Mesenchymal stem cell exosomes: a two-edged sword in cancer therapy

Faezeh Vakhshiteh,1 Fatemeh Atyabi,1,2 Seyed Nasser Ostad3 1Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 3Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Abstract: Mesenchymal stem cells (MSCs) are multipotent stromal cells present in various adult tissues. Several studies suggest that MSCs secrete exosomes that perform as mediators in the tumor niche and play several roles in tumorigenesis, angiogenesis, and metastasis. In contrast, there are other studies supporting the tumor-suppressing effects of MSC-derived exosomes. Therefore, the exact association of MSC exosomes and tumor cells remains open to debate. This review aimed to demonstrate the present knowledge of MSC-derived exosomes in cancer research and to illustrate current approaches to make use of modified exosomes as a platform in therapeutic strategies in cancer. Keywords: mesenchymal stem cells, exosome, drug delivery, exosome engineering, cancer therap

Cytotoxic effect of a dentin bonding agent: AdheSE

Background and Aim: An important requirement for a dentin bonding agent is biological compatibility. Since dentin bonding agents are placed in cavity preparations with subgingival extensions, with direct contact to gingival and mucosal tissues, tissue response to these materials must be investigated. The aim of this study was to examine the cytotoxicity of AdheSE, a self etching adhesive, on human gingival fibroblasts."nMaterials and Methods: In this experimental in vitro study, primary human gingival fibroblasts were exposed to different dilutions of primer & bond of AdheSE (Vivadent, Liechtenstein). The toxicity of the primer was tested in 30 seconds, 300 seconds and 24 hours. The cytotoxicity of the bond was analyzed in uncured mode after 20 seconds, 5 minutes and 24 hours. In cured mode, tested materials were analyzed after 24 and 48 hours. Cytotoxic effects were evaluated using MTT, cell counting and DNA condensation assays. Data were analyzed by two way repeated measure ANOVA with p<0.05 as the level of significance."nResults: MTT Assay revealed that uncured AdheSE Bond was toxic only in 10-1 dilution and the difference with control group was significant (P<0.05). By increasing the time to 300sec. and 24h, dilutions of 10-2 and 10-4 were the most cytotoxic respectively. Cytotoxicity of uncured primer after 30 sec. and 300 sec. began from 10-2 and after 24h began from 10-2 and reached to 10-1. AdheSE in cured mode showed significant difference with control group in 1:2 (P<0.001),1:4 & 1:6 (P<0.01) dilutions. In cell counting assay only the 1:2 dilution was significantly more toxic than control group. Apoptosis (a morphological and biochemical distinct form of cell death that regulates cell turnover) comprised in less than 5% of total death in both cured and uncured adhesives."nConclusions: Based on the results of this study, by increasing the exposure time, smaller amounts of bonding could be cytotoxic. Cytotoxicity was related to material, dilution, time of exposure and curing. It would be necessary to identify the toxic ingredients of this adhesive and replace them by more biocompatible components

Chitosan–Pluronic nanoparticles as oral delivery of anticancer gemcitabine: preparation and in vitro study

Hosniyeh Hosseinzadeh1, Fatemeh Atyabi1, Rassoul Dinarvand1, Seyed Naser Ostad21Nanotechnology Research Centre, 2Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IranAbstract: Nanoparticles have proven to be an effective delivery system with few side effects for anticancer drugs. In this study, gemcitabine-loaded nanoparticles have been prepared by an ionic gelation method using chitosan and Pluronic® F-127 as a carrier. Prepared nanoparticles were characterized using dynamic light scattering, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), scanning electron microscopy, and transmission electron microscopy. Different parameters such as concentration of sodium tripolyphosphate, chitosan, Pluronic, and drug on the properties of the prepared nanoparticles were evaluated. In vitro drug release was studied in phosphate-buffered saline (PBS; pH = 7.4). The cytotoxicity of the nanoparticles was assayed in the HT-29 colon cancer cell line. The mucoadhesion behavior of the nanoparticles was also studied by mucus glycoprotein assay. The prepared nanoparticles had a spherical shape with positive charge and a mean diameter ranging between 80 to 170 nm. FT-IR and DSC studies found that the drug was dispersed in its amorphous form due to its potent interaction with nanoparticle matrix. Maximum drug encapsulation efficiency was achieved at 0.4 mg/mL gemcitabine while maximum drug loading was 6% obtained from 0.6 mg/mL gemcitabine. An in vitro drug release study at 37°C in PBS (pH = 7.4) exhibited a controlled release profile for chitosan–Pluronic® F-127 nanoparticles. A cytotoxicity assay of gemcitabine-loaded nanoparticles showed an increase in the cytotoxicity of gemcitabine embedded in the nanoparticles in comparison with drug alone. The mucoadhesion study results suggest that nanoparticles could be considered as an efficient oral formulation for colon cancer treatment.Keywords: chitosan, nanoparticles, ionic gelation, gemcitabine, mucoadhesion, oral drug delivery, anticance

In vitro evaluation of mutagenicity and cytotoxicity of four root canal sealers

Background and Aim: Root filling materials are usually in close contact with living tissues. So their biological properties like mutagenicity and cytotoxicity are important. These properties help us determine the potential damage to periapical tissues, or potential DNA mutations, and malignant transformation of the cells. The aim of this study was to evaluate the mutagenicity and cytotoxicity of four root canal sealers: AH Plus (Dentsply, DeTrey), Ketac-Endo Aplicap (3M ESPE), Sankin Apatite III (Sankin K.K), and Tubli-Seal EWT (Kerr).Materials and Methods: In this experimental in vitro study fresh and set specimens from AH Plus, Ketac-Endo Aplicap, Sankin Apatite III, and Tubli-Seal EWT were immersed in culture medium for 1, 2 and 7 days. Cytotoxicity was assessed using tetrazolium bromide reduction assay (MTT) after 1, 2 and 7 days exposure of diluted extracts to L929 cells. Extracts of sealers in phosphate buffer saline (PBS) were used to examine the mutagenic effects by sos-umu test according to standard procedures. Data were analyzed using one way ANOVA, Kruskall Wallis, Mann Whitney and Post hoc tests with P<0.05 as the level of significance. Results: Extracts of all freshly mixed sealers were cytotoxic. Ketac-Endo Aplicap and Sankin Apatite III showed the lowest toxicity respectively and Tubli-Seal EWT the highest. In contrast to other sealers, the cytotoxicity of Tubli-Seal showed no decrease with time. -galactosidase did not increase significantly thus none of the sealers showed mutagenic effects.Conclusion: Based on the results of this study, Tubli-Seal EWT showed the highest cytotoxicity with time. Other sealers showed decreasing cytotoxicity with time. No mutagenicity effects was observed in none of  tested materials

The Neuroprotective Effect of Lithium in cannabinoid Dependence is Mediated through Modulation of Cyclic AMP, ERK1/2 and GSK-3β Phosphorylation in Cerebellar Granular Neurons of Rat

Lithium (Li), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has used to attenuate the cannabinoid-induced dependence/withdrawal signs, but molecular mechanisms related to this are unclear. Recent studies indicate the involvement of upstream extracellular signal kinase1/2 (ERK1/2) and downstream GSK-3β pathways in the development of cannabinoid-induced dependence. This is mediated through cannabinoid receptor 1 (CB1) enriched in cerebellar granular neurons (CGNs). Accordingly, the present study aimed to investigate the mechanism of modulatory/neuroprotective effects of Li on a cannabinoid agonist (WIN 55,212-2 (WIN))-induced dependence, through quantitative analysis of some involved proteins such as ERK1/2, GSK-3β and related signaling pathways including their phosphorylated forms; and cAMP level as the other molecular mechanisms leading to dependence, in CGNs model. The CGNs were prepared from 7-day-old Wistar rat pup in a 12-well plate, pretreated with Li (1mM) and an ERK1/2 inhibitor SL327 (SL, 10 µM). The WIN (1 µM) was added 30 minutes prior to treatment and AM251 (AM, 1 µM), as a cannabinoid antagonist was co-treated with WIN. The cAMP level, as an indicator of cannabinoid-induced dependence, was measured by ELISA following forskolin (FSK) stimulation. Western blot analyses determined the phosphorylated forms of ERK1/2 (p-ERK1/2), GSK-3β (p-GSK-3β) as well as their total expressions in various treatment times and doses in CGNs. WIN alone could down regulate the cAMP/p-ERK1/2 cascade compared to AM treatment. However, P-GSK-3β was up-regulated with Li and WIN or with SL and Li pretreatment to AM-induced cellular response, which was the highest 60 minutes after CGNs exposure. Results further suggested the potential role of Li pretreatment to diminish the development of cannabinoid-induced dependence/neuronal injury through possible mechanisms of modulating the cAMP/p-ERK1/2 cascade independent of p-GSK-3β signaling pathway in-vitro

Mesoporous silica nanoparticles functionalized with folic acid/methionine for active targeted delivery of docetaxel

Pegah Khosravian,1 Mehdi Shafiee Ardestani,2 Mehdi Khoobi,3 Seyed Naser Ostad,4 Farid Abedin Dorkoosh,1 Hamid Akbari Javar,1,* Massoud Amanlou5,6,* 1Department of Pharmaceutics, 2Department of Radiopharmacy, 3Department of Pharmaceutical Biomaterials, 4Department of Pharmacology and Toxicology, 5Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, 6Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran *These authors contributed equally to this work Abstract: Mesoporous silica nanoparticles (MSNs) are known as carriers with high loading capacity and large functionalizable surface area for target-directed delivery. In this study, a series of docetaxel-loaded folic acid- or methionine-functionalized mesoporous silica nanoparticles (DTX/MSN-FA or DTX/MSN-Met) with large pores and amine groups at inner pore surface properties were prepared. The results showed that the MSNs were successfully synthesized, having good pay load and pH-sensitive drug release kinetics. The cellular investigation on MCF-7 cells showed better performance of cytotoxicity and cell apoptosis and an increase in cellular uptake of targeted nanoparticles. In vivo fluorescent imaging on healthy BALB/c mice proved that bare MSN-NH2 are mostly accumulated in the liver but MSN-FA or MSN-Met are more concentrated in the kidney. Importantly, ex vivo fluorescent images of tumor-induced BALB/c mice organs revealed the ability of MSN-FA to reach the tumor tissues. In conclusion, DTX/MSNs exhibited a good anticancer activity and enhanced the possibility of targeted drug delivery for breast cancer. Keywords: targeted delivery, mesoporous silica nanoparticle, folic acid, methionine, docetaxe

Instructional design and delivery of a virtual short course of pharmaceutical care and evaluating participants’ satisfaction

Abstract Introduction: There is more need for pharmacy managers’ development regarding pharmaceutical care after Heath Reform Project. In this study, we designed, delivered and evaluated a virtual one-year short course of pharmaceutical care for pharmacy managers. Methods: We interviewed with five hospital pharmacy managers for educational need assessment. Then we developed the curriculum and performed a systematic instructional design for its blended delivery. Faculty members participated in a three-day workshop and then developed their course plans, multimedia e-contents and completed their assessment (courses’ panels) in the university Learning Management System. We delivered the one-year MBA in three modules. At the end of each module, participants evaluated the courses via a researcher-made questionnaire. Results: In total, 38 pharmacy managers participated in the course. Ten participants (26%) left the study and 28 participants succeeded to pass the final written exam with the overall score of 18.0/20 (±0.45). The participants found the program useful for their career. Conclusion: Considering the participants’ feedback, We recommend this virtual pharmaceutical care are program for hospital pharmacy managers