Mitoprotective effect of mesenchymal stem cells-derived conditioned medium in myocardial reperfusion injury of aged rats: role of SIRT-1/PGC-1α/NRF-2 network.

BACKGROUND: The aged myocardium experiences various forms of stress that cause reduction of its tolerance to injury induced by ischemia/reperfusion (I/R). Developing effective cardioprotective modalities to prevent the amplification of I/R injury during aging is under focus of investigation. Mesenchymal stem cells (MSCs) have the ability to regenerate infarcted myocardium mostly by producing multiple secretory factors. This study aimed to explore the mechanisms of mitoprotection by MSCs-conditioned medium (CM) in myocardial I/R injury of aged rats. METHODS: Male Wistar rats (n = 72, 400-450 g, 22-24 months old) were randomized into groups with/without I/R and/or MSCs-CM treatment. To establish myocardial I/R injury, the method of LAD occlusion and re-opening was employed. MSCs-CM was administered intramyocardially (150 µl) at the onset of reperfusion in recipient group. After 24 h reperfusion, myocardial infarct size, LDH level, mitochondrial functional endpoints, expression of mitochondrial biogenesis-associated genes, and the levels of pro-inflammatory cytokines were evaluated. After 28 days reperfusion, echocardiographic assessment of cardiac function was performed. RESULTS: MSCs-CM treatment improved myocardial function and decreased infarct size and LDH level in aged I/R rats (P < .05 to P < .001). It also decreased mitochondrial ROS formation, enhanced mitochondrial membrane potential and ATP content, upregulated mitochondrial biogenesis-related genes including SIRT-1, PGC-1α, and NRF-2, and lessened TNF-α, IL-1ß, and IL-6 levels (P < .05 to P < .01). CONCLUSIONS: MSCs-CM treatment attenuated myocardial I/R injury in aged rats, in part by improving mitochondrial function and biogenesis and restraining inflammatory reaction. the upregulation of SIRT-1/PGC-1α/NRF-2 profiles is a possible target for the mitoprotective effects of MSCs-CM following I/R injury during aging.

An overview on nanoparticle-based strategies to fight viral infections with a focus on COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to COVID-19 and has become a pandemic worldwide with mortality of millions. Nanotechnology can be used to deliver antiviral medicines or other types of viral reproduction-inhibiting medications. At various steps of viral infection, nanotechnology could suggest practical solutions for usage in the fight against viral infection. Nanotechnology-based approaches can help in the fight against SARS-CoV-2 infection. Nanoparticles can play an essential role in progressing SARS-CoV-2 treatment and vaccine production in efficacy and safety. Nanocarriers have increased the speed of vaccine development and the efficiency of vaccines. As a result, the increased investigation into nanoparticles as nano-delivery systems and nanotherapeutics in viral infection, and the development of new and effective methods are essential for inhibiting SARS-CoV-2 infection. In this article, we compare the attributes of several nanoparticles and evaluate their capability to create novel vaccines and treatment methods against different types of viral diseases, especially the SARS-CoV-2 disease.

Induction of Apoptosis by a Combination of 2-Deoxyglucose and Metformin in Esophageal Squamous Cell Carcinoma by Targeting Cancer Cell Metabolism.

BACKGROUND: Both mitochondrial dysfunction and aerobic glycolysis are signs of growing aggressive cancer. If altered metabolism of cancer cell is intended, using the glycolysis inhibitor (2-deoxyglucose (2DG)) would be a viable therapeutic method. The AMP-activated protein kinase (AMPK), as a metabolic sensor, could be activated with metformin and it can also launch a p53-dependent metabolic checkpoint and might inhibit cancer cell growth. METHODS: After treatment with 5 mM metformin and/or 500 µM 2DG, the TE1, TE8, and TE11 cellular viability and apoptosis were assessed by MTT, TUNEL, and ELISA methods. The changes in p53 and Bcl-2 genes expression levels were examined using real-time PCR method. Data were analyzed by Kruskal-Wallis test using the SPSS 17.0 software. RESULTS: Metformin and 2DG, alone and in combination, induced apoptosis in the cell lines. Real-time PCR revealed that metformin induced apoptosis in TE8 and TE11 cells by activating p53, down-regulating Bcl-2 expression. The induced apoptosis by 2DG raised by metformin and the combination modulated the expression of Bcl-2 protein in all cell lines and it was more effective in TE11 cell line. CONCLUSION: Metformin induced apoptosis in ESCC by down-regulating Bcl-2 expression, and up-regulating p53 and induced apoptosis increased by 2-deoxy-d-glucose. Thus, the combination therapy is an effective therapeutic strategy for esophageal squamous cell carcinoma.

Development of Emu oil-loaded PCL/collagen bioactive nanofibers for proliferation and stemness preservation of human adipose-derived stem cells: possible application in regenerative medicine.

Adipose tissue-derived stem cells (ASCs) are promising candidate in stem cell therapies, and maintaining their stemness potential is vital to achieve effective treatment. Natural-based scaffolds have been recently attracted increasing attention in nanomedicine and drug delivery. In the present study, a polymeric nanofibrous scaffold was developed based on the polycaprolactone/Collagen (PCL/Coll) containing Emu oil as a bioactive material to induce the proliferation of ASCs, while simultaneously preserving the stemness property of those cells. Fabrication of the electrospun Emu oil-loaded PCL/Coll nanofibers was confirmed by using FE-SEM, FTIR, and tensile test. ASCs were seeded on two types of nanofibers (PCL/Coll and Emu oil-loaded PCL/Coll) and their proliferation, cell cycle progression, and stemness gene expressions were evaluated using MTT, propidium iodide staining, and qPCR during 14 days, respectively. The results indicated that ASCs displayed improved adhesion capacity with the higher rates of bioactivity and proliferation on the Emu oil-loaded nanofibers than the other groups. The proliferation capacity of ASCs on Emu oil-loaded PCL/Coll nanofibers was further confirmed by the cell cycle progression analysis. It was also found that Emu oil-loaded nanofibers significantly up-regulated the expression of stemness markers including sox-2, nanog, oct4, klf4, and c-Myc. The results demonstrated that the nanofibers containing Emu oil can reinforce the cell adhesion and enhance ASCs proliferation while preserving their stemness; therefore, using scaffolds containing natural products may have a great potential to enhance the in vitro expansion capacity of ASCs in the field of stem cell therapy and regenerative medicine.

Silver nanoparticles: Synthesis methods, bio-applications and properties.

Silver nanoparticles size makes wide range of new applications in various fields of industry. Synthesis of noble metal nanoparticles for applications such as catalysis, electronics, optics, environmental and biotechnology is an area of constant interest. Two main methods for Silver nanoparticles are the physical and chemical methods. The problem with these methods is absorption of toxic substances onto them. Green synthesis approaches overcome this limitation. Silver nanoparticles size makes wide range of new applications in various fields of industry. This article summarizes exclusively scalable techniques and focuses on strengths, respectively, limitations with respect to the biomedical applicability and regulatory requirements concerning silver nanoparticles.

Curcumin inhibits leptin gene expression and secretion in breast cancer cells by estrogen receptors.

BACKGROUND: Recent studies suggested that leptin as a mitogenic factor might play an important role in the process of initiation and progression of human cancer. Therefore, it could be considered as a target for breast cancer therapy. A previous study has showed that expression of leptin gene could be modulated by activation of estrogen receptors. Curcumin is a diferuloylmethane that has been shown to interfere with multiple cell signaling pathways and extensive research over the last 50 years has indicated this polyphenol can both prevent and treat cancer. Based on the fact that targeting of leptin could be considered as a novel strategy for breast cancer therapy, the aim of this study is the investigation of potentiality of curcumin for inhibition of leptin gene expression and secretion, and also, its link with expression of estrogen receptors. METHODS: Cytotoxic effect of curcumin on T47D breast cancer cells was investigated by MTT assay test after 24 and 48 treatments. Thereafter, the cells treated with different concentrations of curcumin. The levels of leptin, estrogen receptor α and estrogen receptor ß genes expression was measured in the treated and control cells by Reverse-transcription real-time PCR. Amount of secreted leptin in the culture medium was also determined by ELISA in both treated and untreated cells. Finally data were statistically analyzed by one-way ANOVA test. RESULTS: Analysis of MTT assay data showed that curcumin inhibits growth of T47D cells with dose dependent manner. There were also significant difference between control and treated cells in the levels of leptin, estrogen receptor α expression levels and the quantity of secreted leptin that both were decreased in the treated cells compared with control cells. CONCLUSION: Based on the results, curcumin inhibits the expression and secretion of leptin and it could probably be used as a drug candidate for the breast cancer therapy through the leptin targeting in the future.

Preparation of pH sensitive insulin-loaded nano hydrogels and evaluation of insulin releasing in different pH conditions.

In the recent years, temperature and pH-sensitive hydrogels were developed as suitable carriers for drug delivery. In this study, four different pH-sensitive nanohydrogels were designed for an oral insulin delivery modeling. NIPAAm-MAA-HEM copolymers were synthesized by radical chain reaction with 80:8:12 ratios respectively. Reactions were carried out in four conditions including 1,4-dioxan and water as two distinct solution under nitrogen gas-flow. The copolymers were characterized with FT-IR, SEM and TEM. Copolymers were loaded with regular insulin by modified double emulsion method with ratio of 1:10. Release study carried out in pH 1.2 and pH 6.8 at 37 °C. For pH 6.8 and pH 1.2, 2 mg of the insulin loaded nanohydrogels was float in a beaker containing 100 mL of PBS with pH 6.8 and 100 mL of HCl solution with pH 1.2, respectively. Sample collection was done in different times and HPLC was used for analysis of samples using water/acetonitrile (65/35) as the mobile phase. Nanohydrogels synthesis reaction yield was 95 %, HPLC results showed that loading in 1,4-dioxan without cross-linker nanohydrogels was more than others, also indicated that the insulin release of 1,4-dioxan without cross-linker nanohydrogels at acidic pH is less, but in pH 6.8 is the most. Results showed that by opting suitable polymerization method and selecting the best nanohydrogels, we could obtain a suitable insulin loaded nanohydrogels for oral administration.

Synthesis and in vitro study of cisplatin-loaded Fe3O4 nanoparticles modified with PLGA-PEG6000 copolymers in treatment of lung cancer.

In the field of cancer therapy, magnetic nanoparticles modified with biocompatible copolymers are promising vehicles for the delivery of hydrophobic drugs such as Cisplatin. The major aim of this effort was to evaluate whether Cisplatin-Encapsulated magnetic nanoparticles improved the anti-tumour effect of free Cisplatin in lung cancer cells. The PLGA-PEG triblock copolymer was synthesised by ring-opening polymerisation of d,l-lactide and glycolide with polyethylene glycol (PEG6000) as an initiator. The bulk properties of these copolymers were characterised using Fourier transform infrared spectroscopy. Cisplatin-loaded nanoparticles (NPs) were prepared by double emulsion solvent evaporation technique and were characterised for size, drug entrapment efficiency (%), drug content (% w/w), and surface morphology. In vitro release profile of cisplatin-loaded NP formulations was determined. Cytotoxic assays were evaluated in lung carcinoma (A549)-treated cells by the MTT assay technique. In addition, the particles were characterised by X-ray powder diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and vibrating sample magnetometry. The anti-proliferative effect of Cisplatin appeared much earlier when the drug was encapsulated in magnetic nanoparticles than when it was free. Cisplatin-Encapsulated magnetic nanoparticles significantly enhanced the decrease in IC50 rate. The in vitro cytotoxicity test showed that the Fe3O4-PLGA-PEG6000 magnetic nanoparticles had no cytotoxicity and were biocompatible. The chemotherapeutic effect of free Cisplatin on lung cancer cells is improved by its encapsulation in modified magnetic nanoparticles. This approach has the prospective to overcome some major limitations of conventional chemotherapy and may be a promising strategy for future applications in lung cancer therapy.

Development of an injectable chitosan-based hydrogel containing nano-hydroxy-apatite and alendronate for MSC-based therapy.

BACKGROUND: The combination of cells and biomaterials has become a powerful approach to regenerative medicine in recent years. Understanding the in-vitro interactions between cells and biomaterials is crucial for the success of regenerative medicine. AIM: In this study, we developed an AD-pectin/chitosan/nano-crystalline cellulose scaffold with nano-hydroxy-apatite (n-HAP) and alendronate (ALN). The second step was to evaluate its effect on the immunomodulatory properties and biological behaviors of seeded adipose-derived mesenchymal stem cells (ADSCs) for bone tissue repair. MATERIAL AND METHOD: After preparing and evaluating the characterization tests of the new combined n-HAP scaffold, we established different culture conditions to evaluate ADSC growth on this scaffold with or without ALN. The main assays were MTT assay, RT-PCR, and ELISA. RESULTS: Our data regarding characterization tests (including SEM, TGA, FTIR, gelation time, swelling ratio, rheology and degradation tests) of ALN-loaded n-HAP scaffold showed the proper stability and good mechanical status of the scaffold. ADSC proliferation and viability increased in the presence of the scaffold compared with other conditions. Moreover, our data demonstrated increased gene expression and protein levels of anti-inflammatory TGF-ß, HGF, and IDO cytokines in the presence of the ALN-loaded n-HAP scaffold, indicating the increased immunosuppressive activity of ADSCs in vitro. CONCLUSION: This study demonstrates the promising abilities of the ALN-loaded n-HAP scaffold to increase the proliferation, viability, and immunomodulatory capacity of ADSCs, elucidating new aspects of cell-material interactions that can be used for bone tissue regeneration/repair, and paving the path of future research in developing new approaches for MSC- based therapy.

Biomarkers and optical based biosensors in cardiac disease detection: early and accurate diagnosis.

Rapid and precise detection methods for the early-stage detection of cardiovascular irregularities are crucial to stopping and reducing their development. Cardiovascular diseases (CVDs) are the leading cause of death in the world. Hence, cardiac-related biomarkers are essential for monitoring and managing of process. The necessity for biomarker detection has significantly widened the field of biosensor development. Bio-sensing methods offer rapid detection, low cost, sensitivity, portability, and selectivity in the development of devices for biomarker detection. For the prediction of cardiovascular diseases, some biomarkers can be used, like C-reactive protein (CRP), troponin I or T, creatine kinase (CK-MB), B-type natriuretic peptide (BNP), myoglobin (Mb), suppression of tumorigenicity 2 protein (ST2) and galectin-3 (Gal3). In this review, recent research studies were covered for gaining insight into utilizing optical-based biosensors, including surface plasmon resonance (SPR), photonic crystals (PCs), fluorescence-based techniques, fiber optics, and also Raman spectroscopy biosensors for the ultrasensitive detection of cardiac biomarkers. The main goal of this review is to focus on the improvement of optical biosensors in the future for the diagnosis of heart diseases and to discuss how to enhance their properties for use in medicine. Some main data from each study reviewed are emphasized, including the CVD biomarkers and the response range of the optical-based devices and biosensors.

The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology.

Epigenetic mechanisms are gene regulatory processes that control gene expression and cellular identity. Epigenetic factors include the "writers", "readers", and "erasers" of epigenetic modifications such as DNA methylation. Accordingly, the nuclear protein Methyl-CpG-Binding Protein 2 (MeCP2) is a reader of DNA methylation with key roles in cellular identity and function. Research studies have linked altered DNA methylation, deregulation of MeCP2 levels, or MECP2 gene mutations to different types of human disease. Due to the high expression level of MeCP2 in the brain, many studies have focused on its role in neurological and neurodevelopmental disorders. However, it is becoming increasingly apparent that MeCP2 also participates in the tumorigenesis of different types of human cancer, with potential oncogenic properties. It is well documented that aberrant epigenetic regulation such as altered DNA methylation may lead to cancer and the process of tumorigenesis. However, direct involvement of MeCP2 with that of human cancer was not fully investigated until lately. In recent years, a multitude of research studies from independent groups have explored the molecular mechanisms involving MeCP2 in a vast array of human cancers that focus on the oncogenic characteristics of MeCP2. Here, we provide an overview of the proposed role of MeCP2 as an emerging oncogene in different types of human cancer.

Cytotoxicity of curcumin against CD44± prostate cancer cells: Roles of miR-383 and miR-708.

Objective: Cancer stem cells (CSCs) remaining in the tumor tissues after applying treatments may cause recurrence or metastasis of prostate cancer (PC). Curcumin has the promising potential to target CSCs. Here, we aim to evaluate the cytotoxic effects of curcumin on the expression of miR-383-5p and miR-708-5p and their target genes in CD44+ CSCs and CD44- non-CSCs isolated from the PC3 prostate cancer cell line. Materials and Methods: We used MTT assay to determine the optimal cytotoxic dose of curcumin on CD44± PC cells. Then, we assessed nuclear morphological changes using DAPi staining. We used Annexin V-FITC/PI to quantify apoptotic cell death. qRT-PCR was also used to detect miRNA and gene expression levels after curcumin treatment. Results: Curcumin significantly enhanced the apoptosis in both CD44- and CD44+ PC cells in a dose-dependent manner (p < 0.05). The cytotoxicity of curcumin against CD44- cells (IC50 40.30±2.32 µM) was found to be greater than that against CD44+ cells (IC50 83.31±2.91 µM). Also, curcumin promoted miR-383-5p and miR-708-5p overexpression while downregulating their target genes LDHA, PRDX3, and RAP1B, LSD1, respectively. Conclusion: Our findings indicate that curcumin, by promoting the expression of tumor suppressors, miR-383-5p and miR-708-5p, and inhibiting their target genes, induced its cytotoxicity against CD44± PC cells. We trust that curcumin could be established as a promising adjuvant therapy to current PC treatment options following more research in clinical settings.

The Schiff base hydrazine copper(II) complexes induce apoptosis by P53 overexpression and prevent cell migration through protease-independent pathways.

Although chemotherapy has increased the life expectancy of cancer patients, its toxic side effects remain a major challenge. Recently, organometallic compounds, such as Schiff base copper complexes, have become promising candidates for next-generation anticancer drugs owing to their unique anticancer activities. In this study, binuclear copper(II) complex-1 and mononuclear copper(II) complex-2 were examined to analyze their anticancer mechanisms further. For this purpose, a viability test, flow cytometry analysis of apoptosis and the cell cycle, migration assay, and gene expression analysis were performed. According to our results, complex-1 was more cytotoxic than complex-2 at 24/48-h intervals. Our findings also demonstrated that both complexes induced apoptosis at IC50 concentrations and arrested the cell cycle at the G1-S checkpoint. However, complex-1 accelerates cell cycle arrest at the sub-G0/G1 phase more than complex-2 does. Furthermore, gene expression analysis showed that only complex-1 induces the expression of p53. Interestingly, both complexes induced Bcl-2 overexpression. However, they did not affect MMP-13 expression. More interestingly, both complexes inhibited cell migration in different ways, including amoeboid and collective, by recruiting protease-independent pathways. This study confirmed that adding several metal cores and co-ligands increased the activity of the complex. It also appeared that Cu-containing complexes could prevent the migration of cancer cells through protease-independent pathways, which can be used for novel therapeutic purposes.

Current and Novel Emerging Medical Therapies for Peripheral Artery Disease: A Literature Review.

Despite the improvements in endovascular techniques during the last decades, there is still an increase in the prevalence of peripheral artery disease (PAD) with limited practical treatment, which timeline impact of any intervention for critical limb ischemia (CLI) is poor. Most common treatments are not suitable for many patients due to their underlying diseases, including aging and diabetes. On the one hand, there are limitations for current therapies due to the contraindications of some individuals, and on the other hand, there are many side effects caused by common medications, for instance, anticoagulants. Therefore, novel treatment strategies like regenerative medicine, cell-based therapies, Nano-therapy, gene therapy, and targeted therapy, besides other traditional drugs combination therapy for PAD, are newly considered promising therapy. Genetic material encoding for specific proteins concludes with a potential future for developed treatments. Novel approaches for therapeutic angiogenesis directly used the angiogenetic factors originating from key biomolecules such as genes, proteins, or cell-based therapy to induce blood vessel formation in adult tissues to initiate the recovery process in the ischemic limb. As PAD is associated with high mortality and morbidity of patients causing disability, considering the limited treatment choices for these patients, developing new treatment strategies to prevent PAD progression and extending life expectancy, and preventing threatening complications is urgently needed. This review aims to introduce the current and the novel strategies for PAD treatment that lead to new challenges for relief the patient's suffered from the disorder.

STA-21, a small molecule STAT3 inhibitor, ameliorates experimental autoimmune encephalomyelitis by altering Th-17/Treg balance.

BACKGROUND: Numerous studies have demonstrated the role of T helper (Th) 17 and T regulatory (reg) cells and pro-inflammatory and anti-inflammatory cytokines related to these cells in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). STAT3 is one of the downstream signaling proteins of IL-23, IL-6, and IL-21 that are required for Th17 cells differentiation. STA-21 is a STAT3 inhibitor that functions by inhibiting STAT3 dimerization and binding to DNA impairing the expression of STAT3 target genes including, RORγt, IL-21 and IL-23R that are also required for Th17 cell differentiation. AIM: In this study, we evaluated the effect of STA-21 on EAE Model and investigated how this small molecule can change Th17/Treg balance leading to amelioration of disease. METHODS: After EAE induction and treatment with STA-21, its effects were assessed. Major assays were H&E and LFB staining, Flow cytometric analysis, Reverse transcription-PCR (RT-PCR), and ELISA. RESULTS: STA-21 ameliorated the EAE severity and decreased the EAE inflammation and demyelination. It also decreased STAT3 phosphorylation, the proportion of Th17 cells and the protein level of IL-17. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine, IL-10 increased in STA-21-treated mice. Moreover, STA-21 significantly decreased the expression of Th17 related transcription factors, RORɣt and IL-23R while FOXP3 expression associated with Treg differentiation was increased. CONCLUSION: This study showed that STA-21 has therapeutic effects in EAE by reducing inflammation and shifting inflammatory immune responses to anti-inflammatory and can be used as a suitable treatment strategy for the treatment of EAE. The effectiveness of inhibiting or strengthening the functional cells of the immune system by these small molecules in terms of easy to access, simple construction and inexpensive expansion make them as a suitable tool for the treatment of inflammatory and autoimmune diseases.

Curcumin Upregulates miR-148a to Increase the Chemosensitivity of CD44-Positive Prostate Cancer Stem Cells to Paclitaxel Through Targeting the MSK1/IRS1 axis.

BACKGROUND: In men, prostate cancer (PC) is the second most common cause of cancer-related death. However, paclitaxel resistance is a major challenge in advanced PC. Curcumin, a natural antioxidant, has been demonstrated to have cytotoxic effects on cancer stem cells (CSCs). The goal of this study is to explore if curcumin can help lower chemoresistance to paclitaxel through the regulation of miR-148a-mediated apoptosis in prostate CSCs. METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and 4',6-diamidino-2-phenylindole (DAPi) labeling were used to determine cell survival. Immunohistochemistry was used to detect the expression of P-glycoprotein protein (P-gp) and CD44 proteins. Finally, real-time PCR was used to evaluate the regulatory effects of curcumin and paclitaxel on miR-148a and its target genes. RESULTS: Curcumin and paclitaxel co-treatment significantly reduced the IC50 value in CD44+cells compared to paclitaxel alone. Additionally, combining these drugs considerably increased apoptosis in CD44+cells. We also discovered that when curcumin and paclitaxel were combined, the expression of CD44 and P-gp was significantly reduced compared to paclitaxel alone. Curcumin and paclitaxel co-treatment also increased miR-148a levels and regulated the levels of its target genes MSK1 and IRS1. CONCLUSION: Curcumin may restore paclitaxel sensitivity by raising miR-148a expression and inhibiting its target genes.

The role of exosomes in the molecular mechanisms of metastasis: Focusing on EMT and cancer stem cells.

Exosomes are cell-derived small membrane-encapsulated vesicles that transfer biomolecules to surrounding cells. Exosomes play fundamental roles in cell-cell communications. They can also aggravate cancer progression and metastasis. Metastasis is a complicated and multi-serial process that is regulated by various mechanisms. Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are important participants in cancer metastasis. Recent studies demonstrate that exosomes are associated with metastasis by modulating the EMT and the function of CSCs. Accumulating evidence shows that exosomes are implicated in regulating tumor cell metastasis by modulating signaling pathways involved in EMT and CSCs. This review aims to discuss the effect of exosomes on signaling pathways associated with EMT and CSCs, as well as possible therapeutic strategies of exosomes in cancer metastasis.

Simvastatin Induces Apoptosis in Medulloblastoma Brain Tumor Cells via Mevalonate Cascade Prenylation Substrates.

Medulloblastoma is a common pediatric brain tumor and one of the main types of solid cancers in children below the age of 10. Recently, cholesterol-lowering "statin" drugs have been highlighted for their possible anti-cancer effects. Clinically, statins are reported to have promising potential for consideration as an adjuvant therapy in different types of cancers. However, the anti-cancer effects of statins in medulloblastoma brain tumor cells are not currently well-defined. Here, we investigated the cell death mechanisms by which simvastatin mediates its effects on different human medulloblastoma cell lines. Simvastatin is a lipophilic drug that inhibits HMG-CoA reductase and has pleotropic effects. Inhibition of HMG-CoA reductase prevents the formation of essential downstream intermediates in the mevalonate cascade, such as farnesyl pyrophosphate (FPP) and gernaylgerany parophosphate (GGPP). These intermediates are involved in the activation pathway of small Rho GTPase proteins in different cell types. We observed that simvastatin significantly induces dose-dependent apoptosis in three different medulloblastoma brain tumor cell lines (Daoy, D283, and D341 cells). Our investigation shows that simvastatin-induced cell death is regulated via prenylation intermediates of the cholesterol metabolism pathway. Our results indicate that the induction of different caspases (caspase 3, 7, 8, and 9) depends on the nature of the medulloblastoma cell line. Western blot analysis shows that simvastatin leads to changes in the expression of regulator proteins involved in apoptosis, such as Bax, Bcl-2, and Bcl-xl. Taken together, our data suggests the potential application of a novel non-classical adjuvant therapy for medulloblastoma, through the regulation of protein prenylation intermediates that occurs via inhibition of the mevalonate pathway.

Recent Advances in Cell Electrospining of Natural and Synthetic Nanofibers for Regenerative Medicine.

The progression of nanotechnology provides opportunities to manipulate synthetic and natural materials to mimic the natural structure for tissue engineering applications. The electrospinning technique applies electrostatic principle to fabricate electrospun nanofibers. Nanofiber scaffolds are precisely similar to the native extracellular matrix (ECM) and support cell proliferation, adhesion, tendency to preserve their phenotypic shape and directed growth according to the nanofiber direction. This study reviewed both the natural and synthetic type of nanofibers and described the different properties used to trigger certain process in the tissue development. Also, the potential applications of electrospun scaffolds for regenerative medicine were summarized.

A Biomimetic Emu Oil-Blended Electrospun Nanofibrous Mat for Maintaining Stemness of Adipose Tissue-Derived Stem Cells.

BACKGROUND: Emu oil (EO) with anti-inflammatory, antioxidative, and wound healing properties can be blended for preparing bioactive nanofibrous scaffold. Adipose tissue-derived stem cells (ADSCs) are promising candidates for tissue engineering, and preserving their stemness potential is vital for further therapeutic applications. AIM: The aim of this study was to fabricate EO-blended nanofiber and investigate its effect on proliferation, survival, and stemness preservation of ADSCs. MATERIALS AND METHODS: Pure EO composition was characterized using a gas chromatograph mass spectrometer. EO-PCL-polyethylene glycol (PEG) nanofibers were successfully fabricated using an electrospinning technique and characterized by field emission scanning electron microscopy (FE-SEM) and fourier-transform infrared spectroscopy (FTIR). Cell viability and adhesion were measured using the MTT assay and FE-SEM. Finally, quantitative PCR (qPCR) was used to quantify the expression level of cell cycle regulated genes and pluripotency-associated transcription factors. RESULTS: Findings showed that 20% (w/w) of EO is the optimum oil content in the electrospun solution to achieve good morphology and ultrafine fibers. The relatively high optical densities and FE-SEM images indicated that EO highly supported cell adhesion and proliferation on the matrices. In addition, EO-PCL-PEG electrospun nanofibrous mats significantly upregulated the expression levels of cell cycle regulated genes (Cyclin D1, pRb, and P53) and stemness markers (Nanog, OCT-4, Rex-1, and Sox-2) than PCL-PEG nanofiber and tissue culture polystyrene in 7 and 14 days of cell culture. CONCLUSION: These results demonstrate that the EO-blended nanofibrous mat can be used as a bioactive scaffold to support cell adhesion and proliferation while simultaneously maintaining the stemness of ADSCs.