Recent advances in tissue engineering have adapted the additive manufacturing technology, also known as three-dimensional printing, which is used in several industrial applications, for the ...fabrication of bioscaffolds and viable tissue and/or organs to overcome the limitations of other in vitro conventional methods. 3D bioprinting technology has gained enormous attention as it enabled 3D printing of a multitude of biocompatible materials, different types of cells and other supporting growth factors into complex functional living tissues in a 3D format. A major advantage of this technology is its ability for simultaneously 3D printing various cell types in defined spatial locations, which makes this technology applicable to regenerative medicine to meet the need for suitable for transplantation suitable organs and tissues. 3D bioprinting is yet to successfully overcome the many challenges related to building 3D structures that closely resemble native organs and tissues, which are complex structures with defined microarchitecture and a variety of cell types in a confined area. An integrated approach with a combination of technologies from the fields of engineering, biomaterials science, cell biology, physics, and medicine is required to address these complexities. Meeting this challenge is being made possible by directing the 3D bioprinting to manufacture biomimetic-shaped 3D structures, using organ/tissue images, obtained from magnetic resonance imaging and computerized tomography, and employing computer-aided design and manufacturing technologies. Applications of 3D bioprinting include the generation of multilayered skin, bone, vascular grafts, heart valves, etc. The current 3D bioprinting technologies need to be improved with respect to the mechanical strength and integrity in the manufactured constructs as the presently used biomaterials are not of optimal viscosity. A better understanding of the tissue/organ microenvironment, which consists of multiple types of cells, is imperative for successful 3D bioprinting.
Co-encapsulated doxorubicin (DOX) and curcumin (CUR) in poly(butyl cyanoacrylate) nanoparticles (PBCA-NPs) were prepared with emulsion polymerization and interfacial polymerization. The mean particle ...size and mean zeta potential of CUR–DOX–PBCA-NPs were 133±5.34nm in diameter and +32.23±4.56mV, respectively. The entrapment efficiencies of doxorubicin and curcumin were 49.98±3.32% and 94.52±3.14%, respectively. Anticancer activities and reversal efficacy of the formulations and various combination approaches were assessed using 3-4,5-dimethylthiazol-2-yl 2,5-diphenyltetrazolium bromide assay and western blotting. The results showed that the dual-agent loaded PBCA-NPs system had the similar cytotoxicity to co-administration of two single-agent loaded PBCA-NPs (DOX–PBCA-NPs+CUR–PBCA-NPs), which was slightly higher than that of the free drug combination (DOX+CUR) and one free drug/another agent loaded PBCA-NPs combination (DOX+CUR–PBCA-NPs or CUR+DOX–PBCA-NPs). The simultaneous administration of doxorubicin and curcumin achieved the highest reversal efficacy and down-regulation of P-glycoprotein in MCF-7/ADR cell lines, an MCF-7 breast carcer cell line resistant to adriamycin. Multidrug resistance can be enhanced by combination delivery of encapsulated cytotoxic drugs and reversal agents.
MicroRNAs (miRNAs) are small noncoding RNAs about 22 nt long that negatively regulate gene expression at the post-transcriptional level. Their key effects on various biological processes, e.g., ...embryonic development, cell division, differentiation and apoptosis, are widely recognized. Evidence suggests that aberrant expression of miRNAs may contribute to many types of human diseases, including cancer. Here we present a database of differentially expressed miRNAs in human cancers (dbDEMC), to explore aberrantly expressed miRNAs among different cancers.
We collected the miRNA expression profiles of 14 cancer types, curated from 48 microarray data sets in peer-reviewed publications. The Significance Analysis of Microarrays method was used to retrieve the miRNAs that have dramatically different expression levels in cancers when compared to normal tissues. This database provides statistical results for differentially expressed miRNAs in each data set. A total of 607 differentially expressed miRNAs (590 mature miRNAs and 17 precursor miRNAs) were obtained in the current version of dbDEMC. Furthermore, low-throughput data from the same literature were also included in the database for validation. An easy-to-use web interface was designed for users. Annotations about each miRNA can be queried through miRNA ID or miRBase accession numbers, or can be browsed by different cancer types.
This database is expected to be a valuable source for identification of cancer-related miRNAs, thereby helping with the improvement of classification, diagnosis and treatment of human cancers. All the information is freely available through http://159.226.118.44/dbDEMC/index.html.
Aims: Metformin is a biguanide that has been widely used to treat type 2 diabetes. Several studies have shown that metformin is also effective in treating cancer, including hepatocellular carcinoma ...(HCC). The objective of this study was to evaluate the antitumor effects of metformin in HCC, and to investigate the potential molecular target(s) of metformin‐mediated antitumor activity.
Methods: The antiproliferative effects of metformin were assessed in human HCC cell lines and normal human liver cells at various concentrations. Orthotopic xenograft tumors were established in athymic nude mice, and tumor growth was monitored after metformin treatment. Western blot analysis and cell cycle regulation were performed to determine the involvement of various mediators of apoptosis.
Results: Metformin specifically inhibited the growth of HCC cells without affecting the growth of normal liver cells both in vitro and in vivo. Metformin caused cell cycle arrest in HCC cells, which resulted in caspase‐3 activation. Livin levels decreased in a dose‐dependent manner upon metformin treatment. Metformin activated 5′‐adenosine monophosphate‐activated protein kinase, inhibited the mammalian target of rapamycin pathway and downregulated Livin protein expression.
Conclusion: Our findings indicate that metformin is effective at initiating apoptosis and inhibiting key survival signaling pathways in HCC cells. These data provide a foundation for further studies to evaluate metformin in the clinic either as a single agent or in combination with other first‐line agents as a treatment option for HCC.
A novel cationic curcumin-chitosan PBCA nanoparticle synthesized by emulsion polymerization simply, can not only improve the bioavailability of hydrophobic drug curcumin, but also suppress ...hepatocellular carcinoma growth and inhibit tumor angiogenesis efficiently
in vitro and
in vivo.
We have synthesized novel cationic poly(butyl) cyanoacrylate (PBCA) nanoparticles coated with chitosan, formulation of curcumin nanoparticles. The size and zeta potential of prepared curcumin nanoparticles were about 200
nm and +29.11
mV, respectively with 90.04% encapsulation efficiency. The transmission electron microscopy (TEM) study revealed the spherical nature of the prepared nanoparticles along with confirmation of particle size. Curcumin nanoparticles demonstrate comparable
in vitro therapeutic efficacy to free curcumin against a panel of human hepatocellular cancer cell lines, as assessed by cell viability (3-4,5-dimethylthiazol-2-yl2,5-diphenyltetrazolium bromide assay MTT assay) and proapoptotic effects (annexin V/propidium iodide staining).
In vivo, curcumin nanoparticles suppressed hepatocellular carcinoma growth in murine xenograft models and inhibited tumor angiogenesis. The curcumin nanoparticles’ mechanism of action on hepatocellular cancinoma cells is a mirror that of free curcumin.
Endostar, a novel recombinant human endostatin, which was approved by the Chinese State Food and Drug Administration in 2005, has a broad spectrum of activity against solid tumors. In this study, we ...aimed to determine whether the anticancer effect of Endostar is increased by using a nanocarrier system. It is expected that the prolonged circulation of endostar will improve its anticancer activity. Endostar-loaded nanoparticles were prepared to improve controlled release of the drug in mice and rabbits, as well as its anticancer effects in mice with colon cancer. A protein release system could be exploited to act as a drug carrier. Nanoparticles were formulated from poly (ethylene glycol) modified poly (DL-lactide-co-glycolide) (PEG-PLGA) by a double emulsion technique. Physical and release characteristics of endostar-loaded nanoparticles in vitro were evaluated by transmission electron microscopy (TEM), photon correlation spectroscopy (PCS), and micro bicinchoninic acid protein assay. The pharmacokinetic parameters of endostar nanoparticles in rabbit and mice plasma were measured by enzyme-linked immunosorbent assay. Western blot was used to detect endostatin in different tissues. To study the effects of endostar-loaded nanoparticles in vivo, nude mice in which tumor cells HT-29 were implanted, were subsequently treated with endostar or endostar-loaded PEG-PLGA nanoparticles. Using TEM and PCS, endostar-loaded PEG-PLGA nanoparticles were found to have a spherical core-shell structure with a diameter of 169.56 ± 35.03 nm. Drug-loading capacity was 8.22% ± 2.35% and drug encapsulation was 80.17% ± 7.83%. Compared with endostar, endostar-loaded PEG-PLGA nanoparticles had a longer elimination half-life and lower peak concentration, caused slower growth of tumor cell xenografts, and prolonged tumor doubling times. The nanoparticles changed the pharmacokinetic characteristics of endostar in mice and rabbits, thereby reinforcing anticancer activity. In conclusion, PEG-PLGA nanoparticles are a feasible carrier for endostar. Endostar-loaded PEG-PLGA nanoparticles seem to have a better anticancer effect than conventional endostar. We believe that PEG-PLGA nanoparticles are an effective carrier for protein medicines.
Irritable bowel syndrome (IBS) is a common functional bowel disorder. The post-infectious IBS (PI-IBS) occurs in IBS patients with a history of intestinal infection preceding the onset of symptoms. ...However, the underlying cause of PI-IBS is not fully understood, and the purpose of this study was to investigate the immune regulatory mechanism of PI-IBS.
Participants enrolled in this study were divided into three groups including PI-IBS patients (n = 20), IBS patients without a history of infection (non-PI-IBS, n = 18), and healthy controls (n = 20). The expression levels of the Th1-derived cytokines IFN-γ and IL-12, and the Th2-derived cytokines IL-4 and IL-10 in the mucosal specimens, and in the ascending colon, the descending colon, and the rectal segments were measured by RT-PCR and western blot.
The IFN-γ mRNA levels in the intestinal mucosa were significantly higher in the PI-IBS group than in the non-PI-IBS or control group (both P < 0.05), but there was no difference between the non-PI-IBS and control groups. A trend toward IFN-γ protein upregulation was found in the PI-IBS group, while the IL-12 and IL-4 mRNA and protein levels were not different between any groups. The IL-10 mRNA and protein levels in the PI-IBS group were both significantly lower than in the non-PI-IBS or control groups (P < 0.05, respectively), but there was no difference between the non-PI-IBS and control groups. There were no differences in the cytokine mRNA and protein levels among the ascending colon, the descending colon, and the rectum of all groups.
An increase in IFN-γ levels and a decrease in IL-10 levels were found in the intestinal mucosa of PI-IBS patients, suggesting that the infection may affect the Th1/Th2 balance. Thus, the dysregulation of the immune response is likely an important cause of IBS.
Bladder Cancer and Genetic Mutations Zhang, Xiaoying; Zhang, Yangde
Cell biochemistry and biophysics,
09/2015, Letnik:
73, Številka:
1
Journal Article
Recenzirano
The most common type of urinary bladder cancer is called as transitional cell carcinoma. The major risk factors for bladder cancer are environmental, tobacco smoking, exposure to toxic industrial ...chemicals and gases, bladder inflammation due to microbial and parasitic infections, as well as some adverse side-effects of medications. The genetic mutations in some chromosomal genes, such as FGFR3, RB1, HRAS, TP53, TSC1, and others, occur which form tumors in the urinary bladder. These genes play an important role in the regulation of cell division which prevents cells from dividing too quickly. The changes in the genes of human chromosome 9 are usually responsible for tumor in bladder cancer, but the genetic mutation of chromosome 22 can also result in bladder cancer. The identification of p53 gene mutation has been studied at NIH, Washington, DC, USA, in urine samples of bladder cancer patients. The invasive bladder cancers were determined for the presence of gene mutations on p53 suppressor gene. The 18 different bladder tumors were evaluated, and 11 (61 %) had genetic mutations of p53 gene. The bladder cancer studies have suggested that 70 % of bladder cancers involve a specific mutation in a particular gene, namely telomerase reverse transcriptase (TERT) gene. The TERT gene is involved in DNA protection, cellular aging processes, and cancer. The Urothelial carcinomas of the bladder have been described in Atlas of genetics and cytogenetics in oncology and hematology. HRAS is a proto-oncogene and has potential to cause cancer in several organs including the bladder. The TSC1 c. 1907 1908 del (E636fs) mutation in bladder cancer suggests that the location of the mutation is Exon 15 with frequency of TSC1 mutation of 11.7 %. The recent findings of BAP1 mutations have shown that it contributes to BRCA pathway alterations in bladder cancer. The discoveries of more gene mutations and new biomarkers and polymerase chain reaction bioassays for gene mutations in bladder cancer need further research.
Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based ...nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive FR(+) cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5-2.5 nm. The host-guest association constant K a was 1,639 M(-1) as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.
Aim: To investigate the expression of erythropoietin‐producing hepatocellular (Eph)A2 receptor, matrix metalloproteinase (MMP)‐9, and angiogenesis in hepatocellular carcinoma (HCC), in order to ...reveal their expression correlations with tumor invasion, metastasis, and prognosis.
Methods: From January 2000 to June 2003, 129 specimens of resected tumors from the patients with HCC were obtained. Corresponding pericarcinomatous liver tissues were also obtained and selected as a control group. Expressions of EphA2, MMP‐9, and CD34 were detected with immunohistochemical staining. Microvascular density (MVD) was calculated with counting of CD34‐positive vascular endothelial cells.
Results: The expressions of EphA2, MMP‐9, and MVD in the HCC tissues were significantly higher than those in the pericarcinomatous liver tissues (P < 0.01). Statistical analysis showed there were significant correlations between the expressions of EphA2, MMP‐9 and MVD in some classicclinicopathological parameters (i.e. tumor nodule, vein invasion, tumor, node, metastasis stages, extrahepatic metastasis; P < 0.05). The correlation between EphA2 and MMP‐9 expression was positive (r = 0.625, P = 0.011). Tumor MVD was closely associated with EphA2 (r = 0.281, P = 0.01) and MMP‐9 (r = 0.319, P < 0.01) expressions. In particular, EphA2, MMP‐9, and MVD expressions levels were found to be independent prognostic factors after HCC resection.
Conclusions: Overexpressions of EphA2 and MMP‐9 relate to tumor progression, metastasis, and prognosis in HCC. The present study suggests that EphA2 is associated with key mediators of angiogenesis and invasion.
PDF
