study, we constructed and validated a novel autophagy-related gene signature to predict the recurrence of HCC patients. A total of 29 autophagy-related differentially expressed genes were identified. A five-gene signature (CLN3, HGF, TRIM22, SNRPD1, and SNRPE) was constructed for HCC recurrence prediction. Patients in high-risk groups exhibited a significantly poor prognosis compared with low-risk patients both in the training set (GSE14520 dataset) and the validation set (TCGA and GSE76427 dataset). Multivariate cox regression analysis demonstrated that the 5-gene signature was an independent risk factor for recurrence-free survival (RFS) in HCC patients. The nomograms incorporating 5-gene signature and clinical prognostic risk factors were able to effectively predict RFS. KEGG and GSEA analysis revealed that the high-risk group was enriched with multiple oncology characteristics and invasive-related pathways. Besides, the high-risk group had a higher level of immune cells and higher levels of immune checkpoint-related gene expression in the tumor microenvironment, suggesting that they might be more likely to benefit from immunotherapy. Finally, the immunohistochemistry and cell experiments confirmed the role of SNRPE, the most significant gene in the gene signature. SNRPE was significantly overexpressed in HCC. After SNRPE knockdown, the proliferation, migration and invasion ability of the HepG2 cell line were significantly inhibited. Our study established a novel five-gene signature and nomogram to predict RFS of HCC, which may help in clinical decision-making for individual treatment.

Undescribed sesquiterpene coumarins from the aerial parts of Ferula sinkiangensis and their anti-inflammatory activities in lipopolysaccharide-stimulated RAW 264.7 macrophages.

Eight undescribed sesquiterpene coumarins (1-8) and twenty known ones (9-28), were isolated from the aerial parts of Ferula sinkiangensis K. M. Shen. Their structures were elucidated based on the comprehensive analysis of UV, IR, HRESIMS, 1D, and 2D NMR data. The absolute configuration of 1 was determined by single crystal X-Ray diffraction, while the absolute configurations of 2-8 were determined by comparisons of experimental and calculated electrostatic circular dichroism spectra. Compound 2 is the first hydroperoxy sesquiterpene coumarin from the genus Ferula, while compound 8 has an unusual 5',8'-peroxo bridge. Griess reaction results indicated compound 18 significantly decreased nitric oxide production of the lipopolysaccharide-stimulated RAW 264.7 macrophages with an IC50 value of 2.3 µM, and ELISA results revealed that compound 18 effectively inhibited tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 expressions.

Nomogram Based on Platelet-Albumin-Bilirubin for Predicting Tumor Recurrence After Surgery in Alpha-Fetoprotein-Negative Hepatocellular Carcinoma Patients.

Purpose: In this study, we developed a nomogram based on the platelet-albumin-bilirubin (PALBI) score to predict recurrence-free survival (RFS) after curative resection in alpha-fetoprotein (AFP)-negative (≤20 ng/mL) hepatocellular carcinoma (HCC) patients. Patients and Methods: A total of 194 pathologically confirmed AFP-negative HCC patients were retrospectively analyzed. Univariate and multivariate Cox regression analyses were performed to screen the independent risk factors associated with RFS, and a nomogram prediction model for RFS was established according to the independent risk factors. The receiver operating characteristic (ROC) curve and the C-index were used to evaluate the accuracy and the efficacy of the model prediction. The correction curve was used to assess the calibration of the prediction model, and decision curve analysis was performed to evaluate the clinical application value of the prediction model. Results: PALBI score, MVI, and tumor size were independent risk factors for postoperative tumor recurrence (P < 0.05). A nomogram prediction model based on the independent predictive factors was developed to predict RFS, and it achieved a good C-index of 0.704 with an area under the ROC curve of 0.661 and the sensitivity was 73.2%. Patients with AFP-negative HCC could be divided into the high-risk group or the low-risk group by the risk score calculated by the nomogram, and there was a significant difference in RFS between the two groups (P < 0.05). Decision curve analysis (DCA) showed that the nomogram increased the net benefit in predicting the recurrence of AFP-negative HCC and exhibited a wider range of threshold probabilities than the independent risk factors (PALBI score, MVI, and tumor size) by risk stratification. Conclusion: The nomogram based on the PALBI score can predict RFS after curative resection in AFP-negative HCC patients and can help clinicians to screen out high-risk patients for early intervention.

Sesquiterpenes and Sesquiterpene Derivatives from Ferula: Their Chemical Structures, Biosynthetic Pathways, and Biological Properties.

Ferula is a genus of flowering plants known for its edible and medicinal properties. Since ancient times, many species of Ferula have been used in traditional medicine to treat various health issues across countries, such as digestive disorders, respiratory problems, and even as a remedy for headaches and toothaches. In addition, they are also used as a flavoring agent in various cuisines. As the main active ingredients in Ferula, sesquiterpenes and their derivatives, especially sesquiterpene coumarins, sesquiterpene phenylpropanoids, and sesquiterpene chromones, have attracted the attention of scientists due to the diversity of their chemical structures, as well as their extensive and promising biological properties, such as antioxidative, anti-inflammatory, antibacterial properties. However, there has not been a comprehensive review of sesquiterpenes and their derivatives from this plant. This review aims to provide an overview of the chemical structures, biosynthetic pathways, and biological properties of sesquiterpenes and sesquiterpene derivatives from Ferula, which may help guide future research directions and possible application methods for this valuable edible and medicinal plant.

High MCM8 expression correlates with unfavorable prognosis and induces immune cell infiltration in hepatocellular carcinoma.

BACKGROUND: MCM8 has been reported highly expressed in several human malignancies. However, its role in HCC has not yet been researched. METHODS: The prognostic significance of MCM8 mRNA expression was analyzed using datasets from TCGA and GEO databases. Immunohistochemistry (IHC) assay was used to detect the MCM8 protein expression in HCC tissues. The Cox regression analysis was employed to determine the independent prognostic value of MCM8. Then, we established a nomogram for OS and RFS prediction based on MCM8 protein expression. We analyzed the DNA methylation and genetic alteration of MCM8 in HCC. Moreover, GO, KEGG and GSEA were utilized to explore the potential biological functions of MCM8. Subsequently, we evaluate the correlations between MCM8 expression and composition of the tumor microenvironment as well as immunocyte infiltration ratio in HCC. RESULTS: MCM8 mRNA and protein were significantly overexpressed in HCC tissues. High MCM8 protein expression was an independent risk factor for OS and RFS of HCC patients. MCM8 expression is altered in 60% of queried HCC patients. In addition, higher methylation of the CpG site cg03098629, cg10518808, and 17230679 correlated with lower MCM8 levels. MCM8 expression correlated with cell cycle and DNA replication signaling. Moreover, MCM8 may be correlated with different compositions of the tumor microenvironment and immunocyte infiltration ratio in HCC. CONCLUSIONS: MCM8 was highly expressed in HCC tissues and was associated with poor prognosis. Meanwhile, high expression of MCM8 may induce immune cell infiltration and may be a promising prognostic biomarker for HCC.

High cathepsin A protein expression predicts poor prognosis and tumor recurrence of hepatocellular carcinoma patients after curative hepatectomy.

Cathepsin A (CTSA) is overexpressed in various types of cancer and is linked to poor clinical outcomes. However, the clinical application of CTSA in HCC has not been explored. In this study, we examined the protein level of CTSA in the archived HCC samples from 161 patients by Immunohistochemistry (IHC). The high protein level of CTSA was significantly correlated to the poor clinicopathological parameters, such as TNM stage, serum AFP level, tumor differentiation, liver cirrhosis, Child-Pugh class, vascular invasion, tumor encapsulation, tumor recurrence, and patient death. In addition, multivariate Cox regression analysis indicated that high CTSA expression was an independent prognostic factor of OS and RFS. We also analyzed the area under the curve (AUC) of the time-dependent receiver operating characteristic (ROC) of CTSA expression for 1-, 3-, and 5-year OS and RFS prediction. Furthermore, we constructed a nomogram that exhibited excellent prediction performance, which was validated by the calibration curve and decision curve analysis. Together, our study demonstrated that CTSA protein level is strongly associated with poor clinical outcome of HCC patients and may be used as a potential diagnostic and prognostic biomarker in HCC.

Overexpression of OAS1 Is Correlated With Poor Prognosis in Pancreatic Cancer.

Background: OAS1 expression in pancreatic cancer has been confirmed by many studies. However, the prognostic value and mechanism of OAS1 in pancreatic cancer have not been analyzed. Methods: The RNA-seq in pancreatic cancer were obtained by UCSC XENA and GEO database. In addition, immunohistochemical validation and analysis were performed using samples from the 900th hospital. The prognosis of OAS1 was evaluated by timeROC package, Cox regression analysis, and Kaplan-Meier survival curves. Then, the main functional and biological signaling pathways enrichment and its relationship with the abundance of immune cells were analyzed by bioinformatics. Results: OAS1 was highly expressed in pancreatic cancer compared with normal pancreatic tissue. High OAS1 expression was associated with poor overall survival (p<0.05). The OAS1 was significantly correlated to TNM staging (p=0.014). The timeROC analysis showed that the AUC of OAS1 was 0.734 for 3-year OS. In addition, the expression of OAS1 was significantly correlated with the abundance of a variety of immune markers. GSEA showed that enhanced signaling pathways associated with OAS1 include Apoptosis, Notch signaling pathway, and P53 signaling pathway. Conclusions: OAS1 is a valuable prognostic factor in pancreatic cancer. Moreover, it may be a potential immunotherapeutic target.

Elevated Small Nuclear Ribonucleoprotein Polypeptide an Expression Correlated With Poor Prognosis and Immune Infiltrates in Patients With Hepatocellular Carcinoma.

Background: Elevated Small Nuclear Ribonucleoprotein Polypeptide A (SNRPA) can enhance tumor cell growth and proliferation in various cancers. However, rarely studies focus on the comprehensive analysis of SNRPA in hepatocellular carcinoma (HCC). Methods: TCGA and GEO databases were used to analyze the mRNA expression of SNRPA in HCC. Protein expression of SNAPA was validated using immunohistochemistry. Stably transfected HCC cells were used to investigate the role of SNRPA in the progression of HCC. The functional enrichment analysis was utilized for the biological function prediction. The CIBERSORT and ssGSEA algorithms were used to evaluate the composition of the tumor microenvironment and immunocyte infiltration ratio. Results: The SNRPA expression was upregulated in HCC and positively correlated with tumor stage and grade. SNRPA overexpression were independent risk factors for poor overall survival (OS) and recurrence-free survival (RFS). In patients with early-stage disease, low alpha-fetoprotein expression, and better differentiation, SNRPA still exhibited the excellent prognostic value. Knockdown of SNRPA inhibited the proliferation and migration while promoting the apoptosis of HCC cells. Higher methylation of the CpG site cg16596691 correlated with longer OS in HCC patients. Genes co-expressed with SNRPA were overexpressed in HCC and correlated with shorter OS. The GO and KEGG enrichment analysis showed that SNRPA expression was related to mRNA splicing, spliceosome signaling. GSEA demonstrated that the main enrichment pathway of SNRPA-related differential genes was spliceosome signaling, cell cycle signaling, P53 signaling pathway, T cell receptor signaling pathway, natural killer cell-mediated signaling. CIBERSORT and ssGSEA algorithm revealed that SNRPA was mainly associated with the higher proportion of CD8+T cells, T cells follicular helper, T cells regulatory, Macrophages M0, and the lower proportion of T cells CD4 memory resting, NK cells resting, Monocytes, and Mast cells resting. Conclusion: Elevated SNRPA enhances tumor cell proliferation and correlated with poor prognosis and immune infiltrates in patients with HCC.

miR-6071 inhibits hepatocellular carcinoma progression via targeting PTPN11.

Hepatocellular carcinoma (HCC) is a deadly malignancy. Liver cancer stem cells (LCSCs) participated in HCC progression and caused failure of chemotherapy. However, the underlying mechanism for the LCSCs regulation was unclear. In this study, we found that miR-6071 expression was decreased in LCSCs. Gain-of-function assays showed that miR-6071 overexpression repressed LCSCs self-renewal and tumorigenesis and inhibited HCC cells proliferation and migration. In mechanism, bioinformatics and luciferase reporter assay demonstrated that miR-6071 targeted 3'UTR of PTPN11 mRNA. Pearson analysis revealed a negative correlation between miR-6071 expression and PTPN11 levels in HCC tissue samples. Further study showed that PTPN11 interference and specific inhibitors IACS-13909 abrogated the discrepancy of self-renewal ability, proliferation, migration and tumorigenicity capacity between miR-6071 overexpression HCC cells and control cells. Moreover, upregulation of miR-6071 sensitized HCC cells to lenvatinib treatment. Clinical cohort analysis revealed that HCC patients with high miR-6071 expression got more survival benefit from postoperative lenvatinib treatment than patients with low miR-6071 levels. In conclusion, our study demonstrated a regulation mechanism of LCSCs, a target against LSCSs, and a biomarker for postoperative lenvatinib treatment.

A novel ferroptosis-related gene signature for clinically predicting recurrence after hepatectomy of hepatocellular carcinoma patients.

High recurrence rate in HCC is the primary cause of the poor prognosis after hepatectomy. Therefore, in this study, we aimed to construct a gene signature for predicting the recurrence rate in HCC. The mRNA expression profiles and clinical information of HCC patients from GEO and TCGA databases were used, and ferroptosis-related gene list was obtained from the FerrDb database. We identified 39 ferroptosis-related genes (FDEGs) that were differentially expressed between HCC samples and normal tissues from the GSE14520 dataset. The univariate and multivariate Cox regression analyses were employed to construct a prognostic signature. Seven FDEGs (MAPK9, SLC1A4, PCK2, ACSL3, STMN1, CDO1, and CXCL2) were included to construct a risk model, which was validated in the TCGA dataset. Patients in high-risk groups exhibited a significantly poor prognosis compared with patients in low-risk groups in both the training set (GSE14520 cohort) and the validation set (TCGA cohort). Multivariate cox regression analyses demonstrated that the 7-gene signature was an independent risk factor for RFS in HCC patients. KEGG analysis showed that FDEGs were mainly enriched in Ferroptosis, Hepatocellular carcinoma pathway, and MAPK signaling pathway. GSEA analysis suggested that the high-risk group was correlated with multiple oncogenic signatures and invasive-related pathways. These results indicated that this risk model can accurately predict recurrence after hepatectomy and offer novel research directions for personalized treatment in HCC patients.

miR-517b-3p promotes the progression of portal vein tumor thrombus via activating Wnt/ß-catenin signaling pathway in hepatocellular carcinoma.

AIMS: This study was aimed to investigate the expression patterns and prognostic value of microRNA-517b-3p (miR-517b-3p) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). METHODS: The expression of miR-517b-3p in PVTT tissues and cells was estimated using qRT-PCR. Through Kaplan-Meier survival analysis, Cox regression assay and ROC analysis, the significance of miR-517b-3p was explored. In addition, cell experiments were performed to examine the functional role of miR-517b-3p during progression of PVTT. Moreover, the biological process and biological pathway analysis analyses were conducted through GSEA and FunRich. Besides, the protein-protein interaction (PPI) network of the DEGs was established through cBioPortal website. RESULTS: Compared with the controls, the miR-517b-3p was upregulated in both PVTT tissues and cells. The upregulated miR-517b-3p, which served as a potential diagnostic biomarker to distinguish PVTT from PT and controls, was associated with poor overall survival and acted as an independent prognostic factor. The cell proliferation, migration and invasion were proved to be enhanced by overexpression of miR-517b-3p. Furthermore, Wnt/ß-catenin signaling was suppressed by miR-517b-3p knockdown and might be involved in the progression of PVTT. CONCLUSION: miR-517b-3p may promote PVTT cell proliferation, migration and invasion via activation of Wnt/ß-catenin signaling pathway. Meanwhile, miR-517b-3p has overexpression in PVTT samples, and serves as a candidate diagnostic and prognostic biomarker in HCC patients with PVTT.

Novel Triterpenoid Alkaloids With Their Potential Cytotoxic Activity From the Roots of Siraitia grosvenorii.

Four novel triterpenoid alkaloids, siragrosvenins A-D (1-4), and two new cucurbitane-type triterpenoids, siragrosvenins E-F (5, 6), together with eight known analogs (7-14), were isolated from the roots of Siraitia grosvenorii. Compounds 1-4 possessed a rare cucurbitane-type triterpenoid scaffold, featuring an extra pyrazine unit via the Strecker reaction in the cucurbitane framework. Compound 5 displayed a 6/6/6/5/6/5-fused polycyclic ring system, with an uncommon fused furan and pyran ring in the side chain. All the structures were characterized by extensive spectroscopic analysis, including HRESIMS, NMR, and X-ray crystallographic data. It is worth noting that the DP4+ analysis method was applied for the first time to determine the absolute configurations of the trihydroxybutyl moiety in the side chain of compounds 1-4. In vitro cytotoxicity screening found that compounds 4, 8, 9, 13, and 14 exhibited remarkable cytotoxic activities against three cell lines with IC50 values ranging from 1.44 to 9.99 µM. Siragrosvenin D shows remarkable cytotoxic activity on MCF-7 cells. As a result, it inhibited the proliferation of MCF-7 cells and reduced their viability via the induction of G2/M phase arrest and significantly induced apoptosis in MCF-7 cells.

The Inhibition of Gastric Cancer Cells' Progression by 23,24-Dihydrocucurbitacin E through Disruption of the Ras/Raf/ERK/MMP9 Signaling Pathway.

Gastric cancer is considered to be one of the most common causes of cancer death worldwide due to its high recurrence and metastasis rates. The molecule 23,24-Dihydrocucurbitacin E (DHCE) is a cucurbitacin-derived tetracyclic triterpenoid compound that has anti-tumor activity, but the exact mechanism remains to be elucidated. This research aimed to explore the effects of DHCE on human gastric cancer cells and the possible mechanisms. The results showed that DHCE suppressed proliferation, migration, and invasion of gastric cancer cells, as well as induced apoptosis and G2/M phase arrest. Mechanistically, the potential targets and pathways of DHCE were predicted using database screening and verified using a molecular docking study, fluorescence staining, and Western blot. The results indicated that DHCE obviously inhibited the kinase activity of ERK2 via targeting its ATP-binding domain, destroyed F-actin microfilament, and reduced the expression levels of Ras, p-c-Raf, ERK, p-ERK, and MMP9 proteins. Collectively, our study demonstrated that DHCE suppressed gastric cancer cells' proliferation, migration, and invasion through targeting ERK2 and disrupting the Ras/Raf/ERK/MMP9 signaling pathway. These properties make DHCE a promising candidate drug for the further design and development of novel and effective Ras/Raf/ERK/MMP9 pathway inhibitors for treating gastric cancer.