Promotion of cardiac microtissue assembly within G-CSF-enriched collagen I-cardiogel hybrid hydrogel.

Tissue engineering as an interdisciplinary field of biomedical sciences has raised many hopes in the treatment of cardiovascular diseases as well as development of in vitro three-dimensional (3D) cardiac models. This study aimed to engineer a cardiac microtissue using a natural hybrid hydrogel enriched by granulocyte colony-stimulating factor (G-CSF), a bone marrow-derived growth factor. Cardiac ECM hydrogel (Cardiogel: CG) was mixed with collagen type I (ColI) to form the hybrid hydrogel, which was tested for mechanical and biological properties. Three cell types (cardiac progenitor cells, endothelial cells and cardiac fibroblasts) were co-cultured in the G-CSF-enriched hybrid hydrogel to form a 3D microtissue. ColI markedly improved the mechanical properties of CG in the hybrid form with a ratio of 1:1. The hybrid hydrogel demonstrated acceptable biocompatibility and improved retention of encapsulated human foreskin fibroblasts. Co-culture of three cell types in G-CSF enriched hybrid hydrogel, resulted in a faster 3D structure shaping and a well-cellularized microtissue with higher angiogenesis compared to growth factor-free hybrid hydrogel (control). Immunostaining confirmed the presence of CD31+ tube-like structures as well as vimentin+ cardiac fibroblasts and cTNT+ human pluripotent stem cells-derived cardiomyocytes. Bioinformatics analysis of signaling pathways related to the G-CSF receptor in cardiovascular lineage cells, identified target molecules. The in silico-identified STAT3, as one of the major molecules involved in G-CSF signaling of cardiac tissue, was upregulated in G-CSF compared to control. The G-CSF-enriched hybrid hydrogel could be a promising candidate for cardiac tissue engineering, as it facilitates tissue formation and angiogenesis.

Folic acid-conjugated dextran-coated Zn0.6Mn0.4Fe2O4 nanoparticles as systemically delivered nano heaters with self-regulating temperature for magnetic hyperthermia therapy of liver tumors.

Successful cancer treatment using magnetic hyperthermia therapy (MHT) strongly depends on biocompatible magnetic nanoparticles (NPs). They can effectively accumulate in tumor tissues after systemic injection and generate heat in the therapeutic temperature range (42-48 °C) by exposure to an AC magnetic field (AMF). For this purpose, folic acid-conjugated dextran-coated Zn0.6Mn0.4Fe2O4 (FA-Dex-ZMF) NPs were synthesized as smart nano heaters with self-regulating temperatures for MHT of liver tumors. Animal studies on BALB/c mice showed that the prepared NPs did not cause acute toxicity upon administration up to 100 mg kg-1. Likewise, no significant changes in hematological and biochemical factors were observed. FA-Dex-ZMF NPs were studied by exposing them to different safe AC magnetic fields (f = 150 kHz, H = 6, 8, and 10 kA m-1). Calorimetric experiments revealed that the NPs reached the desired temperature range (42-48 °C), which was suitable for MHT. Moreover, the efficacy of FA-Dex-ZMF NPs in MHT of liver tumors was investigated in vivo in liver-tumor-bearing mice. The obtained results revealed that the average volume of tumors in the control group increased 2.2 times during the study period. In contrast, the tumor volume remained almost constant during treatment in the MHT group. The results indicated that folic acid-conjugated dextran-coated Zn0.6Mn0.4Fe2O4 NPs with self-regulating temperature could be a promising tool for systemically delivered MHT.

Single-Cell Transcriptomics for Unlocking Personalized Cancer Immunotherapy: Toward Targeting the Origin of Tumor Development Immunogenicity.

Cancer immunotherapy is a promising approach for treating malignancies through the activation of anti-tumor immunity. However, the effectiveness and safety of immunotherapy can be limited by tumor complexity and heterogeneity, caused by the diverse molecular and cellular features of tumors and their microenvironments. Undifferentiated tumor cell niches, which we refer to as the "Origin of Tumor Development" (OTD) cellular population, are believed to be the source of these variations and cellular heterogeneity. From our perspective, the existence of distinct features within the OTD is expected to play a significant role in shaping the unique tumor characteristics observed in each patient. Single-cell transcriptomics is a high-resolution and high-throughput technique that provides insights into the genetic signatures of individual tumor cells, revealing mechanisms of tumor development, progression, and immune evasion. In this review, we explain how single-cell transcriptomics can be used to develop personalized cancer immunotherapy by identifying potential biomarkers and targets specific to each patient, such as immune checkpoint and tumor-infiltrating lymphocyte function, for targeting the OTD. Furthermore, in addition to offering a possible workflow, we discuss the future directions of, and perspectives on, single-cell transcriptomics, such as the development of powerful analytical tools and databases, that will aid in unlocking personalized cancer immunotherapy through the targeting of the patient's cellular OTD.

Breast tumor metastasis following filgrastim administration due to the SDF-1/CXCR4 pathway.

Filgrastim, a recombinant type of granulocyte-colony stimulating factor (G-CSF), has a high potential to manage chemotherapy-induced leukopenia. It can increase stromal cell-derived factor 1 (SDF-1) which may stimulate C-X-C chemokine receptor type 4 (CXCR4) to migrate bone marrow-derived stem/progenitor cells to the bloodstream. Here, we aimed to investigate in vitro and in vivo effects of filgrastim on cell migration, invasion, and metastasis. A lentivirus vector of the anti-CXCR4 receptor was first used for the CXCR4 knockout. Effects of filgrastim on cell proliferation and migration were then investigated on 4T1 cells by Transwell migration and wound healing assay. At last, the effects of filgrastim on cell metastasis and the possible involved mechanisms have been investigated in a metastatic murine breast tumor. The knockout of the CXCR4 receptor could lead to a decrease in cell proliferation, migration, and invasion of the 4T1 cells. Filgrastim could directly target SDF-1 and upregulate the expression of the CXCR4 receptor. The knockout of the CXCR4 receptor reduced cell metastasis in an animal model of breast cancer. CXCR4 receptor stimulation by the filgrastim-affected pathways is a conserved evolutionary response that could increase cancer cell proliferation and consequent cell metastasis. Our results suggest that the activation of the CXCR4 receptor is a conserved evolutionary response that can increase cell proliferation, migration, and consequent metastasis. It seems that filgrastim may increase the chance of cancer cell metastasis in people continuously receiving it to increase the number of neutrophils. Filgrastim induces the SDF-1/CXCR4 axis on tumor cell growth. SDF-1 and its receptor CXCR4 are vital targets for filgrastim. The CXCR4 can stimulate the PI3K/AKT, NF-κB, and JAK/STAT signaling pathways. The SDF-1/CXCR4 pathway promotes cell chemotaxis and proliferation via MAPKs signaling. It also enhances cell survival, proliferation, and angiogenesis, increasing tumor cell metastasis. The STAT3-mediated inflammation is essential for tumorigenesis processes, and Akt, Wnt, STAT3, and CXCR4 signaling pathways are all correlated. CXCR4 = C-X-C chemokine receptor type 4, SDF-1 = stromal-derived-factor-1, MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-κB, PI3K = phosphoinositide 3-kinase, JAK = Janus kinase, STAT = signal transducer and activator of transcription, PLC = phospholipase C, PKC = Protein kinase C, GRK = G protein-coupled receptor kinase.

Stem Cell Therapy in Limb Ischemia: State-of-Art, Perspective, and Possible Impacts of Endometrial-Derived Stem Cells.

As an evidence-based performance, the rising incidence of various ischemic disorders has been observed across many nations. As a result, there is a growing need for the development of more effective regenerative approaches that could serve as main therapeutic strategies for the treatment of these diseases. From a cellular perspective, promoted complex inflammatory mechanisms, after inhibition of organ blood flow, can lead to cell death in all tissue types. In this case, using the stem cell technology provides a safe and regenerative approach for ischemic tissue revascularization and functional cell formation. Limb ischemia (LI) is one of the most frequent ischemic disease types and has been shown to have a promising regenerative response through stem cell therapy based on several clinical trials. Bone marrow-derived mononuclear cells (BM-MNCs), peripheral blood CD34-positive mononuclear cells (CD34+ PB-MNCs), mesenchymal stem cells (MSCs), and endothelial stem/progenitor cells (ESPCs) are the main, well-examined stem cell types in these studies. Additionally, our investigations reveal that endometrial tissue can be considered a suitable candidate for isolating new safe, effective, and feasible multipotent stem cells for limb regeneration. In addition to other teams' results, our in-depth studies on endometrial-derived stem cells (EnSCs) have shown that these cells have translational potential for limb ischemia treatment. The EnSCs are able to generate diverse types of cells which are essential for limb reconstruction, including endothelial cells, smooth muscle cells, muscle cells, and even peripheral nervous system populations. Hence, the main object of this review is to present stem cell technology and evaluate its method of regeneration in ischemic limb tissue.

Layered dermal reconstitution through epigallocatechin 3-gallate loaded chitosan nanoparticle within enzymatically crosslinked polyvinyl alcohol/collagen fibrous mat.

Biocompatible electrospun fiber comprising bioactive substrates has potential to implant into the wound site as a reliable therapeutic approach in tissue regeneration. Here, electrospun polyvinyl alcohol conjugated tyramine (PVA-Tyr) and collagen (Col) fibrous mat containing chitosan nanoparticle loaded with epigallocatechin 3-gallate (NCs-EGCG) developed and the composite was applied to evaluate in vivo wound healing ability of fabricated wound patch. The synthesized PVA-Tyr and Col were electrospun and crosslinked through peroxidase reaction in presence of vaporized H2O2 as an electron donor which covalently proceeded conjugation of phenolic groups and could develop hybrid fibrous mat in stable structure and uniform shapes. The EGCG as anti-oxidative/inflammatory substrate was encapsulated efficiently in NCs and released in a sustained manner. The hybrid fibers seeded with adipose-derived stem cells presented appropriate biocompatibility from biophysical and biochemical viewpoints and in following wound healing ability in a full-thickness excisional animal model. Fourier transform infrared spectroscopy (FTIR) confirmed all typical absorption characteristics of PVA-Tyr and Col as well as NCs and EGCG. The results showed the perfect hydrophilic/hydrophobic ratio and good mechanical and structural characteristics including shape uniformity and porosity. Interestingly, cellular attachment and proliferation on the PVA-Tyr/Col fibers containing NCs-EGCG were higher than control samples. The histological analysis of hybrid fibrous patch could be suggested the applicability of this structure as suitable skin substitutes to repair injured skin.

Dual effects of atorvastatin on angiogenesis pathways in the differentiation of mesenchymal stem cells.

Atorvastatin (ATO) can improve the transplantation efficacy of mesenchymal stem cells (MSCs) after acute myocardial infarction. The present study aimed at ATO effects on the angiogenesis-signaling pathways from MSCs' differentiation to tissue angiogenesis. MSCs were first prepared from BALB/c mouse bone marrow. MTT assay was then done for the biodegradability of MSCs with the extracellular matrix. After that, the differentiation of cells into the bone and fat tissues was confirmed by Alizarin and Oil Red O staining. The extracellular matrix was then combined with the cells to the implant. Animals were intraperitoneally treated with ATO (2 and 40 mg/kg, daily) three days before cell transplantation to one week after. Finally, the assays were carried out by electron microscopy, immunocytochemistry, ELISA, Western blot, and RT-qPCR techniques. A phase-contrast microscope confirmed the morphology of cells. The cell differentiation into bone and fat tissues was confirmed by Alizarin red staining and flow cytometry, and the cell proliferation was confirmed by MTT assay. Unlike ATO 40 mg/kg group, ATO 2 mg/kg was significantly increased the CD31, eNOS, podocalyxin, von Willibrand factor, and alpha-smooth muscle actin proteins levels compared to the control group in vitro experiment. The expression of CD31 and VEGF proteins, as angiogenesis markers, and Ki-67 protein, as a proliferation marker, was significantly higher in a low dose of ATO (2 mg/kg) than that of the control group in vivo experiment. Unlike ATO 40 mg/kg, the expression levels of ERK, AKT, NF-ҝB, Rho, STAT3, Ets-1, HIF-1α, and VEGF proteins and genes were significantly increased in ATO 2 mg/kg compared to the control. A low dose of ATO can be a beneficial tool in the function of MSCs and their differentiation to tissue angiogenesis.

Stem cells-derived natural killer cells for cancer immunotherapy: current protocols, feasibility, and benefits of ex vivo generated natural killer cells in treatment of advanced solid tumors.

Nowadays, natural killer (NK) cell-based immunotherapy provides a practical therapeutic strategy for patients with advanced solid tumors (STs). This approach is adaptively conducted by the autologous and identical NK cells after in vitro expansion and overnight activation. However, the NK cell-based cancer immunotherapy has been faced with some fundamental and technical limitations. Moreover, the desirable outcomes of the NK cell therapy may not be achieved due to the complex tumor microenvironment by inhibition of intra-tumoral polarization and cytotoxicity of implanted NK cells. Currently, stem cells (SCs) technology provides a powerful opportunity to generate more effective and universal sources of the NK cells. Till now, several strategies have been developed to differentiate types of the pluripotent and adult SCs into the mature NK cells, with both feeder layer-dependent and/or feeder laye-free strategies. Higher cytokine production and intra-tumoral polarization capabilities as well as stronger anti-tumor properties are the main features of these SCs-derived NK cells. The present review article focuses on the principal barriers through the conventional NK cell immunotherapies for patients with advanced STs. It also provides a comprehensive resource of protocols regarding the generation of SCs-derived NK cells in an ex vivo condition.

Role of oxytocin and c-Myc pathway in cardiac remodeling in neonatal rats undergoing cardiac apical resection.

Oxytocin (OT) is a nonapeptide hormone that can improve cardiomyocyte proliferation, suggesting a potential heart regeneration function. Here, we investigated the role of oxytocin and the c-Myc pathway in cardiac remodeling in neonatal rats undergoing cardiac apical resection. We have utilized a knockout of oxytocin receptor (OTR) with OTR-shRNA. A neonatal rat model of cardiac resection (≈10%-15%) was first established. The protein levels of OTR and c-Myc and the expression of cyclin d1 and c-Myc genes were then evaluated in the cardiac tissues at 1, 7, and 21 days after cardiac resection. We also analyzed the proliferation of cardiomyocytes through α-actinin, BrdU, and ki-67 markers. At last, the hemodynamic and electrophysiologic functions were evaluated eight weeks after cardiac resection. At 21 days, the regeneration of cardiomyocytes was repaired among rats in the control and resection groups, while OTR-shRNA groups were failed to improve. Inhibition of OTR failed cardiac regeneration and reduced the number of proliferating cardiomyocytes. The c-Myc protein was significantly reduced in the OTR-shRNA injection hearts. Moreover, we have severely found a depressed heart function in the OTR-shRNA injection animals. These observations revealed that the OT must improve cardiac remodeling in neonatal rat hearts by regulating the c-Myc pathway.

Regulation of Long Non-Coding RNAs by Plant Secondary Metabolites: A Novel Anticancer Therapeutic Approach.

Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs that play an essential role in various cellular activities, such as differentiation, proliferation, and apoptosis. Dysregulation of lncRNAs serves a fundamental role in the progression and initiation of various diseases, including cancer. Precision medicine is a suitable and optimal treatment method for cancer so that based on each patient's genetic content, a specific treatment or drug is prescribed. The rapid advancement of science and technology in recent years has led to many successes in this particular treatment. Phytochemicals are a group of natural compounds extracted from fruits, vegetables, and plants. Through the downregulation of oncogenic lncRNAs or upregulation of tumor suppressor lncRNAs, these bioactive compounds can inhibit metastasis, proliferation, invasion, migration, and cancer cells. These natural products can be a novel and alternative strategy for cancer treatment and improve tumor cells' sensitivity to standard adjuvant therapies. This review will discuss the antineoplastic effects of bioactive plant secondary metabolites (phytochemicals) via regulation of expression of lncRNAs in various human cancers and their potential for the treatment and prevention of human cancers.

Gamma-radiated immunosuppressed tumor xenograft mice can be a new ideal model in cancer research.

Tumor xenograft models can create a high capacity to study human tumors and discover efficient therapeutic approaches. Here, we aimed to develop the gamma-radiated immunosuppressed (GIS) mice as a new kind of tumor xenograft model for biomedical studies. First, 144 mice were divided into the control and treated groups exposed by a medical Cobalt-60 apparatus in 3, 4, and 5 Gy based on the system outputs. Then, 144 BALB/c mice were divided into four groups; healthy, xenograft, radiation, and radiation + xenograft groups. The animals in the xenograft and radiation + xenograft groups have subcutaneously received 3 × 106 MCF-7 cells 24 h post-radiation. On 3, 7, 14, and 21 days after cell injection, the animals were sacrificed. Then, the blood samples and the spleen and tumor tissues were removed for the cellular and molecular analyses. The whole-body gamma radiation had a high immunosuppressive effect on the BALB/c mice from 1 to 21 days post-radiation. The macroscopic and histopathological observations have proved that the created clusters' tumor structure resulted in the xenograft breast tumor. There was a significant increase in tumor size after cell injection until the end of the study. Except for Treg, the spleen level of CD4, CD8, CD19, and Ly6G was significantly decreased in Xen + Rad compared to the Xen alone group on 3 and 7 days. Unlike IL-4 and IL-10, the spleen level of TGF-ß, INF-γ, IL-12, and IL-17 was considerably decreased in the Xen + Rad than the Xen alone group on 3 and 7 days. The spleen expressions of the VEGF, Ki67, and Bax/Bcl-2 ratio were dramatically increased in the Xen + Rad group compared to the Xen alone on 3, 7, 14, and 21 days. Our results could confirm a new tumor xenograft model via an efficient immune-suppressive potential of the whole-body gamma radiation in mice.

Simultaneous impact of atorvastatin and mesenchymal stem cells for glioblastoma multiform suppression in rat glioblastoma multiform model.

Glioblastoma multiform (GBM) is known as an aggressive glial neoplasm. Recently incorporation of mesenchymal stem cells with anti-tumor drugs have been used due to lack of immunological responses and their easy accessibility. In this study, we have investigated the anti-proliferative and apoptotic activity of atorvastatin (Ator) in combination of mesenchymal stem cells (MSCs) on GBM cells in vitro and in vivo. The MSCs isolated from rats and characterized for their multi-potency features. The anti-proliferative and migration inhibition of Ator and MSCs were evaluated by MTT and scratch migration assays. The annexin/PI percentage and cell cycle arrest of treated C6 cells were evaluated until 72 h incubation. The animal model was established via injection of C6 cells in the brain of rats and subsequent injection of Ator each 3 days and single injection of MSCs until 12 days. The growth rate, migrational phenotype and cell cycle progression of C6 cells decreased and inhibited by the interplay of different factors in the presence of Ator and MSCs. The effect of Ator and MSCs on animal models displayed a significant reduction in tumor size and weight. Furthermore, histopathology evaluation proved low hypercellularity and mitosis index as well as mild invasive tumor cells for perivascular cuffing without pseudopalisading necrosis and small delicate vessels in Ator + MSCs condition. In summary, Ator and MSCs delivery to GBM model provides an effective strategy for targeted therapy of brain tumor.

Effects of multiple injections on the efficacy and cytotoxicity of folate-targeted magnetite nanoparticles as theranostic agents for MRI detection and magnetic hyperthermia therapy of tumor cells.

Folate-targeted iron oxide nanoparticles (FA@Fe3O4 NPs) were prepared by a one-pot hydrothermal method and then used as cancer theranostic agents by combining magnetic resonance imaging (MRI) and magnetic hyperthermia therapy (MHT). Crystal structure, morphology, magnetic properties, surface functional group, and heating efficacy of the synthesized nanoparticles were characterized by XRD, TEM, VSM, FTIR, and hyperthermia analyses. The results indicated that the crystal structure, magnetic properties, and heating efficacy of the magnetite nanoparticles were improved by hydrothermal treatment. Toxicity of the prepared NPs was assessed in vitro and in vivo on the mammary cells and BALB/c mice, respectively. The results of the in vitro toxicity analysis showed that the FA@Fe3O4 NPs are relatively safe even at high concentrations of the NPs up to 1000 µg mL-1. Also, the targetability of the FA@Fe3O4 NPs for the detection of folate over-expressed cancer cells was evaluated in an animal model of breast tumor using MRI analysis. It was observed that T2-weighted magnetic resonance signal intensity was decreased with the three-time injection of the FA@Fe3O4 NPs with 24 h interval at a safe dose (50 mg kg-1), indicating the accumulation and retention of the NPs within the tumor tissues. Moreover, the therapeutic efficacy of the MHT using the FA@Fe3O4 NPs was evaluated in vivo in breast tumor-bearing mice. Hyperthermia treatment was carried out under a safe alternating magnetic field permissible for magnetic hyperthermia treatment (f = 150 kHz, H = 12.5 mT). The therapeutic effects of the MHT were evaluated by monitoring the tumor volume during the treatment period. The results showed that the mice in the control group experienced an almost 3.5-fold increase in the tumor volume during 15 days, while, the mice in the MHT group had a mild increase in the tumor volume (1.8-fold) within the same period (P < 0.05). These outcomes give promise that FA@Fe3O4 NPs can be used as theranostic agents for the MRI and MHT applications.

Inflammatory Microenvironment of Acute Myocardial Infarction Prevents Regeneration of Heart with Stem Cells Therapy.

Over the past years, the benefits of stem cell therapy approach for treatment of the cardiovascular diseases have been shown through the rebuilding of new cardiomyocytes and blood vessels. while a successful regeneration of the myocardium has been proven on the animal models of acute myocardial injuries resulted from the stem cells transplantation, no significant long-term regenerative with autologous stem cell therapy in patients with acute myocardial infarction have been reported based on recent meta-analyses. It seems that the inflammatory microenvironment of acute myocardial infarction has an inhibitory effect on the stem cells potential for regenerating the injured myocardium. Secretion of critical cytokines with pro-inflammatory properties including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 as well as induction of hypoxic condition and finally formation of cytotoxic elements cause the cellular death and hinder the stem cells proliferation and differentiation. Based on the evidence, application of some approaches like co-delivery of mesenchymal stem cells with the other useful cells, using the stem cells derived productions, administration of preconditioned and modified cells, and also using the anti-inflammatory agents besides the cell therapy are hypothesized as the primary developed safe and practical approaches for decreasing destructive effects of the inflammation on the implanted stem/progenitor cells. In this review, we critically discuss the quiddity of the inflammatory microenvironment and its promoted mechanisms as the main elements to hinder the efficacy of stem cell therapy in the cases of acute myocardial infarction. Also, we finally propose some applied solutions to the problem of cardiac regeneration with stem cells therapy.

Rolipram optimizes therapeutic effect of bevacizumab by enhancing proapoptotic, antiproliferative signals in a glioblastoma heterotopic model.

The unstable response to bevacizumab is a big dilemma in the antiangiogenic therapy of high-grade glioma that appears to be linked to an increase in the post-treatment intratumor levels of hypoxia-inducible factor 1 α (HIF1α) and active AKT. Particularly, a selective phosphodiesterase IV (PDE4) inhibitor, rolipram is capable of inhibiting HIF1α and AKT in cancer cells. Here, the effect of bevacizumab alone and in presence of rolipram on therapeutic efficacy, intratumor hypoxia levels, angiogenesis, apoptosis and proliferation mechanisms were evaluated. BALB/c mice bearing C6 glioma were received bevacizumab and rolipram either alone or combined for 30 days (n = 11/group). At the last day of treatments, apoptosis, proliferation and microvessel density, in xenografts (3/group) were detected by TUNEL staining, Ki67 and CD31 markers, respectively. Relative expression of target proteins was measured using western blotting. Bevacizumab initially hindered the tumor progression but its antitumor effect was weakened later despite the vascular regression and apoptosis induction. Unpredictably, bevacizumab-treated tumors exhibited the highest cell proliferation coupled with PDE4A, HIF1α and AKT upregulation and p53 downregulation and reversed by co-treatment with rolipram. Unlike a similar antivascular pattern to bevacizumab, rolipram consistently led to a more tumor growth suppression and proapoptotic effect versus bevacizumab. Co-treatment maximally hampered the tumor progression and elongated survival along with the major vascular regression, hypoxia, apoptosis induction, p53 and caspase activities. In conclusion, superior and persistent therapeutic efficacy of co-treatment provides a new insight into antiangiogenic therapy of malignant gliomas, suggesting to be a potential substitute in selected patients.

Application of Stem Cell Technologies to Regenerate Injured Myocardium and Improve Cardiac Function.

In the recent decades, cardiovascular diseases emerged as the major leading cause of human mortality. However, current clinical approaches still do not encompass a thorough therapeutic solution for improving heart function of the patients who suffered an extensive myocardial injury. Based on this status quo, stem cells could become a novel option, as a natural source of the new myocardium lineage cells, being capable of paracrine factors secretion, protection or even regeneration of the damaged heart muscle. Efficient stem cell-based therapy of the heart should lead to repair or/and replacement of the degenerated tissue with functional myocardial and endothelial cells. Hereon, various types of pluripotent and multipotent stem cells have been already studied in the pre-clinical and clinical settings, demonstrating their cardiomyogenic and regenerative potential. In this context, as a type of male adult stem/ progenitors, spermatogonial stem cells feature a remarkable ability for a formation of cardiovascular lineages, based on our own observations. Presented data supports the presumption, that spermatogonial stem cells not only have a suitable capacity to generate functional heart cells but can also potentially improve the function of an injured myocardium. In this review article, we first describe the essential molecular and pathophysiological mechanisms involved in the heart tissue injury. Afterwards, based on our ongoing study, we review the impact of the stem cell technologies on the regeneration therapy in cardiovascular and myocardial diseases. Particular emphasis is being put on the usability of spermatogonial stem cells in cardiac therapy.

The toxicity and therapeutic effects of single-and multi-wall carbon nanotubes on mice breast cancer.

Herein, we have investigated the toxicity of SWCNTs and MWCNTs in vitro and in vivo, and assessed their therapeutic effects on a typical animal model of breast cancer in order to obtain: first, the cytotoxicity effects of CNTs on MC4L2 cell and mice, second the impact of CNTs on ablation of breast tumor. CNTs especially SWCNTs were toxic to organs and induced death at high dosages. In this case, some of the liver cells showed a relative shrinkage which was also confirmed by Annexin test in MC4L2 cells. Moreover, CNTs decreased the tumor volume. BCL2 gene was down-regulated, and BAX and Caspase-3 were also up-regulated in the treated groups with CNTs. As a result, CNTs especially MWCNT in lower dosages can be used as a promising drug delivery vehicle for targeted therapy of abnormal cells in breast cancer.

Acute Toxicity Evaluation of Glycosylated Gd3+-Based Silica Nanoprobe.

PURPOSE: Early stage diseases diagnosed using magnetic resonance imaging (MRI) techniques is of high global interest as a potent noninvasive modality. MRI contrast agents are improved through modifications in structural and physicochemical properties of the applied nanoprobes. But, the potential toxic effects of nanoprobes upon exposure to biological systems are still a major concern. PROCEDURE: In this study, the acute toxicity of glycosylated Gd3+-based silica mesoporous nanospheres (GSNs) as a MRI contrast agent was evaluated in Balb/c mice. In order to evaluate in vivo toxicity of GSN, preclinical studies, daily weight monitoring, hematological/blood chemistry tests, and histological assessment were conducted. Magnetic resonance relaxivities of GSN was determined using a MRI scanner. RESULTS: The obtained results suggest that in vivo toxicity of GSN was mostly influenced by nanoparticle surface area, functionality, and nanoparticle zeta potential. The maximum tolerated dose (MTD) increased in the following order: mesoporous silica nanospheres (MSNs) at 1 mg/mice < GSN (aspect ratio 1, 2, 8) at 40 mg/mice. The results also indicate GSN, one of the best cell imaging contrast agent, which does not show any significant toxicity on multiple vital organs following injection of 20 mg/mice, while a significant T1-weighted enhancement was observed in whole body of a Balb/c mice 15 min postinjection of (5 µmol/kg) of body weight of GSN. CONCLUSIONS: These results shed light on the functionality of MSNs to minimize in vivo toxicity. Also, glyconanoprobe can be beneficially used for nanomedicine and cellular imaging applications without any significant toxicity.