The role of angiotensin-(1-7) on acquired platinum resistance-induced angiogenesis in non-small cell lung cancer in vitro and in vivo.

Renin-angiotensin system (RAS) signaling has been implicated in the development of cancer. The new RAS ACE2/Ang-(1-7)/Mas axis antagonizes the classical ACE/Ang II/AT1R axis. Ang-(1-7) has pleiotropic roles in lung cancer including suppressing proliferation, angiogenesis, and metastasis. This research was designed to investigate the effect of Ang-(1-7) on tumor-associated angiogenesis in DDP-resistant lung cancer cell lines. We first established acquired DDP-resistant cell lines A549 (A549-DDP) and LLC (LLC-DDP). We next performed RT-qPCR, western blot, ELISA, tube formation, microvessel density detection, immunohistochemistry, and tumor formation assays. The results showed that the mRNA and protein levels of RAS components and vascular endothelial growth factor A (VEGFa) were lessened in the A549/LLC-DDP+Ang-(1-7) group compared with the A549/LLC-DDP group. This effect could be blocked by the MAS receptor antagonist A779. The data revealed that Ang-(1-7) could perform its antiangiogenic function by PI3K/AKT and MAPK pathways. Furthermore, the impact of Ang-(1-7) on tumor-associated angiogenesis has been confirmed in lung cancer xenograft model with acquired DDP resistance. These results provide a theoretical basis for designing therapeutic strategies for targeting Ang-(1-7) in the treatment of NSCLC.

Bufalin reverses multidrug resistance by regulating stemness through the CD133/nuclear factor-κB/MDR1 pathway in colorectal cancer.

Recent studies have shown that MDR could be induced by the high stemness of cancer cells. In a previous study, we found bufalin could reverse MDR and inhibit cancer cell stemness in colorectal cancer, but the relationship between them was unclear. Here we identified overexpressing CD133 increases levels of Akt/nuclear factor-κB signaling mediators and MDR1, while increasing cell chemoresistance. Furthermore, bufalin reverses colorectal cancer MDR by regulating cancer cell stemness through the CD133/nuclear factor-κB/MDR1 pathway in vitro and in vivo. Taken together, our results suggest that bufalin could be developed as a novel 2-pronged drug that targets CD133 and MDR1 to eradicate MDR cells and could ultimately be combined with conventional chemotherapeutic agents to improve treatment outcomes for patients with colorectal cancer.

Targeting CD133 reverses drug-resistance via the AKT/NF-κB/MDR1 pathway in colorectal cancer.

BACKGROUND: Recent studies have shown that multidrug resistance may be induced by the high stemness of cancer cells. Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in CRC, but the relationship between them is unclear. METHODS: The relationship between MDR and CSC properties in CRC was determined via CCK-8 assay, apoptosis assay, DOX uptake and retention, immunohistochemistry, immunofluorescence and flow cytometry. The correlations between their expression levels were evaluated using Spearman's rank statistical test and the Mann-Whitney test. Furthermore, the effect of CD133 on the repression of the AKT/NF-κB/MDR1 signalling pathway was investigated in vitro and in vivo. RESULTS: We found that CD133 increased with the emergence of drug-resistance phenotypes, and the high expression of MDR1/P-gp was consistently accompanied by positive expression of CD133 as demonstrated by the analysis of patient samples. Up- or downregulation of CD133 could regulate MDR via AKT/NF-κB/MDR1 signalling in CRC. A rescue experiment showed that the AKT/NF-κB signalling pathway is the main mechanism by which CD133 regulates MDR1/P-gp expression in CRC. CONCLUSIONS: Taken together, our results suggest that targeting CD133 reverses drug resistance via the AKT/NF-κB/MDR1 pathway and that this pathway might serve as a potential therapeutic target to reverse MDR in CRC.

miR-139-5p reverses stemness maintenance and metastasis of colon cancer stem-like cells by targeting E2-2.

Colon cancer stem cells (CCSCs) stand for a critical subpopulation of colon cancer cells that possess self-renewal and multilineage differentiation potentials and drive tumorigenicity. Due to their impact on treatment tolerance, CCSCs have been a hot research topic in the past few years. We have previously reported that miR-139-5p is a vital tumor repressive noncoding RNA whose level decreases in the clinical colon cancer samples with the increase of tumor malignancy. This research discovered that miR-139-5p targets the Wnt/ß-catenin/TCF7L2 downstream effector E2-2 in CCSCs. E2-2 is a pivot molecule in the negative feedback loop of miR-139-5p/Wnt/ß-catenin/TCF7L2. Its small interfering RNA reverses the stemness maintenance and epithelial-mesenchymal transition of colon cancer CSCs. This study provides a theoretical foundation for the clinical diagnosis and medical treatment of recurrent or metastatic colon cancer with miR-139-5p and its target E2-2.

EpCAM Aptamer-Functionalized Cationic Liposome-Based Nanoparticles Loaded with miR-139-5p for Targeted Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide. MicroRNAs (miRNAs) play a vital role in a variety of biology processes. Our previous work identified miR-139-5p as a tumor suppressor gene overexpressed in CRC that assisted in inhibiting progression of cancer. The main challenge of miRNAs as therapeutic agents is their rapid degradation in plasma, poor uptake, and off-target effects. Therefore, the development of miRNA-based therapies is necessary. In this study, we developed a cationic liposome-based nanoparticle loaded with miR-139-5p (miR-139-5p-HSPC/DOTAP/Chol/DSPE-PEG2000-COOH nanoparticles, MNPs) and surface-decorated with epithelial cell adhesion molecule (EpCAM) aptamer (Apt) (miR-139-5p-EpCAM Apt-HSPC/DOTAP/Chol/DSPE-PEG2000-COOH nanoparticles, MANPs) for the targeted treatment of CRC. The size of MANPs was 150.3 ± 8.8 nm, which had a round-shaped appearance and functional dispersion capabilities. It also showed negligible hemolysis in the blood. MANPs markedly inhibited the proliferation, migration, and invasion of one or more CRC cell lines in vitro. Furthermore, we demonstrated the uptake and targeting ability of MANPs in vivo and in vitro. MANPs inhibit the growth of HCT8 cells in vitro and have a significant tumor suppressive effect on subcutaneous HCT8 colorectal tumor mice. Our results demonstrated that MANPs were an effective carrier approach to deliver therapeutic miRNAs to CRC.

Therapeutic Potential of Polyscias fruticosa (L.) Harms Leaf Extract for Parkinson's Disease Treatment by Drosophila melanogaster Model.

Parkinson's disease (PD) is characterized by progressive locomotive defects and loss of dopaminergic neurons. Polyscias fruticosa leaves are used by Vietnamese as herbal medicines to support the treatment of some diseases related to neurodegeneration such as Parkinson's and Alzheimer's diseases. However, recent scientific data have not provided sufficient evidence for the use of P. fruticosa leaves to treat PD or decelerate PD progression. In the present study, the capacity of P. fruticosa leaf extract for PD treatment on the dietary supplementation was investigated using dUCH-knockdown Drosophila model. The results indicated that P. fruticosa leaf extract decelerated dopaminergic neuron degeneration induced by dUCH knockdown in not only the larval stage but also the adult stage, which might result in the amelioration in locomotor ability of dUCH-knockdown larvae and flies. Furthermore, antioxidant activities and some key phytochemicals such as saponins, polyphenols, and flavonoids that might contribute to the effects of the P. fruticosa leaf extract were identified.

The complete chloroplast genome of Mimosa pigra L. (Fabaceae), a notorious invasive plant.

Mimosa pigra L., also called the giant sensitive tree, is native to tropical America and has invaded Africa, Asia, and Australia. Here, we report the complete chloroplast genome of M. pigra, which was 165,996 bp in length and composed of a large single-copy region (LSC; 93,299 bp), a small single-copy region (SSC; 17,989 bp) and two inverted repeat regions (IRs; 27,354 bp). The complete M. pigra chloroplast genome included 83 protein-coding genes, 37 tRNAs and 8 rRNAs. Phylogenetic analysis using the maximum likelihood method revealed the monophyly of M. pigra and related taxa of the subfamily Caesalpinioideae. In comparison, the members of Papilionoideae were paraphyletic.

A Novel Liposomal S-Propargyl-Cysteine: A Sustained Release of Hydrogen Sulfide Reducing Myocardial Fibrosis via TGF-ß1/Smad Pathway.

PURPOSE: S-propargyl-cysteine (SPRC; alternatively known as ZYZ-802) is a novel modulator of endogenous tissue H2S concentrations with known cardioprotective and anti-inflammatory effects. However, its rapid metabolism and excretion have limited its clinical application. To overcome these issues, we have developed some novel liposomal carriers to deliver ZYZ-802 to cells and tissues and have characterized their physicochemical, morphological and pharmacological properties. METHODS: Two liposomal formulations of ZYZ-802 were prepared by thin-layer hydration and the morphological characteristics of each liposome system were assessed using a laser particle size analyzer and transmission electron microscopy. The entrapment efficiency and ZYZ-802 release profiles were determined following ultrafiltration centrifugation, dialysis tube and HPLC measurements. LC-MS/MS was used to evaluate the pharmacokinetic parameters and tissue distribution profiles of each formulation via the measurements of plasma and tissues ZYZ-802 and H2S concentrations. Using an in vivo model of heart failure (HF), the cardio-protective effects of liposomal carrier were determined by echocardiography, histopathology, Western blot and the assessment of antioxidant and myocardial fibrosis markers. RESULTS: Both liposomal formulations improved ZYZ-802 pharmacokinetics and optimized H2S concentrations in plasma and tissues. Liposomal ZYZ-802 showed enhanced cardioprotective effects in vivo. Importantly, liposomal ZYZ-802 could inhibit myocardial fibrosis via the inhibition of the TGF-ß1/Smad signaling pathway. CONCLUSION: The liposomal formulations of ZYZ-802 have enhanced pharmacokinetic and pharmacological properties in vivo. This work is the first report to describe the development of liposomal formulations to improve the sustained release of H2S within tissues.

A collagen-based multicellular tumor spheroid model for evaluation of the efficiency of nanoparticle drug delivery.

Targeted drug delivery systems, especially those that use nanoparticles, have been the focus of research into cancer therapy during the last decade, to improve the bioavailability and delivery of anticancer drugs to specific tumor sites, thereby reducing the toxicity and side effects to normal tissues. However, the positive antitumor effects of these nanocarriers observed in conventional monolayer cultures frequently fail in vivo, due to the lack of physical and biological barriers resembling those seen in the actual body. Therefore, the collagen-based 3-D multicellular culture system, to screen new nanocarriers for drug delivery and to obtain more adequate and better prediction of therapeutic outcomes in preclinical experiments, was developed. This 3-D culture model was successfully established using optimized density of cells. Our result showed that 3-D cell colonies were successfully developed from 95-D, U87 and HCT116 cell lines respectively, after a seven-day culture in the collagen matrix. The coumarin-conjugated nanoparticles were able to penetrate the matrix gel to reach the tumor cells. The model is supposedly more accurate in reflecting/predicting the dynamics and therapeutic outcomes of candidates for drug transport in vivo, and/or investigation of tumor biology, thus speeding up the pace of discovery of novel drug delivery systems for cancer therapy.

An investigation of antitumor efficiency of novel sustained and targeted 5-fluorouracil nanoparticles.

Traditional chemotherapeutic drugs remain the major treatment for advanced colorectal cancer. However, due to the lack of tumor specificity these drug also destroy healthy tissue and organs, which has been the main reason for treatment failure and mortality. Folate-based drug delivery systems for improving nanoparticle endocytosis have been used to address these problems. Here, folic acid (FA) conjugated mPEG-b-P(CABCL-co-ACL) diblock copolymers were synthesized and characterized by TEM and NMR. Drug loaded nanoparticles were prepared using dialysis method and was obtained with a mean diameter of 45.2 nm with sustained in vitro release profile. In vitro cytotoxicity assay indicated that the cytotoxicity of folate modified nanoparticles were significantly increased compared to free drug and non-folate nanoparticles. In addition, results of hemolytic and histopathologic study suggested that the non-loaded nanoparticle (NL/NP) was non-toxic and biocompatible at the testing concentration. Moreover, in vivo results showed that FA/5-FU/NP effectively inhibited growth of HCT-8 cell-based xenograft tumors in BALB/c mice and revealed stronger antitumor efficacy than other treated groups. Thus, both in vitro and in vivo results exhibited that the folate conjugated mPEG-b-P(CABCL-co-ACL) copolymers have great potential to be used as sustainable and specific colon cancer targeting delivery system for anticancer agents.

Overcoming multidrug resistance in 2D and 3D culture models by controlled drug chitosan-graft poly(caprolactone)-based nanoparticles.

The principal limitations of chemotherapy are dose-limiting systemic toxicity and the development of multidrug-resistant phenotypes. The aim of this study was to investigate the efficiency of a new sustained drug delivery system based on chitosan and ε-caprolactone to overcome multidrug resistance in monolayer and drug resistance associated with the three-dimensional (3D) tumor microenvironment in our established 3D models. The 5-fluorouracil (5-FU)-loaded nanoparticles (NPs) were characterized by transmission electron microscope and dynamic light scattering, and its released property was determined at different pH values. 5-FU/NPs exhibited well-sustained release properties and markedly enhanced the cytotoxicity of 5-FU against HCT116/L-OHP or HCT8/VCR MDR cells in two-dimensional (2D) and its parental cells in 3D collagen gel culture with twofold to threefold decrease in the IC50 values, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Hoechst/propidium iodide staining and flow cytometry analysis. Furthermore, the possible mechanism was explored by high-performance liquid chromatography and rhodamine 123 accumulation experiment. Overall, the results demonstrated that 5-FU/NPs increase intracellular concentration of 5-FU and enhance its anticancer efficiency by inducing apoptosis. It was suggested that this novel NPs are a promising carrier to decrease toxic of 5-FU and has the potential to reverse the forms of both intrinsic and acquired drug resistance in 2D and 3D cultures.