[Research progress on development and utilization of minor ginsenosides].

Minor ginsenosides are a class of processed saponins with minor natural content, high bioavailability, and outstanding bio-logical activity, which are usually obtained by biological or chemical transformation of prototype saponins directly extracted from Panax plants. In recent years, with the clarification of the biosynthetic pathway of saponins and the development of synthetic biology, it has become possible to use synthetic metabolic engineering methods with microorganisms as hosts to produce saponins. Minor ginsenosides have received widespread attention because of their remarkable biological activities in enhancing the immune function of the body and antitumor property. At present, most of the reviews on minor ginsenosides focus on transformation preparation, process optimization, and pharmacological activity, but there are some deficiencies in industrial analysis. This study summarized structural types, pharmacological activities, sources of acquisition, and transformation pathways of minor ginsenosides based on the relevant literature in China and abroad, proposed problems in the preparation of existing minor ginsenosides, and discussed the future research and utilization prospects, to provide a theoretical basis for improving the basic research of minor ginsenosides and promoting their industrialization.

Overexpression of MTFR1 promotes cancer progression and drug-resistance on cisplatin and is related to the immune microenvironment in lung adenocarcinoma.

OBJECTIVE: The roles of MTFR1 in the drug resistance of lung adenocarcinoma (LAC) to cisplatin remain unexplored. In this study, the expression, clinical values and mechanisms of MTFR1 were explored, and the relationship between MTFR1 expression and immune microenvironment was investigated in LAC using bioinformatics analysis, cell experiments, and meta-analysis. METHODS: MTFR1 expression and clinical values, and the relationship between MTFR1 expression and immunity were explored, through bioinformatics analysis. The effects of MTFR1 on the growth, migration and cisplatin sensitivity of LAC cells were identified using cell counting kit-8, wound healing and Transwell experiments. Additionally, the mechanisms of drug resistance of LAC cells involving MTFR1 were investigated using western blotting. RESULTS: MTFR1 was elevated in LAC tissues. MTFR1 overexpression was associated with sex, age, primary therapy outcome, smoking, T stage, unfavourable prognosis and diagnostic value and considered an independent risk factor for an unfavourable prognosis in patients with LAC. MTFR1 co-expressed genes involved in the cell cycle, oocyte meiosis, DNA replication and others. Moreover, interfering with MTFR1 expression inhibited the proliferation, migration and invasion of A549 and A549/DDP cells and promoted cell sensitivity to cisplatin, which was related to the inhibition of p-AKT, p-P38 and p-ERK protein expression. MTFR1 overexpression was associated with stromal, immune and estimate scores along with natural killer cells, pDC, iDC and others in LAC. CONCLUSIONS: MTFR1 overexpression was related to the unfavourable prognosis, diagnostic value and immunity in LAC. MTFR1 also participated in cell growth and migration and promoted the drug resistance of LAC cells to cisplatin via the p-AKT and p-ERK/P38 signalling pathways.

Decreased APOC1 expression inhibited cancer progression and was associated with better prognosis and immune microenvironment in esophageal cancer.

Several studies have demonstrated the involvement of apolipoprotein C1 (APOC1) in multiple cancers. However, the role of APOC1 in esophageal cancer (ESCA) has not been elucidated. Hence, we examined the expression of APOC1 in ESCA tissues acquired from The Cancer Genome Atlas (TCGA) database and clinical samples from our hospital. An investigation of the association of APOC1 with the clinicopathological characteristics, prognosis, and diagnosis of ESCA was carried out on the basis of survival, receiver operating characteristics, and correlation analyses. Gene ontology, KEGG analysis, and protein-protein interaction network showed that co-expressed APOC1 genes were involved in the functions, mechanisms, and action network. The effects of APOC1 expression on ESCA cells were explored using CCK-8, migration and invasion assays. The relationship between APOC1 expression and ESCA immune-infiltrating cells and cell markers were examined using correlation analysis. We found that APOC1 was overexpressed in TCGA ESCA tissues and the same was validated in clinical ESCA tissues, with the area under the curve for APOC1 being 0.887. Overexpression of APOC1 was associated with short overall survival, disease-specific survival, progression-free interval, T stage, pathological stage, body mass index, and histological grade. Inhibition of APOC1 expression significantly reduced the proliferation, migration, and invasion of ESCA cells. Furthermore, APOC1 expression positively correlated with the ESTIMATE, immune, and stromal scores in ESCA. Overexpression of APOC1 correlated with the tumor purity, B cells, T helper cells, natural killer cells, cytotoxic cells, and other immune cells. Moreover, APOC1 was involved in ESCA progression via T cell receptor, B cell receptor, and other immune signaling pathways. Thus, APOC1 overexpression is expected to be a biomarker for dismal prognosis and diagnosis of ESCA. Inhibition of APOC1 expression significantly reduced the proliferation, migration, and invasion of ESCA cells. Overexpression of APOC1 was associated with the immune microenvironment in ESCA. Thus, APOC1 may be an efficient biomarker for proper prognosis and diagnosis of ESCA.

The Risk Model Based on the Three Oxidative Stress-Related Genes Evaluates the Prognosis of LAC Patients.

Background: Oxidative stress plays a role in carcinogenesis. This study explores the roles of oxidative stress-related genes (OSRGs) in lung adenocarcinoma (LAC). Besides, we construct a risk score model of OSRGs that evaluates the prognosis of LAC patients. Methods: OSRGs were downloaded from the Gene Set Enrichment Analysis (GSEA) website. The expression levels of OSRGs were confirmed in LAC tissues of the TCGA database. GO and KEGG analyses were used to evaluate the roles and mechanisms of oxidative stress-related differentially expressed genes (DEGs). Survival, ROC, Cox analysis, and AIC method were used to screen the prognostic DEGs in LAC patients. Subsequently, we constructed a risk score model of OSRGs and a nomogram. Further, this work investigated the values of the risk score model in LAC progression and the relationship between the risk score model and immune infiltration. Results: We discovered 163 oxidative stress-related DEGs in LAC, involving cellular response to oxidative stress and reactive oxygen species. Besides, the areas under the curve of CCNA2, CDC25C, ERO1A, CDK1, PLK1, ITGB4, and GJB2 were 0.970, 0.984, 0.984, 0.945, 0.984, 0.771, and 0.959, respectively. This indicates that these OSRGs have diagnosis values of LAC and are significantly related to the overall survival of LAC patients. ERO1A, CDC25C, and ITGB4 overexpressions were independent risk factors for the poor prognosis of LAC patients and were associated with risk scores in the risk model. High-risk score levels affected the poor prognosis of LAC patients. Notably, a high-risk score may be implicated in LAC progression via cell cycle, DNA replication, mismatch repair, and other mechanisms. Further, ERO1A, CDC25C, and ITGB4 expression levels were related to the immune infiltrating cells of LAC, including mast cells, NK cells, and CD8 T cells. Conclusion: In summary, ERO1A, CDC25C, and ITGB4 of OSRGs are associated with poor prognosis of LAC patients. We confirmed that the risk model based on the ERO1A, CDC25C, and ITGB4 is expected to assess the prognosis of LAC patients.

SPDL1 Overexpression Is Associated With the 18F-FDG PET/CT Metabolic Parameters, Prognosis, and Progression of Esophageal Cancer.

Esophageal cancer (ESCA) is one of the common malignant tumors. The roles and signaling mechanisms of spindle apparatus coiled-coil protein 1 (SPDL1) in ESCA progression have not been reported previously. Therefore, the expression levels and potential clinical roles of SPDL1 were investigated using data from multiple databases and tissue samples of 53 ESCA patients who underwent 18F-FDG positron emission tomography (PET)/computed tomography (CT) before therapy. The signaling mechanisms of SPDL1 involved in ESCA progression were investigated via bioinformatics analysis. The effects of SPDL1 on the growth and migration of ESCA cells were investigated using CCK-8, Edu, and transwell assays. SPDL1 was upregulated in ESCA tissues. Increased SPDL1 expression was associated with age, grade, drinking history, cancer stage, lymph node metastasis, TP53 mutation, and poor prognosis in patients with ESCA. SPDL1 overexpression was significantly correlated with SUVmax, SUVmean, and TLG of PET/CT. SPDL1 silencing inhibited cell proliferation, migration, and invasion. SPDL1 was significantly enriched in cell cycle, spliceosome, DNA replication, and other processes. The hub genes of a constructed protein-protein interaction network included CDK1, BUB1, CCNB1, BUB1B, CCNA2, CDC20, MAD2L1, AURKB, NDC80, and PLK1, which were related to SPDL1 expression. The findings of this study suggest that SPDL1 may serve as a biomarker of ESCA prognosis.

Evaluation of the roles and regulatory mechanisms of PD-1 target molecules in NSCLC progression.

BACKGROUND: Targeted programmed cell death protein 1 (PD-1) therapy could effectively improve the long-term prognosis of patients with non-small cell lung cancer (NSCLC). The role of PD-1 targets in the progression of NSCLC has not been fully revealed. METHODS: The differentially expressed genes (DEGs) in patients' blood after NSCLC treatment with PD-1 blocker nivolumab in the GSE141479 dataset were analyzed by GEO2R and identified in the TCGA database. The mechanism of action involved in the PD-1 target molecules via the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein-protein interaction (PPI) network shows the relationship between PD-1 target molecules. The factors affecting the prognosis of NSCLC patients were identified via the COX regression analysis and survival analysis to build the risk model and nomogram. RESULTS: There were 64 DEGs in patients' blood after nivolumab treatment and 48 DEGs in NSCLC tissues. The PD-1 target molecules involved cell proliferation, DNA replication, cell cycle, lung cancer, and other cellular processes. The prognostic factors CCNA2, CHEK1, DLGAP5, E2F8, FOXM1, HIST1H2BH, HJURP, MKI67, PLK1, TPX2, and TYMS, and the independent factors HIST1H2BH and PLK1, influenced the prognosis of NSCLC patients. HIST1H2BH and PLK1 were overexpressed in LUAD and LUSC tissues. The elevated expression levels of HIST1H2BH and PLK1 were related to the overall survival (OS) and the progression-free survival of NSCLC patients. High-risk NSCLC patients had a poor prognosis and were an independent factor influencing the poor prognosis of NSCLC patients. The high-risk model group was enriched with signaling mechanisms such as cell cycle, DNA replication, and homologous recombination. CONCLUSIONS: The risk model based on PD-1 target molecules was helpful to assess the prognosis of NSCLC patients. HIST1H2BH and PLK1 might become prognostic biomarkers of NSCLC patients.

The roles of risk model based on the 3-XRCC genes in lung adenocarcinoma progression.

BACKGROUND: The abnormal expression of deoxyribonucleic acid (DNA) repair genes might be the cause of tumor development and resistance of malignant cells to chemotherapeutic drugs. A risk model based on the X-ray repair of cross-complementary (XRCC) genes was constructed to improve the diagnosis and treatment of lung adenocarcinoma (LUAD) patients. METHODS: The expression levels, diagnostic values, and prognostic values of XRCC genes were identified, and the roles and regulatory mechanisms of the risk model based on the XRCC4/5/6 in LUAD progression was explored via The Cancer Genome Atlas (TCGA) and Oncomine databases. RESULTS: XRCC1/2/3/4/5/6, XRCC7 (PRKDC), and XRCC9 (FANCG) were overexpressed, and had diagnostic value for LUAD. The XRCC genes were involved in DNA repair, and participated in the regulation of non-homologous end-joining, homologous recombination, etc. The overall survival (OS), tumor (T) stage, and survival status of patients were significantly different between the Cluster1 and Cluster2 groups. XRCC4/5/6 were independent risk factors affecting the prognosis of LUAD patients. The risk score was related to the prognosis, sex, clinical stage, T, lymph node (N), and metastasis (M) stage, as well as the survival status of LUAD patients. The clinical stage and risk score were independent risk factors for poor prognosis in LUAD patients. The risk model was involved in RNA degradation, cell cycle, basal transcription factors, DNA replication etc. The risk scores were significantly correlated with the expression levels of TGFBR1, CD160, TNFSF4, TNFRSF14, IL6R, CXCL16, TNFRSF25, TAPBP, CCL16, and CCL14. CONCLUSIONS: The risk model based on the XRCC4/5/6 genes could predict the progression of LUAD patients.

DEPTOR suppresses the progression of esophageal squamous cell carcinoma and predicts poor prognosis.

As a naturally occurring inhibitor of mTOR, accumulated evidence has suggested that DEPTOR plays a pivotal role in suppressing the progression of human malignances. However, the function of DEPTOR in the development of esophageal squamous cell carcinoma (ESCC) is still unclear. Here we report that the expression of DEPTOR is significantly reduced in tumor tissues derived from human patients with ESCC, and the downregulation of DEPTOR predicts a poor prognosis of ESCC patients. In addition, we found that the expression of DEPTOR negatively regulates the tumorigenic activities of ESCC cell lines (KYSE150, KYSE510 and KYSE190). Furthermore, ectopic DEPTOR expression caused a significant suppression of the cellular proliferation, migration and invasion of KYSE150 cells, which has the lowest expression level of DEPTOR in the three cell lines. Meanwhile, CRISPR/Cas9 mediated knockout of DEPTOR in KYSE-510 cells significantly promoted cellular proliferation, migration and invasion. In addition, in vivo assays further revealed that tumor growth was significantly inhibited in xenografts with ectopic DEPTOR expression as compared to untreated KYSE150 cells, and was markedly enhanced in DEPTOR knockout KYSE-510 cells. Biochemical studies revealed that overexpression of DEPTOR led to the suppression of AKT/mTOR pathway as evidenced by reduced phosphorylation of AKT, mTOR and downstream SGK1, indicating DEPTOR might control the progression of ESCC through AKT/mTOR signaling pathway. Thus, these findings, for the first time, demonstrated that DEPTOR inhibits the tumorigenesis of ESCC cells and might serve as a potential therapeutic target or prognostic marker for human patients with ESCC.

Magnetic resonance imaging in early rheumatoid arthritis: a multicenter, prospective study.

To identify the magnetic resonance imaging (MRI) features of hands and wrists in early rheumatoid arthritis (RA). A total of 129 early arthritis patients (≤1 year) were enrolled in the study. At presentation, MRI of the hands was performed, with clinical and laboratory analyses. After a 1-year follow-up, clinical diagnosis of early RA or non-RA was confirmed by two rheumatologists. The characteristics of MRI variables at baseline in RA patients not fulfilling ACR 1987 criteria [RA-87(-)] were compared with those fulfilling ACR1987 criteria [RA-87(+)] and non-RA. In the 129 early arthritis patients, 90 were diagnosed with RA in a 1-year follow-up. There were 47.8 % (43/90) of the RA patients not fulfilling ACR 1987 criteria [RA-87(-)]. The scores of synovitis in RA-87(-) patients were similar with those in RA-87(+) [Synovitis score, 14.0 (IQR, 4.0-25.0) vs. 14.0 (IQR, 10.0-25.0), p > 0.05]. Compared with those in non-RA, RA-87(-) patients had higher synovitis scores and occurrence of synovitis in proximal interphalangeal (PIP) joints [synovitis score, 14.0 (IQR, 4.0-25.0) vs. 6.0 (IQR, 2.0-14.5), p = 0.046; occurrence of PIP synovitis: 53.5 vs. 27.3 %, p = 0.02]. There was no significant difference of bone marrow edema, bone erosion, and tenosynovitis between RA-87(-) and non-RA. Synovitis in PIP joints was independent predictor for RA-87(-) [OR, 3.1 (95 %CI 1.2-8.1)]. High synovitis scores and synovitis in PIP joints on MRI were important in early RA, especially those not fulfilling ACR 1987 criteria.

Efficacy and safety of weekly leflunomide for the treatment of early rheumatoid arthritis: a randomized, multi-center study.

AIM: The aim of this study was to determine the efficacy and safety of a weekly dose of leflunomide (50 mg/week) in early rheumatoid arthritis patients with mild or moderate disease activity. METHODS: The patients of early rheumatoid arthritis (ERA) with mild or moderate disease activity were randomly selected for inclusion in this study and were assigned to either the treatment group (leflunomide 50 mg/week, LEF50) or the control group (leflunomide 10 mg/day, LEF10). All patients were treated for 24 weeks. Clinical efficacy was assessed using the disease activity score in 28 joints (DAS28) - erythrocyte sedimentation rate (ESR) and European League Against Rheumatism (EULAR) response. A Chi-squared test, Fisher's exact-test and paired t-tests were used to analyze the data. RESULTS: A total of 244 patients who met the inclusion criteria and received at least one medicine dose were analyzed. At the baseline, the DAS28 (ESR) of the ERA patients were 4.41 ± 0.69 in LEF 50 group and 4.52 ± 0.64 in LEF 10 group, respectively. At week 24, the DAS28 (ESR) in two groups ( 2.94 ± 1.10 and 3.02 ± 1.14 ) were significant decreased compare with the baseline, respectively (P<0.01). There was no significant difference in DAS28 (ESR) between the LEF50 and LEF10 groups at week 24. (P > 0.05). At weeks 8, 12 and 24, the EULAR response (good responses + moderate responses) were 47.6%, 58.7% and 59.5%, in the LEF50 group and 43.2%, 49.1% and 53.4% in the LEF10 group, respectively. There was no significant different of EULAR response rates in the two groups at week 8, 12, and 24, respectively (P>0.05). There was no serious adverse events during the study. CONCLUSION: A weekly dose of 50 mg leflunomide showed similar benefits to a daily dose of 10 mg leflunomide for the treatment of mild-to-moderate early rheumatoid arthritis.

Determinants of brachial-ankle pulse wave velocity in Chinese patients with rheumatoid arthritis.

OBJECTIVE: To investigate the relationship between Brachial-ankle pulse wave velocity (baPWV), and its associated risk factors in Chinese patients with RA. METHODS: 138 Chinese RA patients and 150 healthy subjects were included. baPWV of all the participants was measured. RA related factors were determined, as well as traditional cardiovascular risk factors. RESULTS: baPWV was significant higher in RA group (1705.44 ± 429.20 cm/s) compared to the healthy control group (1386.23 ± 411.09 cm/s) (P < 0.001). Compared with low baPWV group, high baPWV group patients were significantly older (P = 0.008) and taller (P = 0.033). Serum cholesterol (P = 0.035), triglycerides (P = 0.004), and LDL level (P = 0.006) were significantly higher in high baPWV group patients compared with low baPWV group patients. The baPWV of RA patients was positively correlated with age (r = 0.439, P < 0.001), and serum cholesterol level (r = 0.231, P = 0.035), serum triglycerides level (r = 0.293, P < 0.001), serum LDL level (r = 0.323, P = 0.003). Meanwhile, baPWV negatively correlated with the height of RA patients (r = -0.253, P = 0.043). Multivariate regression analysis showed that baPWV of RA group was independently associated with age and serum triglycerides level. CONCLUSIONS: The old age and high level of serum triglycerides may be the major determinants of arterial stiffness in Chinese RA patients.

Significance of anti-cell membrane-associated DNA (mDNA) antibodies in systemic lupus erythematosus.

The aim of this study was to evaluate the value of anti-cell membrane-associated DNA (mDNA) antibodies in the diagnosis of systemic lupus erythematosus (SLE). Antibodies against mDNA were detected with indirect immunofluorescence assay in 207 SLE, 167 other rheumatic diseases, and 82 healthy controls. Association of clinical features and anti-mDNA antibodies was analyzed. The prevalence of anti-mDNA antibodies was 73.3% in SLE, 8.3% in Sjögren's syndrome, and 4.8% in rheumatoid arthritis. The incidences of anti-mDNA antibodies in SLE lacking antideoxyribonucleoprotein, antihistone antibodies, antinuclesome antibodies, anti-dsDNA, and anti-Sm antibodies were 73.8, 62.7, 65.3, 57.8 and 51.6%, respectively. Skin rash, alopecia, oral ulcer, and joint pain are more common in patients with anti-mDNA antibodies. The anti-mDNA antibody is one of the most valuable markers in SLE. It is also informative in some SLE patients lacking other autoantibodies.

[Effect of multiple amino acid substitutions of collagen II 263-272 on collagen-induced arthritis].

OBJECTIVE: To evaluate the effect of multiple amino acid substitutions of C II 263-272 peptide on collagen-induced arthritis, and explore a therapeutic strategy of rheumatoid arthritis. METHODS: A panel of altered C II 263-272 peptides was synthesized with substitutions of TCR-contact residues of C II 263-272 with alanine. The competitive inhibition of APL to wild type C II 263-272 was analyzed by 3H incorporation assay. CIA model was induced by intradermal injection of bovine CII. Altered CII peptide was injected subcutaneously in different doses (1, 10, 100 microg, respectively, twice per week) after onset of CIA. The arthritis index, radiologic and histologic scores were recorded to evaluate the severity change of arthritis. Serum levels of IFN-gamma were examined by ELISA. RESULTS: Competitive inhibition to wild type C II 263-272 of the altered C II 263-272 peptides (APL1, APL2, APL3) was found in PBMC from RA patients. Among them, APL3 with substitution of residues 267(Q), 270(K) and 271(G) to A showed the most significant effect and thus was used in the treatment of CIA rats. We observed significantly reduced arthritis scores in CIA rats treated with 100 microg/dose of APL as compared with rats treated with PBS and peptide control. The mean radiographic and histologic scores was also markedly lower in APL-treated CIA rats than in PBS or peptide control-treated rats. On day 35 after immunization, the serum level of IFN-gamma in rats was examined and a significantly low level of serum IFN-gamma was found in APL-treated rats. CONCLUSION: C II 263-272 peptide with TCR-contact residues substitutions inhibited joint destruction in CIA rats and down-regulated IFN-gamma production, suggesting that altered CII peptide might be potentially therapeutic in rheumatoid arthritis.