Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

In recent years, cyclic peptides have attracted increasing attention in the field of drug discovery due to their excellent biological activities, and, as ...

Anhui medical university

Human adipose derived mesenchymal stem cells (ADMSCs) are multipotential stem cells, originated from the vascular stromal compartment of fat tissues which can be used as an alternative cell source for many different cell therapies. However, their response to chemotherapeutic agants remains unknown. Here we assessed the acute direct effects of individual chemotherapeutic drug on ADMSCs. Using an in vitro culture system, the response of ADMSCs to the three chemotherapeutic agents cisplatin, comptothecin and vincristine was determined in comparison with that of testicular germ cell tumour (TGCT) cell line. The recovery of cell numbers following exposure to chemotherapeutic agents were also evaluated. Our results showed that human ADMSCs were resistant to chemo-therapeutic agents which are commonly used in clinic, the full recovery was seen respectively in ADMSCs after the drug treatment. Moreover, ADMSCs maintained their stem cell characteristics in vitro after the exposure to all chemotherapeutic agents.

Human adipose tissue derived mesenchymal stem cells are resistant to several chemotherapeutic agents.

Many reports have demonstrated that human bone marrow mesenchymal stem cells (BMMSCs) are resistant to several chemotherapeutic agents or ionic radiation when compared with sensitive tumor cell lines; however, the underlying molecular mechanism is rarely known. In our previous studies, we found that p53 family member p73 was not expressed in BMMSCs with or without the treatment of chemotherapeutic drugs, and the exogenous induction of p73 protein could reduce the resistance of BMMSCs to the drugs. In order to elucidate which factor leads to the inhibition of p73 expression, we used a methylation-specific polymerase chain reaction to investigate the epigenetic methylation status of the p73 gene promoter CpG region. Our data showed that the p73 gene promoter was hypermethylated in BMMSCs but not in tumor cell lines, which were sensitive toward chemotherapeutic agents. Using the demethylation agent 5-aza-2'-deoxycytidine significantly reactivated p73 expression both at the transcriptional and at the protein level. In addition, the treatment of 5-aza-2'-deoxycytidine rendered BMMSCs more sensitive to chemotherapeutic agents through the process of enhanced apoptosis cell death. Taken together, our results suggest that the silencing of the p73 gene mediated by promoter hypermethylation may play a crucial role in leading to the high resistance of BMMSCs to chemotherapeutic drugs and thus we conclude that the p73 gene may be an important element regulating human BMMSCs in response to DNA damage.

5-Aza-2'-deoxycytidine increases the sensitivity of human bone marrow mesenchymal stem cells to chemotherapeutic agents by demethylation of p73.

Citral, 3,7-dimethyl-2,6-octadienal, is a key component of the essential oils extracted from several lemon-scented herbal plants. Besides its antifungal activity, the anticancer effect of citral was studied in recent years. In this study, we investigated the effect of citral on the acute promyelocytic leukemia cell line NB4. Citral treatment had an antiproliferative effect in NB4 cells via the induction of apoptosis assessed by morphology, proliferation assay, DNA electrophoresis, Annexin V-FITC/PI staining and caspase-3 activation. And citral induced apoptosis of NB4 cells in a dose- and time-dependent manner. In addition, citral treatment induced decreased mitochondrial membrane potential, indicating that citral induced apoptosis via the mitochondrial pathway. Bax up-regulation and Bcl-2 down-regulation on mRNA level and NF-κB down-regulation on protein level was found in this study, suggesting that Bcl-2, Bax and NF-κB may be involved in the mechanism of the apoptotic effect of citral on NB4 cells. These data suggest that citral has a potential therapeutic effect on leukemia.

The in vitro study of apoptosis in NB4 cell induced by citral.

Laparoscopic radical gastrectomy has been increasingly applied in China. However, how to reduce surgery-related trauma, shorten operative time and achieve the long-term prognosis equal to the conventional open surgery is still hot research topics. Along with the change in learning curve and the optimization of endoscopic techniques, laparoscopic lymph node dissection can achieve or even exceed the extent that can be achieved in open surgery. Therefore, it has gradually replaced the conventional digestive tract reconstruction using an auxiliary incision. By completing the laparoscopic digestive tract reconstruction with EndoGIA, we describe the laparoscopy-assisted D2 radical distal gastrectomy for gastric cancer (Billroth II anastomosis). 

Laparoscopy-assisted D2 radical distal gastrectomy for gastric cancer (Billroth II anastomosis).

Inhibition of the interaction between p53 and MDM2/MDMX has attracted significant attention in anticancer therapy development. We designed a series of in-tether chiral center-induced helical stabilized peptides, among which MeR/PhR effectively reactivated p53. The activation of p53 inhibits cell proliferation and induces apoptosis in both the MCF-7 normal tumor cell line and the PA-1 pluripotent cancer cell line with only minimal cellular toxicity towards normal cells or cancer cell lines with p53 mutations. The in vivo bioactivity study of the peptide in the ovarian teratocarcinoma (PA-1) xenograft model showed a tumor growth rate inhibition of 70% with a dosage of 10 mg/kg (one injection every other day). This is the first application of a stabilized peptide modulator targeting stem-like cancer cell both in vitro and in vivo and provides references to cancer stem cell therapy.

In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell.

[This corrects the article DOI: 10.7150/thno.19840.].

Erratum: In-Tether Chiral Center Induced Helical Peptide Modulators Target p53-MDM2/MDMX and Inhibit Tumor Growth in Stem-Like Cancer Cell: Erratum.

FDA-approved HDAC inhibitors exhibit dose-limiting adverse effects; thus, we sought to improve the therapeutic windows for this class of drugs. In this report, we describe a new class of peptide-based HDAC inhibitors derived from the HDAC1-specific substrate H3K56 with improved nonspecific toxicity compared with traditional small-molecular inhibitors. We showed that our designed peptides exerted superior antiproliferation effects on cancer stem-like cells with minimal toxicity to normal cells compared with the small-molecular inhibitor SAHA, which showed nonspecific toxicity to normal and cancer cells. These peptide inhibitors also inactivated cellular HDAC1 and HDAC6 and disrupted the formation of the HDAC1, LSD1, and CoREST complex. In ovarian teratocarcinoma (PA-1) and testicular embryonic carcinoma (NTERA-2) cell xenograft animal models (5 mice/group, 50 mg/kg, every other day, intraperitoneal injection), these peptides inhibited tumor growth by 80% to 90% with negligible organ (heart, liver, spleen, lung, kidney, brain) lesions. These results represent the first attempt to design chemically stabilized peptide inhibitors to investigate HDAC inhibition in cancer stem-like cells. These novel peptide inhibitors have significantly enhanced therapeutic window and offer promising opportunities for cancer therapy. SIGNIFICANCE: Selective antiproliferative effects of stabilized peptide HDAC inhibitors toward cancer stem-like cells provide a therapeutic alternative that avoids high nonspecific toxicity of current drugs. http://cancerres.aacrjournals.org/content/canres/79/8/1769/F1.large.jpg.

Stabilized Peptide HDAC Inhibitors Derived from HDAC1 Substrate H3K56 for the Treatment of Cancer Stem-Like Cells .

Growing evidence has suggested that long noncoding RNAs (lncRNAs) play an essential role in the progression of papillary thyroid cancer (PTC). LncRNA LINC00311 was found to be able to regulate many cellular process in several diseases. However, the function and regulatory mechanism of LINC00311 remains unclear in PTC. In the present study, the results showed that the expression of LINC00311 was upregulated in PTC tissues and cells. Furthermore, knockdown of LINC00311 dramatically suppressed spheroid formation, proliferation, migration, and invasion in PTC cells in vitro. Mechanistic investigations revealed that LINC00311 was negatively correlated with the expression of miR-330-5p, meanwhile, TLR4 was a direct target of miR-330-5p. In addition, rescue assays further determined that LINC00311 contributed to the progression of PTC through regulating TLR4 expression. Taken together, these findings indicated that LINC00311 could promote cancer stem-like properties by targeting miR-330-5p/TLR4 pathway in PTC.

LINC00311 promotes cancer stem-like properties by targeting miR-330-5p/TLR4 pathway in human papillary thyroid cancer.

Accurately delineating clinical target volumes (CTV) is essential for completing radiotherapy plans but is time-consuming, labor-intensive, and prone to inter-observer variation. Automating CTV delineation has the benefits of both speeding up contouring process and improving the quality of contours. Recently, auto-segmentation approaches based on deep learning have achieved some improvements. However, unlike organ segmentation, the CTV contains potential tumor spread tissues or subclinical disease tissues, resulting in poorly defined margin interface and irregular shape. It is not reasonable to directly apply the deep learning segmentation algorithms to CTV tasks without considering the unique characteristics of shape and margin. In this work, we propose a novel automatic CTV delineation algorithm based on deep learning addressing the unique shape and margin challenges.

Automatic clinical target volume delineation for cervical cancer in CT images using deep learning.

N6-Methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in eukaryotes. The underlying molecular mechanisms of m6A modification in chronic glomerulonephritis (CGN) remain unexplored. Here, we performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) analyses to assess the alterations of epitranscriptome-wide m6A profile in lipopolysaccharide (LPS)-induced mouse mesangial cells (MMC). The results of our data showed 2153 significantly differential m6A peaks and 358 significantly differentially expressed genes. Furthermore, integrated analysis from MeRIP-seq and RNA-seq identified a total of 64 genes with differential m6A modification and expressed levels, of which 5 genes displayed hypermethylation and upregulation, 42 genes displayed hypermethylation and downregulation, 11 genes displayed hypomethylation and upregulation, and 8 genes displayed hypomethylation and downregulation. Many of them (including Fosl1, Sorbs1, Ambp, Fgfr3, Nedd9, Fgg, Trim13, Fgf22, Mylk, and Muc6) are implicated in the regulation of the immune and inflammatory response. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis found that differential 64 genes were mainly enriched in fatty acid oxidation, apoptosis signaling pathway, complement and coagulation cascades, and PPAR signaling pathway. Together, our study provided a new perspective on the understanding of molecular features of m6A modification in CGN pathogenic pathogenesis.

Alteration of N6-methyladenosine epitranscriptome profile in lipopolysaccharide-induced mouse mesangial cells.

To investigate the application value of bone marrow megakaryocyte count, the proportion of megakaryocytes at each stage, and the platelet parameter in the clinical diagnosis of primary immune thrombocytopenia (ITP).  The megakaryocyte and platelet parameter level in 62 ITP and 40 control group patients were compared and analyzed. Linear correlation analysis, Pearson correlation analysis, and ROC curves were performed for the correlation between megakaryocytes and platelet parameters.  Compared to the control group, the total number of megakaryocytes, the promegakaryocytes the granular megakaryocytes (GMeg), and naked megakaryocytes (NMeg), MPV, and P-LCR% in the ITP group increased. All differences were statistically significant (<0.05). While the proportion of platelet-producing megakaryocytes (PMeg), PLT, and PCT decreased in the ITP group. These differences were statistically significant ( 0.05). PLT was strongly positively correlated with PCT (r = 0.921, p<0.01). PCT was weakly positively with MPV (r = 0.309, p<0.05). MPV was positively correlated with P-LCR (r = 0.856, p<0.01). PDW was weakly positively correlated with P-LCR (r = 0.296, p<0.05) and Meg (r = 0.301, p<0.05), and negatively correlated with PMeg (r = -0.336, p<0.05). ROC curve analysis showed that PLT, PCT MPV and P-LCR% gave a high sensitivity（100.0%，81.0%，74.6%，90.5%，respectively.) and specificity (100.0%, 92.5%, 80.0%, 77.5%, respectively.) in diagnosis of ITP.  The combined analysis of bone marrow megakaryocyte count, the proportion of megakaryocyte classification at each stage, and platelet parameters have an important reference value for auxiliary diagnosis of ITP.

Wei Liang

Department of Radiation Oncology,
The First Affiliated Hospital,
Department of Radiation Oncology, the First Affiliated Hospital

Anhui medical university

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

Wei Liang

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Radiation Oncology,The First Affiliated Hospital,Department of Radiation Oncology, the First Affiliated Hospital

Anhui medical university

Constructing Cyclic Peptides Using an On-Tether Sulfonium Center

Department of Radiation Oncology,
The First Affiliated Hospital,
Department of Radiation Oncology, the First Affiliated Hospital