Network pharmacology, molecular docking, and molecular dynamics simulations shed light on the mechanism behind Gynostemma pentaphyllum's efficacy against osteosarcoma.

Osteosarcoma (OS) is the most common type of malignant bone tumor, that poses a serious threat to the lives and health of children and adolescents. Traditional Chinese medicines (TCM) have gained attention for treating OS because of their potent anti-cancer effects and fewer side effects. It is commonly understood that Gynostemma pentaphyllum (Thunb.) Makino (GP) exhibits inhibitory effects on most tumors. However, the knowledge of the systematic mechanisms involved is limited. In this study, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was searched to screen the effective ingredients and corresponding target genes of GP, and disease target databases were searched to identify relevant targets for OS. Venn analysis was used to visualize overlapping genes, which were further extracted using the protein-protein interaction network. R software was used to conduct gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analysis, molecular docking and molecular dynamics simulation further validate the binding efficacy of potential therapeutic targets to compound molecules. In total, 161 and 1981 proteins were identified as target genes of GP and OS, respectively, and 104 overlapping genes were identified. Through analysis of the core subnetwork, 12 hub genes were identified, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed that the PI3K/Akt signaling pathway was the most significant. Molecular docking and molecular dynamics simulations show that a high affinity between quercetin and these targets, especially with the combination of TNF free energy (Δ Gbind) minimum, MM/PBSA and MM/GBSA is 42.85 kcal/mol, respectively, and 45.29 kcal/mol. The active ingredients Rhamnazin and Quercetin in Gypenoylum play a therapeutic role in OS through several key targets and pathways. This study provides ideas and references for further research on drug development.

A novel prognostic biomarker CD3G that correlates with the tumor microenvironment in cervical cancer.

Cervical cancer (CESC) is the fourth most common and death-causing gynecological cancer, mostly induced by infection of human papillomavirus (HPV). Multiple components of the tumor microenvironment (TME), such as tumor infiltrating immune cells, could be targets of immunotherapy for HPV-related CESC. However, little is known about the TME of CESC until now. Here, we aimed to uncover the pathogenesis as well as to identify novel biomarkers to predict prognosis and immunotherapy efficacy for CESC. Combining the transcriptomic data and clinical characteristics, we identified differentially expressed genes in CESC samples from TCGA database by comparing the two groups with different ImmuneScore and StromalScore. Next, we detected ten key genes based on the PPI network and survival analyses with the univariate Cox regression model. Thereafter, we focused on CD3G, the only gene exhibiting increased RNA and protein expression in tumors by multiple analyses. Higher CD3G expression was associated with better survival; and it was also significantly associated with immune-related pathways through GSEA analysis. Furthermore, we found that CD3G expression was correlated with 16 types of TICs. Single cell RNA-sequencing data of CD3G in lymphocytes subgroup indicated its possible role in HPV defense. Hence, CD3G might be a novel biomarker in prognosis and immunotherapy for CESC patients.

Alternative ANKHD1 transcript promotes proliferation and inhibits migration in uterine corpus endometrial carcinoma.

Alternative splicing (AS) is common in gene expression, and abnormal splicing often results in several cancers. Overall survival-associated splicing events (OS-SEs) have been used to predict prognosis in cancer. The aim of this study was to investigate the presence and function of OS-SEs in uterine corpus endometrial carcinoma (UCEC). Based on TCGA and TCGASpliceSeq databases, gene expression and the AS data of UCEC samples were retrieved. An alternate terminator of ANKHD1 transcripts named ANKHD1-BP3 was found to be significantly related to metastasis and OS in UCEC and significantly associated with HSPB1. The upregulated expression of HSPB1 induced downregulation of ANKHD1-BP3 and promoted tumor metastasis. These findings indicate that HSPB1, a splicing factor, regulates the expression of ANKHD1-BP3 to promote metastasis in UCEC.

Engineering of Neutrophil Membrane Camouflaging Nanoparticles Realizes Targeted Drug Delivery for Amplified Antitumor Therapy.

PURPOSE: Although the neutrophil membrane (NM)-based nanoparticulate delivery system has exhibited rapid advances in tumor targeting stemmed from the inherited instinct, the antitumor effect requires further improvement due to inefficient cellular internalization in the absence of specific interactions between NM-coated nanoparticles and tumor cells. METHODS: Herein, we fabricated drug-paclitaxel loaded NM camouflaging nanoparticles (TNM-PN) modified with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), favorable for the cellular internalization. RESULTS: The results showed that TNM-PN exerted a significant cytotoxicity to tumor cells by TRAIL-mediated endocytosis and strong adhesion to inflamed endothelial cells in vitro. Due to TRAIL modification as well as the adhesive interactions between neutrophil and inflamed tumor vascular endothelial cells, tumors in TNM-PN group exhibited almost 2-fold higher fluorescence intensities than that of NM camouflaging nanoparticles and 3-fold higher than that of bare nanoparticles, respectively. Significant tumor inhibition and survival rates of mice were achieved in TNM-PN group as a consequence of prolonged blood circulations to 48 h and preferential tumor accumulations, which was ascribed to targeting adhesion originated from NM to immune evasion and subsequent excellent cellular internalization. CONCLUSION: The research unveiled a novel strategy of amplifying cellular internalization based on NM coating nanotechnology to boost antitumor efficacy.

Detection of K-ras gene mutations in feces by magnetic nanoprobe in patients with pancreatic cancer: A preliminary study.

The present study aimed to investigate the feasibility and effectiveness of detecting K-ras mutation by using magnetic nanoparticles in fecal samples of patients with pancreatic cancer at different stages. The novel methodology of K-ras mutation detection was compared to the existing methodology of cancer antigen (CA)19-9 examination. Patients with pancreatic cancer (n=88), pancreatic benign diseases who displayed chronic pancreatitis (n=35), pancreatic mucinous cyst neoplasms (n=10) and pancreatic serous cyst (n=9) admitted to the Department of Surgery, Jiaxing Second Hospital were enrolled in the present study. Fecal samples were collected from all patients, DNA was extracted and magnetic nanoprobe was then used to detect K-ras mutation. The results obtained using the novel magnetic nanoprobe detection technique showed a K-ras mutation rate of 81.8% (72/88) in the patients with pancreatic cancer and 18.5% (10/54) in patients with pancreatic benign diseases. In patients with pancreatic cancer, the K-ras mutation rate was comparable in stages I + IIA and IIB + III + IV (78.9 vs. 84.0%; P>0.05). The sensitivity and specificity of K-ras mutation for detection of pancreatic cancer was 81.8 and 81.5%, respectively. Sixty-eight pancreatic cancer patients had >37 U/ml CA99 with a sensitivity and specificity for pancreatic cancer detection of 77.3 and 77.8%, which was not significantly lower than detection by the fecal K-ras mutations (P>0.05). Combinational detection of fecal K-ras mutations and serum CA19-9 significantly increased the sensitivity regarding pancreatic cancer detection to 97.7% (P<0.05), while the specificity was not enhanced (80.9%; P>0.05) compared with fecal K-ras mutations or CA19-9 alone. The findings showed that the magnetic nanoprobe is able to detect fecal K-ras mutations in different stages of pancreatic cancer, with comparable sensitivity and specificity to CA19-9 examination for differentiating pancreatic cancer. Furthermore, combined detection of CA19-9 and K-ras mutations has enhanced sensitivity compared with CA19-9 alone.

Chlorogenic acid prevents isoproterenol-induced DNA damage in vascular smooth muscle cells.

Numerous clinical therapeutic agents have been identified as DNA damaging. The present study revealed that isoproterenol (Iso) resulted in DNA damage in vascular smooth muscle cells (VSMCs) and increased the levels of intracellular oxygen free radicals. Administration of chlorogenic acid (CGA) inhibited this effect. Pretreatment with CGA abrogated the increase in protein expression levels of γ­H2A histone family member X, phosphorylated ataxia telangiectasia mutated, phosphorylated Rad3­related protein, breast cancer 1 and C­terminal Src homologous kinase induced by Iso. In addition, the increase in levels of intracellular reactive oxygen species (ROS) induced by Iso was inhibited by CGA pretreatment in a dose­dependent manner. The results of the present study suggest that CGA may inhibit Iso­induced VSMC damage via the suppression of ROS generation. Therefore, CGA may be a novel agent for the treatment of vascular diseases.

Aptamer Functionalized Cisplatin-Albumin Nanoparticles for Targeted Delivery to Epidermal Growth Factor Receptor Positive Cervical Cancer.

Targeted nanocarriers may offer a new approach to improve the efficacy and tolerability of cisplatin, which are commonly used to treat cancers as a first line chemotherapy for most types of cancer. In the present study, we have developed EGFR-targeted albumin-cisplatin nanoparticles for tumor targeted delivery of cisplatin. The cisplatin NPs were conjugated with EGFR aptamer, which binded to Hela cells specifically, then taken up by tumor cells through receptor mediated endocytosis. The aptamers accumulate in the tumor and interact with the receptor on the surface of Hela cells, successfully blocked EGF-induced EGFR phosphorylation, exerting its targeting and therapy function. Here we demonstrate that the EGFR aptamer functioned NPs enhanced in vitro antitumor effects and markedly improved its tolerability and in vivo efficacy when compared with free cisplatin and other single treatment. Furthermore, the Apt-Pt NPs treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum in the major organs as quantified by ICP-MS. The Apt-Pt NPs provides a remarkable improvement in the drug therapeutic efficacy and tolerability in vivo, and will be generalized as a principle for development of novel nanocarriers for targeted tumor therapy.

Highly efficient Gab2 siRNA delivery to ovarian cancer cells mediated by chitosan-polyethyleneimine nanoparticles.

Malignant bowel obstruction (MBO) is a serious complication which causes high death rate and low quality of life (QOL) for patients diagnosed at an advanced stage of ovarian cancer. RNA interference (RNAi) could be a promising method for the treatment of ovarian cancer and could decrease the morbidity of MBO. Gab2 gene is overexpressed in ovarian cancer compared with normal ovarian tissue, and regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells. Here, chitosan-polyethyleneimine (PEI, Mw 1800) copolymer nanoparticles were synthesized as nanocarriers to deliver Gab2 siRNA into SKOV3 cells. The silencing effects against the Gab2 gene and the antitumor effects by the chitosan-PEI-Gab2 siRNA nanoparticles (chitosan-PEI-Gab2 NPs) were studied. Results showed that highly efficient silencing effects against Gab2 expression and its downstream effector, AKT protein, at more than 90% deregulation were obtained by chitosan-PEI NP mediated Gab2 siRNA delivery, so as to exhibit obvious antitumor effects against SKOV3 cells with low cytotoxicity, and induce cell apoptosis in early and late stages. The study will provide novel strategies to overcome MBO in ovarian cancer by the efficient knockdown of Gab2 expression.

Effectiveness and risk associated with infliximab alone and in combination with immunosuppressors for Crohn's disease: a systematic review and meta-analysis.

OBJECTIVE: Infliximab (IFX) monotherapy and IFX combined with immunosuppressors have been used in the treatment of Crohn's disease. However, the differences between combination therapy and IFX alone remain controversial. The aim of this meta-analysis was to evaluate the effectiveness and risk associated with combination therapy and IFX monotherapy. METHODS: Systematic searches were performed for randomized controlled trials with PubMed, Web of Science, OVID, and the Cochrane Library. The analyzed contents included induction of remission, short-term maintenance of remission, long-term maintenance of remission, and risks. The final results were estimated using statistical data of odds ratio (OR), relevant 95% confidence interval (CI), and P value. RESULTS: 6 out of 1041 citations met the selection criteria. There was no statistical difference in the effectiveness of induction and long-term maintenance of remission between two groups (P=0.07, 0.12). However, for short-term maintenance of remission, there was mild statistical difference between two groups (P=0.02, OR=1.66). For risks, apart from the difference in the aspect of reaction to infusion (OR=0.43, 95% CI=0.29-0.65, P<0.0001), there was no statistical difference. CONCLUSIONS: There was no significant difference in effectiveness and risks between the therapy groups. However, these outcomes should be interpreted with caution. Specific categories of combination therapy and periodic medication should be paid more attention in future studies.