Capturing the Interaction Kinetics of an Ion Channel Protein with Small Molecules by the Bio-layer Interferometry Assay

The bio-layer interferometry (BLI) assay is a valuable tool for measuring protein-protein and protein-small molecule interactions. Here, we first describe ...

Shanghai Jiao Tong University School of Medicine

The role of histone modifications in the development and progression of cancer remains unclear. Here, we gave an investigation of the relationship between the various histone modifications and the risk prediction of the biochemical recurrence after radical prostatectomy (RP). Histone 3 lysine 4 dimethylation (H3K4diMe), trimethylation (H3K4triMe), lysine 36 trimethylation (H3K36triMe), histone 4 lysine 20 trimethylation (H4K20triMe) and acetylation of histome 3 lysine 9 (H3K9Ac) were evaluated using immnuohistochemistry coupled with the tissue microarray technique in 169 primary prostatectomy tissue samples. Recursive partitioning analysis (RPA) was used to analyze the data. Through global histone modification analysis in patients who underwent radical prostatectomy, we found that H3K4triMe can predict the risk of the biochemical recurrence for the low grade prostate cancer (Gleason score < or = 6) after RP. In the case of high grade prostate cancer (Gleason score > or = 7), H4K20triMe and H3K9Ac accompanying with the pre-operation prostate-specific antigen (PSA) level could also predict the risk of the biochemical recurrence after RP. In combination with the Gleason score and pre-operation PSA level, the acetylation and methylation of histones H3 and H4 can predict the biochemical recurrence of the prostate cancer following RP.

Application of histone modification in the risk prediction of the biochemical recurrence after radical prostatectomy.

The purpose of this experiment was to investigate the visible imaging of gastric adenocarcinoma cells in vitro by targeting tumor-associated glycoprotein 72 (TAG-72) with near-infrared quantum dots (QDs). QDs with an emission wavelength of about 550 to 780 nm were conjugated to CC49 monoclonal antibodies against TAG-72, resulting in a probe named as CC49-QDs. A gastric adenocarcinoma cell line (MGC80-3) expressing high levels of TAG-72 was cultured for fluorescence imaging, and a gastric epithelial cell line (GES-1) was used for the negative control group. Transmission electron microscopy indicated that the average diameter of CC49-QDs was 0.2 nm higher compared with that of the primary QDs. Also, fluorescence spectrum analysis indicated that the CC49-QDs did not have different optical properties compared to the primary QDs. Immunohistochemical examination and in vitro fluorescence imaging of the tumors showed that the CC49-QDs probe could bind TAG-72 expressed on MGC80-3 cells.

Synthesis of CdTe quantum dot-conjugated CC49 and their application for in vitro imaging of gastric adenocarcinoma cells.

Intraoperative lymph node mapping (LNM) is highly significant for many surgeries in patients with cancer. Many types of tracers are currently used, but the ideal method has not yet been identified. We aimed to identify a stable lymphatic drainage pathway in an animal model and compared the effects of quantum dots (QD), a new fluorescent tracer, with those of methylene blue in intraoperative LNM.

In vivo lymph node mapping by Cadmium Tellurium quantum dots in rats.

To evaluate the effects of early-phase drainage on the survival rates and pancreatic pathological changes associated with severe acute pancreatitis (SAP) in a rat model.

Early-phase peritoneal drainage and lavage in a rat model of severe acute pancreatitis.

Hepatic ischemia/reperfusion (I/R) injury often occurs during liver surgery and may cause liver failure. Our previous studies revealed that Mindin is involved in the pathogenesis of ischemic stroke. However, the function of Mindin in hepatic I/R injury remains unknown.

Mindin deficiency protects the liver against ischemia/reperfusion injury.

Angiogenesis is indispensible for tumor growth and metastasis. Antiangiogenic therapy is now a validated major strategy in cancer clinic; several small molecule angiogenic inhibitors have been successfully translated into clinic for multiple cancer indications. In the past decade, many natural products with potent antiangiogenic activity were explored and the underlying molecular mechanisms were revealed. One important mechanism is the inhibition of one or several steps in VEGF/VFGFR signaling pathway. Other factors (bFGF, HIF-1α, NF-κB etc.) capable of regulating angiogenesis, are also down-regulated by some natural products. Moreover, some of the antiangiogenic natural products also significantly inhibit vasculogenic mimicry (VM), another important vessel recruitment avenue in cancer, by regulating the key signaling of VM formation including VE-cadherin, EphA2, and Nodal signaling. In this mini-review, we summarized the natural products with suppressive effect on tumor angiogenesis and VM according to their diverse molecular mechanisms, and discussed the major direction of future research in this field.

Natural Products with Antiangiogenic and Antivasculogenic Mimicry Activity.

Normalization of the tumor microenvironment is a promising approach to render conventional chemotherapy more effective. Although passively targeted drug nanocarriers have been investigated to this end, actively targeted tumor priming remains to be explored. In this work, we demonstrate an effective tumor priming strategy using metronomic application of nanoparticles actively targeted to tumor neovasculature. F56 peptide-conjugated paclitaxel-loaded nanoparticles (F56-PTX-NP) were formulated from PEGylated polylactide using an oil in water emulsion approach. Metronomic F56-PTX-NP specifically targeted tumor vascular endothelial cells (ECs), pruned vessels with strong antiangiogenic activity and induced thrombospondin-1 (TSP-1) secretion from ECs. The treatment induced tumor vasculature normalization as evidenced by significantly increased coverage of basement membrane and pericytes. The tumor microenvironment was altered with enhanced pO2, lower interstitial fluid pressure, and enhanced vascular perfusion and doxorubicin delivery. A "normalization window" of at least 9 days was induced, which was longer than other approaches using antiangiogenic agents. Together, these results show that metronomic, actively-targeted nanomedicine can induce tumor vascular normalization and modulate the tumor microenvironment, opening a window of opportunity for effective combination chemotherapies.

Tumor priming using metronomic chemotherapy with neovasculature-targeted, nanoparticulate paclitaxel.

                    
1 (Eag1, Kv10.1, KCNH1) Kchannel is a member of the voltage-gated Kchannel family mainly distributed in the central nervous system and cancer cells. Like other types of voltage-gated Kchannels, the EAG1 channels are regulated by a variety of endogenous signals including reactive oxygen species, rendering the EAG1 to be in the redox-regulated ion channel family. The role of EAG1 channels in tumor development and its therapeutic significance have been well established. Meanwhile, the importance of hEAG1 channels in the nervous system is now increasingly appreciated. The present review will focus on the recent progress on the channel regulation by endogenous signals and the potential functions of EAG1 channels in normal neuronal signaling as well as neurological diseases.

Eag1 KChannel: Endogenous Regulation and Functions in Nervous System.

Aberrant activation of beta-catenin/TCF signaling is one of the hallmarks of colon cancer. It is of great interest to study the mechanism for the regulation of beta-catenin/TCF signaling. In this study, it was found that LRP1B was down-regulated in colon cancer tissues and inhibited the growth, migration and metastasis of colon cancer cells. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling. Taken together, our study demonstrated the suppressive roles of LRP1B in the progression of colon cancer, implicating that restoring the function of LRP1B would be a promising strategy for the treatment of colon cancer.

Down-regulation of LRP1B in colon cancer promoted the growth and migration of cancer cells.

The complement system is indispensable in immune response, responsible for the wide range of immune surveillance, clearance and defense. Its activation, regulated by several crucial factors, is an important prerequisite for its role in tumor growth and anti-tumor therapy. Membrane attack complex (MAC) and anti-tumor anaphylatoxins like C5a have significant effects on promoting tumor, such as upregulation of oncogenic growth factors, activation of mitogenic signaling pathways and breakage of normal cell cycle. Complement cascades, initiated by anti-tumor antibodies, also play a pivotal role in anti-tumor therapy to suppress the tumor growth. Our review focuses on the recent progress in the understanding of complement activation and the role of it in tumor growth and anti-tumor therapy, in the context of rapid development of monoclonal antibodies and nanomaterials for cancer treatment.

Recent progress in the understanding of complement activation and its role in tumor growth and anti-tumor therapy.

Alantolactone (ALA), a sesquiterpene lactone isolated from several medicinal plants such as Inula helenium, has been identified to have attractive anticancer activity. However, its role in the inhibition of angiogenesis during tumor development remains unclear. In this study, we found ALA can inhibit the proliferation, motility, migration, and tube formation of human umbilical vein endothelial cells. ALA also restrained angiogenesis in chick embryo chorioallantoic membrane and delayed the growth of human MDA-MB-231 breast cancer xenograft in mice through angiogenesis inhibition. Furthermore, ALA suppressed the phosphorylation of vascular endothelial growth factor receptor 2 and its downstream protein kinase including PLCγ1, FAK, Src, and Akt in endothelial cells. Taken together, the antiangiogenic activity of ALA and its molecular mechanism are identified for the first time, indicating that ALA may be a potential drug candidate or lead compound for antiangiogenic cancer therapy.

Peng Sun

Department of General Surgery,
Tongren Hospital,
Department of General Surgery, Tongren Hospital

Shanghai Jiao Tong University School of Medicine

Capturing the Interaction Kinetics of an Ion Channel Protein with Small Molecules by the Bio-layer Interferometry Assay

Peng Sun

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of General Surgery,Tongren Hospital,Department of General Surgery, Tongren Hospital

Shanghai Jiao Tong University School of Medicine

Capturing the Interaction Kinetics of an Ion Channel Protein with Small Molecules by the Bio-layer Interferometry Assay

Department of General Surgery,
Tongren Hospital,
Department of General Surgery, Tongren Hospital