Recent Progress in Biosensors for Detection of Tumor Biomarkers.

Cancer is a leading cause of death worldwide, with an increasing mortality rate over the past years. The early detection of cancer contributes to early diagnosis and subsequent treatment. How to detect early cancer has become one of the hot research directions of cancer. Tumor biomarkers, biochemical parameters for reflecting cancer occurrence and progression have caused much attention in cancer early detection. Due to high sensitivity, convenience and low cost, biosensors have been largely developed to detect tumor biomarkers. This review describes the application of various biosensors in detecting tumor markers. Firstly, several typical tumor makers, such as neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), prostate-specific antigen (PSA), squamous cell carcinoma antigen (SCCA), carbohydrate, antigen19-9 (CA19-9) and tumor suppressor p53 (TP53), which may be helpful for early cancer detection in the clinic, are briefly described. Then, various biosensors, mainly focusing on electrochemical biosensors, optical biosensors, photoelectrochemical biosensors, piezoelectric biosensors and aptamer sensors, are discussed. Specifically, the operation principles of biosensors, nanomaterials used in biosensors and the application of biosensors in tumor marker detection have been comprehensively reviewed and provided. Lastly, the challenges and prospects for developing effective biosensors for early cancer diagnosis are discussed.

Discovery and optimization of a potent and selective indazolamine series of IRAK4 inhibitors.

IRAK4 is a key mediator of innate immunity. There is a high interest in identifying novel IRAK4 inhibitors for the treatment of inflammatory autoimmune diseases. We describe here a highly potent and selective IRAK4 inhibitor (HS271) that exhibited superior enzymatic and cellular activities, as well as excellent pharmacokinetic properties. HS271 displayed robust in vivo anti-inflammatory efficacy as evaluated in rat models of LPS induced TNFα production and collagen-induced arthritis.

Human papillomavirus type 16 E7 oncoprotein-induced upregulation of lysine-specific demethylase 5A promotes cervical cancer progression by regulating the microRNA-424-5p/suppressor of zeste 12 pathway.

Human papillomavirus (HPV) infection and viral protein expression cause several epigenetic alterations that lead to cervical carcinogenesis. Our previous study identified that upregulated lysine-specific demethylase (KDM) 2 A promotes cervical cancer progression by inhibiting mircoRNA (miR)-132 function. However, the roles of histone methylation modifiers in HPV-related cervical cancer remain unclear. In the present study, changes in the expression of 48 histone methylation modifiers were assessed following knockdown of HPV16 E6/E7 in CaSki cells. The dysregulated expression of KDM5A was identified, and its function in cervical cancer was investigated in vitro and in vivo. E7 oncoprotein-induced upregulation of KDM5A promoted cervical cancer cell proliferation and invasiveness in vitro and in vivo, which was correlated with poor prognosis in patients with cervical cancer. KDM5A was found to physically interact with the promoter region of miR-424-5p, and to suppress its expression by removing the tri- and di-methyl groups from H3K4 at the miR-424-5p locus. Furthermore, miR-424-5p repressed cancer cell proliferation and invasiveness by targeting suppressor of zeste 12 (Suz12). KDM5A upregulation promoted cervical cancer progression by repressing miR-424-5p, which resulted in a decrease in Suz12. Therefore, KDM5A functions as a tumor activator in cervical cancer pathogenesis by binding to the miR-424-5p promoter and inhibiting its tumor-suppressive function. These results indicate a function for KDM5A in cervical cancer progression and suggest its candidacy as a novel prognostic biomarker and target for the clinical management of this malignancy.

Effect of monoacylglycerol lipase on the tumor growth in endometrial cancer.

AIM: Abnormal lipid metabolism plays a dual role in tumorigenesis, specifically in the occurrence and development of cancers. Monoacylglycerol lipase (MAGL), a hydrolase that is important for lipid metabolism, plays a vital role in different aspects of tumorigenesis. Many studies have shown that MAGL is highly elevated in a variety of cancers and plays an active role. However, its potential role in supporting endometrial cancer (EC) growth and progression has not yet been explored in depth. METHODS: Immunohistochemistry and quantitative real-time reverse transcription polymerase chain reaction were performed to estimate the protein and messenger RNA (mRNA) levels of MAGL in tumor tissues. Then, JZL184 and small interfering RNA (siRNA) were used to decrease the expression of MAGL in EC cells. The gene and protein expression levels of MAGL were measured using quantitative real-time PCR and western blotting, respectively. Additionally, the effect of MAGL on tumor growth in EC was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide , cell cycle and western blotting assay in vitro. RESULTS: We found that MAGL was overexpressed in EC and was significantly correlated with surgical-pathological stage, myometrial invasion, number of pregnancies and body mass index. The growth and cell cycle progression of tumor cells were significantly impaired in vitro by the pharmacological and siRNA-mediated MAGL inhibition. In addition, MAGL inhibition seemed to repress two target genes, Cyclin D1 and Bcl-2. CONCLUSION: In summary, we have demonstrated that MAGL is involved in EC growth and progression. Our results suggest that targeting MAGL may be a novel and valid treatment for EC.

Fatigue-free, superstretchable, transparent, and biocompatible metal electrodes.

Next-generation flexible electronics require highly stretchable and transparent electrodes. Few electronic conductors are both transparent and stretchable, and even fewer can be cyclically stretched to a large strain without causing fatigue. Fatigue, which is often an issue of strained materials causing failure at low strain levels of cyclic loading, is detrimental to materials under repeated loads in practical applications. Here we show that optimizing topology and/or tuning adhesion of metal nanomeshes can significantly improve stretchability and eliminate strain fatigue. The ligaments in an Au nanomesh on a slippery substrate can locally shift to relax stress upon stretching and return to the original configuration when stress is removed. The Au nanomesh keeps a low sheet resistance and high transparency, comparable to those of strain-free indium tin oxide films, when the nanomesh is stretched to a strain of 300%, or shows no fatigue after 50,000 stretches to a strain up to 150%. Moreover, the Au nanomesh is biocompatible and penetrable to biomacromolecules in fluid. The superstretchable transparent conductors are highly desirable for stretchable photoelectronics, electronic skins, and implantable electronics.

Regulation of cell-matrix adhesion by OLA1, the Obg-like ATPase 1.

Attachment of cells to the extracellular matrix induces clustering of membrane receptor integrins which in turn triggers the formation of focal adhesions (FAs). The adaptor/scaffold proteins in FAs provide linkage to actin cytoskeleton, whereas focal adhesion kinase (FAK) and other FA-associated kinases and phosphatases transduce integrin-mediated signaling cascades, promoting actin polymerization and progression of cell spreading. In this study, we explored the role of OLA1, a newly identified member of Obg-like ATPases, in regulating cell adhesion processes. We showed that in multiple human cell lines RNAi-mediated downregulation of OLA1 significantly accelerated cell adhesion and spreading, and conversely overexpression of OLA1 by gene transfection resulted in delayed cell adhesion and spreading. We further found that OLA1-deficient cells had elevated levels of FAK protein and decreased Ser3 phosphorylation of cofilin, an actin-binding protein and key regulator of actin filament dynamics, while OLA1-overexpressing cells exhibited the opposite molecular alterations in FAK and cofilin. These findings suggest that OLA1 plays an important negative role in cell adhesion and spreading, in part through the regulation of FAK expression and cofilin phosphorylation, and manipulation of OLA1 may lead to significant changes in cell adhesion and the associated phenotypes.

Synthesis and evaluation of an imidazole derivative-fluorescein conjugate.

The murine double minute (MDM2) oncogene a negative regulator of protein 53 (p53) tumor suppressor, is found overexpressed in many different types of cancer and the interaction between MDM2 and p53 has become the target of intensive research. MDM2 inhibitors represent a promising class of p53 activating compounds that may be effective in cancer treatment and diagnostic imaging. Nutlins, a family of cis-imidazoline analogues and small-molecule MDM2 antagonists, have the potential use in cancer therapies. We have synthesized an imidazole derivative (Nutlin-Glycine) conjugated to the commonly used fluorophore, 6-carboxyfluorescein (FAM) and evaluated its possible use as an imaging agent. Cellular uptake studies demonstrated that the fluorescence intensity in human osteosarcoma (SJSA-1) and colon carcinoma (HCT116) cells were significantly increased with the treatment of Nutlin-Glycine-FAM when compared with FAM (control). Blocking studies also confirmed that our imidazole-fluorescein conjugate may be a good candidate for imaging tumors, suggesting the need for further in vivo evaluation by positron emission tomography.

Does the economic growth target overweight induce more polluting activities? Evidence from China.

In China, official promotion evaluation based on economic performance motivates local governments to develop high economic growth targets, which has played an active role in boosting China's economic growth in the past decades, whereas its environmental consequences have not been fully exploited. This paper finds that the economic growth target overweight has a stronger positive impact on the output of high-polluting industries than on the output of low-polluting industries, thus inducing more polluting activities. To deal with the issues of reverse causality and omitted variables bias, we take an instrumental variable approach. Examining mechanisms, we show that economic growth target overweight promotes polluting activities through the deregulation of the polluting activities in high-polluting industries. We also find an increase in the impact of the economic growth target overweight after the 2008 global economic crisis. Our study provides new evidence for explaining the dual presence of rapid economic growth and heavy environmental pollution in China.

LncRNA HOXB-AS3 binding to PTBP1 protein regulates lipid metabolism by targeting SREBP1 in endometrioid carcinoma.

Endometrial cancer (EC) is a malignant tumor with a high incidence in women, and the survival rate of high-risk patients decreases significantly after disease progression. The regulatory role of long non-coding RNAs (LncRNAs) in tumors has been widely appreciated, but there have been few studies in EC. To investigate the effect of HOXB-AS3 in EC, we used bioinformatics tools for prediction and collected clinical samples to detect the expression of HOXB-AS3. Colony formation assay, MTT assay, flow cytometry and apoptosis assay, and transwell assay were used to verify the role of HOXB-AS3 in EC. HOXB-AS3 was upregulated in EC, promoted the proliferation and invasive ability of EC cells, and inhibited apoptosis. In addition, the ROC curve illustrated its diagnostic value. We explored experiments via lentiviral transduction, FISH, Oil Red O staining, TC and FFA content detection, RNA-pulldown, RIP, and other mechanisms to reveal that HOXB-AS3 can bind to PTBP1 and co-regulate the expression of SREBP1, thereby regulating lipid metabolism in EC cells. To the best of our knowledge, this is the first study on HOXB-AS3 in disorders of lipid metabolism in EC. In addition, we believe HOXB-AS3 has the potential to be a neoplastic marker or a therapeutic target.

OLA1, an Obg-like ATPase, suppresses antioxidant response via nontranscriptional mechanisms.

Oxidative stress has been implicated in diverse disease states and aging. To date, induction of cellular responses to combat oxidative stress has been characterized largely at the transcriptional level, with emphasis on Nrf2-mediated activation of antioxidant response elements. In this study, we demonstrate that OLA1, a novel Obg-like ATPase, functions as a negative regulator of the cellular antioxidant response independent of transcriptional processes. Knockdown of OLA1 in human cells elicited an increased resistance to oxidizing agents including tert-butyl hydroperoxide (tBH) and diamide without affecting cell proliferation, baseline apoptosis, or sensitivity to other cytotoxic agents that target the mitochondria, cytoskeleton, or DNA. Conversely, overexpression of OLA1 increased cellular sensitivity to tBH and diamide. When challenged with oxidants, OLA1-knockdown cells had decreased production of intracellular reactive oxygen species and exhibited less depletion of reduced glutathione. Surprisingly, knockdown of OLA1 caused only minimal genomic response; no changes were found in the mRNA levels of genes encoding antioxidant enzymes, enzymes that produce antioxidants (including glutathione), or other genes known to respond to Nrf2. Moreover, when de novo protein synthesis was blocked by cycloheximide in OLA1-knockdown cells, they continued to demonstrate increased resistance to both tBH and diamide. These data demonstrate that OLA1 suppresses the antioxidant response through nontranscriptional mechanisms. The beneficial effects observed upon OLA1-knockdown suggest that this regulatory ATPase is a potential novel target for antioxidative therapy.

A Japanese Herbal Formula, Daikenchuto, Alleviates Experimental Colitis by Reshaping Microbial Profiles and Enhancing Group 3 Innate Lymphoid Cells.

Daikenchuto (DKT) is one of the most widely used Japanese herbal formulae for various gastrointestinal disorders. It consists of Zanthoxylum Fructus (Japanese pepper), Zingiberis Siccatum Rhizoma (processed ginger), Ginseng radix, and maltose powder. However, the use of DKT in clinical settings is still controversial due to the limited molecular evidence and largely unknown therapeutic effects. Here, we investigated the anti-inflammatory actions of DKT in the dextran sodium sulfate (DSS)-induced colitis model in mice. We observed that DKT remarkably attenuated the severity of experimental colitis while maintaining the members of the symbiotic microbiota such as family Lactobacillaceae and increasing levels of propionate, an immunomodulatory microbial metabolite, in the colon. DKT also protected colonic epithelial integrity by upregulating the fucosyltransferase gene Fut2 and the antimicrobial peptide gene Reg3g. More remarkably, DKT restored the reduced colonic group 3 innate lymphoid cells (ILC3s), mainly RORγthigh-ILC3s, in DSS-induced colitis. We further demonstrated that ILC3-deficient mice showed increased mortality during experimental colitis, suggesting that ILC3s play a protective function on colonic inflammation. These findings demonstrate that DKT possesses anti-inflammatory activity, partly via ILC3 function, to maintain the colonic microenvironment. Our study also provides insights into the molecular basis of herbal medicine effects, promotes more profound mechanistic studies towards herbal formulae and contributes to future drug development.

Glutathione is essential for early embryogenesis--analysis of a glutathione synthetase knockout mouse.

Glutathione (GSH) is present in all mammalian tissues and plays a crucial role in many cellular processes. The second and final step in the synthesis involves the formation of GSH from gamma-glutamylcysteine (γ-GC) and glycine and is catalyzed by glutathione synthetase (GS). GS deficiency is a rare autosomal recessive disorder, and is present in patients with a range of phenotypes, from mild hemolytic anemia and metabolic acidosis to severe neurologic disorders or even death in infancy. The substrate for GS, γ-GC, has been suggested as playing a protective role, by substituting for GSH as an antioxidant in GS deficient patients. To examine the role of GS and GSH metabolites in development, we generated mice deficient in GSH by targeted disruption of the GS gene (Gss). Homozygous mice died before embryonic day (E) 7.5, but heterozygous mice survived with no distinct phenotype. GS protein levels and enzyme activity, as well as GSH metabolites, were investigated in multiple tissues. Protein levels and enzyme activity of GS in heterozygous mice were diminished by 50%, while GSH levels remained intact. γ-GC could not be detected in any investigated tissue. These data demonstrate that GSH is essential for mammalian development, and GSH synthesis via GS is an indispensable pathway for survival.

Dietary Derived Micronutrients Modulate Immune Responses Through Innate Lymphoid Cells.

Innate lymphoid cells (ILCs) are a group of innate immune cells that possess overlapping features with T cells, although they lack antigen-specific receptors. ILCs consist of five subsets-ILC1, ILC2, ILC3, lymphoid tissue inducer (LTi-like) cells, and natural killer (NK) cells. They have significant functions in mediating various immune responses, protecting mucosal barrier integrity and maintaining tissue homeostasis in the lung, skin, intestines, and liver. ILCs react immediately to signals from internal and external sources. Emerging evidence has revealed that dietary micronutrients, such as various vitamins and minerals can significantly modulate immune responses through ILCs and subsequently affect human health. It has been demonstrated that micronutrients control the development and proliferation of different types of ILCs. They are also potent immunoregulators in several autoimmune diseases and play vital roles in resolving local inflammation. Here, we summarize the interplay between several essential micronutrients and ILCs to maintain epithelial barrier functions in various mucosal tissues and discuss their limitations and potentials for promoting human health.

CNOT7 modulates biological functions of ovarian cancer cells via AKT signaling pathway.

AIMS: CNOT7 plays an important role in many biological processes, providing attractive opportunities for the treatment of malignant tumors. However, the functions and mechanism of CNOT7 in ovarian cancer (OC) have not been elucidated. The purpose of this study was to assess the role of CNOT7 in OC. MATERIALS AND METHODS: SKOV3 and A2780 cells were chosen as the cell lines for the experiments of this manuscript via the analysis of the expression of CNOT7 protein and the mRNA level in ovarian surface epithelium (OSE) cells, SKOV3, HO8910 and A2780 cells. The expression of CNOT7 was detected by western blot assays and RT-PCR in A2780 and SKOV3 cells. The MTT assays, colony formation assays and EdU assays were used to measure cell proliferation when CNOT7 was knocked down or overexpressed in A2780 and SKOV3 cells. Furthermore, cell migration and invasion ability were achieved from transwell assays. Cell cycle and apoptosis rate after small interference RNA-CNOT7 (siRNA-CNOT7) were detected by flow cytometry assays. Finally, the cell proliferation, migration and invasion ability were detected when A2780 and SKOV3 cells with CNOT7 overexpression were treated with LY294002. KEY FINDINGS: The expression of CNOT7 protein in OC cells, including SKOV3, HO8910 and A2780 cells were significantly higher than that in OSE cells (P < 0.05). The mRNA level of CNOT7 in HO8910 and A2780 cells were significantly higher than that in OSE cells (P < 0.01). However, the mRNA level of CNOT7 in SKOV3 cells was no significant difference compared with OSE cells (P > 0.05). The results suggested that knockdown of CNOT7 could inhibit the cell proliferation, migration and invasion ability in A2780 and SKOV3 cells, and increase cell apoptosis and autophagy. The expression of apoptosis-related molecules (PARP, Caspase3 and Caspase9) and autophagy-related protein (LC3B) were up-regulated after CNOT7 knockdown, while the expression of cycle-related protein (CDK6) and the anti-apoptotic gene (Bcl2) were downregulated. Meanwhile, the opposite results were observed when CNOT7 was overexpressed in A2780 and SKOV3 cells. It is worth noting that the effect of CNOT7 overexpression in A2780 and SKOV3 cells could be partially or completely eliminated by treatment with AKT inhibitor LY294002. SIGNIFICANCE: CNOT7 has a carcinogenic effect in OC, and the carcinogenic effect may be achieved via the AKT signaling pathway.

Clinicalpathologic and Prognostic Significance of CGI-58 in Endometrial Cancer.

Recent studies have reported that CGI-58 played an important role in carcinogenesis and tumoral progression in several cancers. In this study, we investigated the expression and prognostic value of CGI-58 in patients with endometrail cancer. Initially, the expression of CGI-58 was analyzed in 552 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Then, the mRNA level of CGI-58 from 32 normal endometrium and 40 endometrial cancer tissues was determined using real-time PCR. In addition, immunohistochemical staining of CGI-58 was performed in 140 endometrial specimens including 35 normal endometrial tissues, 25 atypical endometrial hyperplasia and 80 endometrial cancers. The expression of CGI-58 was significantly up-regulated in endometrial cancer tissues compared with normal endometrial tissue both in TCGA database and clinical cohorts. Over-expression of CGI-58 was significantly correlated with poor histological differentiation. Furthermore, high levels of CGI-58 expression were significantly associated with shorter overall survival for all analyzed cases. Our findings demonstrate that CGI-58 is up-regulated in endometrial cancer and high CGI-58 expression is a poor prognostic marker for endometrial cancer. CGI-58 may be a potential contributor to endometrial cancer oncogenesis and progression.

Synthesis and evaluation of a near-infrared fluorescent non-peptidic bivalent integrin alpha(v)beta(3) antagonist for cancer imaging.

Computer modeling approaches to identify new inhibitors are essentially a very sophisticated and efficient way to design drugs. In this study, a bivalent nonpeptide intergrin alpha(v)beta(3) antagonist (bivalent IA) has been synthesized on the basis of an in silico rational design approach. A near-infrared (NIR) fluorescent imaging probe has been developed from this bivalent compound. In vitro binding assays have shown that the bivalent IA (IC(50) = 0.40 +/- 0.11 nM) exhibited improved integrin alpha(v)beta(3) affinity in comparison with the monovalent IA (IC(50) = 22.33 +/- 4.51 nM), resulting in an over 50-fold improvement in receptor affinity. NIR imaging probe, bivalent-IA-Cy5.5 conjugate, also demonstrated significantly increased binding affinity (IC(50) = 0.13 +/- 0.02 nM). Fluorescence microscopy studies showed integrin-mediated endocytosis of bivalent-IA-Cy5.5 in U87 cells which was effectively blocked by nonfluorescent bivalent IA. We also demonstrated tumor accumulation of this NIR imaging probe in U87 mouse xenografts.

[Expression of survivin, bcl-2 in cervical carcinoma and its association with HPV16/18 infection].

OBJECTIVE: To investigate the expression and the correlation of surviving, bcl-2 and HPV16/18 in cervical carcinoma. METHODS: Hybridization in situ was used to detect the expression of survivin mRNA and HPV16/18 DNA in 74 cases of CIN and 81 cases of cervical carcinoma and 20 cases of normal cervical tissues. And immunohistochemical analysis was used to detect the expression of bcl-2 protein. RESULTS: The positive rates of survivin mRNA, bcl-2 and HPV16/18 in CIN were 44.6%, 39.2% and 41.0% respectively versus 77.8%, 70.4% and 81.2% in cervical carcinoma. The above three indices gradually rose in normal cervical tissue, CIN and cervical carcinoma. The expression of survivin and bcl-2 in CINIII were obviously higher than those in CINI/II. And it was obviously higher in cervical carcinoma with stage IIb-III than those in stage I-IIa. And it was also obviously higher in cervical carcinoma with a poor differentiation than those with a good or medium differentiation. The expression of survivin in cervical carcinoma with lymphatic metastasis was significantly higher than that without lymphatic metastasis. There were no relationship between the expression of survivin or bcl-2 and the pathological type or tumor type of cervical carcinoma. The infection of HPV16/18 also had nothing to do with the clinical stage or pathological type or tumor type of cervical carcinoma. Inverse correlation was both observed in the expression of survivin and bcl-2 with survival rate. Thus a positive correlation between surviving, bcl-2 and HPV 16/18 was observed in cervical carcinoma. CONCLUSION: Survivin, bcl-2 and HPV16/18 participate in the development of cervical carcinoma. It may be a useful guide in early diagnosis of cervical carcinoma, evaluation of surgery and chemotherapy and prediction of outcome.

Identification and prognostic value of DLGAP5 in endometrial cancer.

BACKGROUND: Endometrial cancer poses a serious threat to women's health worldwide, and its pathogenesis, although actively explored, is not fully understood. DLGAP5 is a recently identified cell cycle-regulation gene not reported in endometrial cancer. This study was aiming to analyze the role of DLGAP5 in tumorigenesis and development and to investigate its prognostic significance of patients with endometrial cancer. METHODOLOGY: Microarray datasets (GSE17025, GSE39099 and GSE63678) from the GEO database were used for comparative analysis, and their intersection was obtained by applying the Venn diagram, and DLGAP5 was selected as the target gene. Next, transcriptome data (n = 578) was downloaded from TCGA-UCEC to analyze the mRNA expression profile of DLGAP5. Then, immunohistochemical data provided by HPA were used to identify the different protein expression levels of DLGAP5 in tumor tissues and normal tissues. Subsequently, the prognostic meaning of DLGAP5 in patients with endometrial cancer was explored based on survival data from TCGA-UCEC (n = 541). Finally, the reliability of DLGAP5 expression was verified by RT-qPCR. RESULTS: Transcriptome data from TCGA-UCEC, immunohistochemical data from HPA, and RT-qPCR results from clinical samples were used for triple validation to confirm that the expression of DLGAP5 in endometrial cancer tissues was significantly higher than that in normal endometrial tissues. Kaplan-Meier survival analysis announced that the expression level of DLGAP5 was negatively correlated with the overall survival of patients with endometrial cancer. CONCLUSIONS: DLGAP5 is a potential oncogene with cell cycle regulation, and its overexpression can predict the poor prognosis of patients with endometrial cancer. As a candidate target for the diagnosis and treatment of endometrial cancer, it is worthwhile to make further study to reveal the carcinogenicity of DLGAP5 and the mechanism of its resistance of organisms.

An Adjustable pH-Responsive Drug Delivery System Based on Self-Assembly Polypeptide-Modified Mesoporous Silica.

In this study, an adjustable pH-responsive drug delivery system using mesoporous silica nanoparticles (MSNs) as the host materials and the modified polypeptides as the nanovalves is reported. Since the polypeptide can self-assemble via electrostatic interaction at pH 7.4 and be disassembled by pH changes, the modified poly(l-lysine) and poly(l-glutamate) are utilized for pore blocking and opening in the study. Poly(l-lysine)-MSN (PLL-MSN) and poly(l-glutamate)-MSN (PLG-MSN) are synthesized via the ring opening polymerization of N-carboxyanhydrides onto the surface of mesoporous silica nanoparticles. The successful modification of the polypeptide on MSN is proved by Zeta potential change, X-ray photoelectron spectroscopy (XPS), solid state NMR, and MALDI-TOF MS. In vitro simulated dye release studies show that PLL-MSN and PLG-MSN can successfully load the dye molecules. The release study shows that the controlled release can be constructed at different pH by adjusting the ratio of PLL-MSN to PLG-MSN. Cellular uptake study indicates that the drug is detected in both cytoplasm and nucleus, especially in the nucleus. In vitro cytotoxicity assay indicates that DOX loaded mixture nanoparticles (ratio of PLL-MSN to PLG-MSN is 1:1) can be triggered for drug release in HeLa cells, resulting in 88% of cell killing.

Oncogenic role of ABHD5 in endometrial cancer.

BACKGROUND: Abhydrolase domain containing 5 (ABHD5) functions as a tumor suppressor in colorectal and prostate cancers. The aim of this study was to investigate the roles of ABHD5 in endometrial cancer. MATERIALS AND METHODS: ABHD5 expression was detected in clinical samples by immunohistochemical staining. Cell proliferation and invasion were evaluated with the Cell Counting Kit-8 and Transwell assay, respectively. Western blotting was performed to analyze protein expression. Glucose uptake was assessed by 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose. Lactate production was detected by a lactate assay kit. RESULTS: In the present study, ABHD5 was overexpressed in endometrial cancer tissues, and its expression was closely correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. In addition, we observed that the knockdown of ABHD5 inhibited cell proliferation, invasion, glucose uptake and lactate production in HEC-1A cells, which expressed high levels of ABHD5. Conversely, the opposite effects were observed when ABHD5 was ectopically expressed in Ishikawa cells, which had low levels of ABHD5. Furthermore, the changes in glycolysis regulators (enolase 1 [ENO1], glucose transporter 1 [GLUT1] and lactate dehydrogenase A [LDHA]) and epithelial-to-mesenchymal transition-related proteins (E-cadherin and Snail) in HEC-1A cells with ABHD5 knockdown were consistent with the effects of ABHD5 on glycolysis and cell invasion. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was increased, while the phosphorylated AKT (p-AKT) was decreased when ABHD5 was downregulated. Notably, treatment with the allosteric AKT inhibitor MK-2206 completely abolished the effects caused by ABHD5 overexpression in Ishikawa cells. Finally, ABHD5 knockdown potently suppressed tumor growth in vivo. CONCLUSION: Overall, these results suggest that ABHD5 may play an oncogenic role in endometrial cancer via the AKT pathway.