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Alzheimer's disease is a progressive and age-related neurodegenerative disorder that is manifested by neuropathological changes and clinical symptoms. Recently, cell-based therapeutic interventions have been considered as the promising and effective strategies in this field. Herein, we investigated therapeutic effects of neural stem cell secretome on Alzheimer's disease-like model by triggering of Wnt/β-catenin signaling pathway. In this study, mice were randomly allocated into three different groups as follows: Control, AD + Vehicle, and AD + NSCs-CM groups. To induce mouse model of AD, Aβ1-42 was injected into intracerebroventricular region. Following AD-like confirmation through thioflavin S staining and Passive avoidance test, about 5 µl mouse NSCs-CM was injected into the target areas 21 days after AD induction. For evaluation of endogenous proliferation rate (BrdU/Nestin

The combination of nanotechnology and stem cell biology is one of the most promising advances in the field of regenerative medicine. This novel combination has widely been utilized in vitro settings in an attempt to develop efficient therapeutic strategies to overcome the limited capacity of the central nervous system (CNS) in replacing degenerating neural cells with functionally normal cells after the onset of acute and chronic neurological disorders. Importantly, biomaterials, not only, enhance the endogenous CNS neurogenesis and plasticity, but also, could provide a desirable supportive microenvironment to harness the full potential of the in vitro expanded neural stem cells (NSCs) for regenerative purposes. Here, first, we discuss how the physical and biochemical properties of biomaterials, such as their stiffness and elasticity, could influence the behavior of NSCs. Then, since the NSCs niche or microenvironment is of fundamental importance in controlling the dynamic destiny of NSCs such as their quiescent and proliferative states, topographical effects of surface diversity in biomaterials, that is, the micro-and nano-patterned surfaces will be discussed in detail. Finally, the influence of biomaterials as artificial microenvironments on the behavior of NSCs through the specific mechanotransduction signaling pathway mediated by focal adhesion formation will be reviewed.

Purpose: Spinal cord injury (SCI) is damage to the spinal cord that resulted in irreversible neuronal loss, glial scar formation and axonal injury. Herein, we used the human amniotic fluid mesenchymal stem cells (hAF-MSCs) and their conditioned medium (CM), to investigate their ability in neuroblast and astrocyte production as well as functional recovery following SCI. Methods: Fifty-four adult rats were randomly divided into nine groups (n=6), included: Control, SCI, (SCI + DMEM), (SCI + CM), (SCI + MSCs), (SCI + Astrocyte), (SCI + Astrocyte+ DMEM), (SCI + Astrocyte+ CM) and (SCI + Astrocyte+ MSCs). Following laminectomy and SCI induction, DMEM, CM, MSCs, and Astrocytes were injected. Wester-blot was performed to explore the levels of the Sox2 protein in the MSCs-CM. The immunofluorescence staining against DCX and GFAP was done. Finally, Basso-Beattie-Brenham (BBB) locomotor test was conducted to assess the neurological outcomes. Results: Our results showed that the MSCs increased the number of endogenous DCX-positive cells and decreased the number of GFAP-positive cells by mediating juxtacrine and paracrine mechanisms (p

This study investigated physical proximity and paracrine activity of neurotrophic factor-secreting cells (NTF-SCs) on beta-amyloid treated cells. Mesenchymal stem cells (MSCs) - to-NTF-SCs (Astrocyte -like cells) trans-differentiation was confirmed using immunofluorescence staining of GFAP. BDNF and NGF levels were measured by ELISA. To mimic AD-like condition, SH-SY5Y cells were exposed to 10 μM Aβ1-42. SH-SY5Y cells were allocated into Control; and Aβ1-42-treated cells. Treated cells were further classified into three subgroups including Aβ1-42 cells, Aβ1-42 cells + NTF-SCs (CM) and Aβ1-42 cells + NTF-SCs co-culture. Cell viability was measured by MTT assay. Anti-inflammatory and anti-tau hyperphosphorylation effects of NTF-SCs were assessed via monitoring TNF-α and hyperphosphorylated Tau protein expression level respectively. To explore the impact of NTF-SCs on synaptogenesis and synaptic functionality, real-time PCR assay was performed to measure the expression of synapsine 1, homer 1 and ZIF268. The level of synaptophysin was monitored via immunofluorescence staining. Data showed MSCs potential in trans-differentiating toward NTF-SCs indicated with enhanced GFAP expression (p 0.05). ELISA assay confirmed the superiority of NTF-SCs in releasing NGF and BDNF compared to the MSCs (p 0.05). Aβ significantly induced SH-SY5Y cells death while juxtacrine and paracrine activity of NTF-SCs significantly blunted these conditions (p 0.05). Trans-differentiated cells had potential to reduce Tau hyperphosphorylation and TNF-α level after treatment with Aβ through juxtacrine and paracrine mechanisms (p 0.05). Moreover, NTF-SCs significantly increased the expression rate of synapsin 1, homer 1 and zif 268 genes in Aβ-treated cells compared to matched-control group coincided with induction of synaptophysin at the protein level(p 0.05). NTF-SCs reversed AD-like neuropathological alterations in SH-SY5Y cells via paracrine and juxtacrine mechanisms.

Despite the poor regenerative capacity of the adult central nervous system (CNS) in mammals, two distinct regions, subventricular zone (SVZ) and the subgranular zone (SGZ), continue to generate new functional neurons throughout life which integrate into the pre-existing neuronal circuitry. This process is not fixed but highly modulated, revealing many intrinsic and extrinsic mechanisms by which this performance can be optimized for a given environment. The capacity for self-renewal, proliferation, migration, and multi-lineage potency of neural stem cells (NSCs) underlines the necessity of controlling stem cell fate. In this context, the native and local microenvironment plays a critical role, and the application of this highly organized architecture in the CNS has been considered as a fundamental concept in the generation of new effective therapeutic strategies in tissue engineering approaches. The brain extracellular matrix (ECM) is composed of biomacromolecules, including glycosaminoglycans, proteoglycans, and glycoproteins that provide various biological actions through biophysical and biochemical signaling pathways. Herein, we review predominantly the structure and function of the mentioned ECM composition and their regulatory impact on multiple and diversity of biological functions, including neural regeneration, survival, migration, differentiation, and final destiny of NSCs.

Known as a main neural MAP (microtubule associated protein), tau protein contributes to stabilizing microtubules involved in cellular transmission. Tau dysfunction is mainly associated with neurodegenerative diseases, particularly Alzheimer's disease (AD). In these patients, all the six tau isoforms, which are in hyperphosphorylated form, are first aggregated and then polymerized into neurofibrillary tangles inside the brain. Tau protein detected in cerebrospinal fluid (CSF) is significantly correlated with AD and is well recognized as a hallmark of the disease. Served for detection of analytes of interest, biosensor device comprises a physical transducer and a keen biological recognition component. Qualitative and quantitative evaluations may be performed through analyzation of the data, which is gathered by measurable signals converted from biological reaction. Antibodies, receptors, microorganisms, nucleic acids, enzymes, cells and tissues, as well as some biomimetic structures, normally constitute the biosensor biological recognition part. Production of nanobiosensor, which was made possible through several accomplishments in nano- and fabrication technology, opens up new biotechnological horizons in diagnosis of multiple diseases. In recent years, many researches have been focused on developing novel and effective tau protein biosensors for rapid and accurate detection of AD. In this review, tau protein function and correlation with AD as well as the eminent research on developing nanobiosensor based on optical, electrochemical and piezoelectric approaches will be highlighted.

Cognitive deficits due to spinal cord injury (SCI) have been elucidated in both animals and humans with SCI. Such disorders may cause concomitant oscillatory changes in regions of the brain involving in cognition; a subject that has not been directed mechanistically. One of the crucial oscillations, having a prominent role in cognition, particularly spatial memory, is hippocampal theta rhythm. Our research revealed that SCI could induce changes not only in the neurogenesis and apoptosis rate of the hippocampus but also in theta power as well as receptors involving in the generation of this rhythm. Herein we used 24 male Wistar rats (Sham/SCI = 12) and examined the effect of spinal cord contusion on hippocampal theta rhythm, spatial memory, and neurodegeneration. We proved that SCI eliminates hippocampus-dependent theta power through spatial working memory, and correlates significantly with neurodegeneration and expression of receptors (NMDA, GABAA, Muscarinic1/M1), which are in turn essential in generation of theta rhythm. The immunohistochemistry analysis also demonstrated a significant decrease in DCX+ and BrdU+ cells; however, according to TUNEL assay, apoptosis is significantly higher in SCI-induced animals. The western blotting analysis further showed a significant reduction of the abovementioned receptors in the hippocampus. We also verified that SCI impairs the spatial memory, proved by poor performance in the Y-maze task. As well as, based on the local field potential recordings analysis, SCI decreases the power of theta rhythm. Eventually, this study demonstrated that chronic brain neurodegeneration occurs after SCI accompanied by theta rhythm and cognitive deficiency.

The integrity of the structural cerebral cortex is disrupted after stroke either at the macroscopic or microscopic levels. Therefore, many attempts have been gathered to circumvent stroke-associated problems in the brain tissue. The current study was aimed to design an animal model of photochemical stroke using rose bengal (RB) plus laser irradiation (L) after 10, 15, and 20 min (´) and evaluate its effect on the cerebral tissue using unbiased stereological quantitative methods and morphometric histological analysis. Photochemical stroke was induced by intraperitoneal injection of RB dye and further activation through the exposure of the right sensorimotor cortex with the green laser radiation (100 mW; 532 nm). Mice were randomly allocated into 4 groups (each in 15) as follows: control (10 μg/gbw RB), RB + 10’L, RB + 15’L, and RB + 20’L. Target irradiation site was adjusted to 2 mm lateral to the bregma. Vernier caliper morphometric evaluation, cresyl violet staining, and unbiased stereological assays including Cavalier’s principle and point counting techniques were used to monitor the pathological changes and lesion volume on days 1, 3, and 7 after the ischemia induction. Our data showed that the mean diameter of the lesion site and lesion infarct volume in the group RB + 20’L) was significantly increased relative to the other groups (P

Exo are natural nano-sized vesicles with an endosomal origin that maintain cell-to-cell communications in a paracrine manner. Owing to their physicochemical properties, Exo transfer various types of bioactive metabolites from origin cells to the recipient cells, resulting in induction/inhibition of specific signaling pathways. Like different tissues, Exo are indispensable for the function of neural cells inside the brain parenchyma. Various aspects such as neurogenesis, microglial polarization, and angiogenesis are closely associated with the reciprocal interchanges of Exo between cells in a tightly regulated manner. Similar to physiological conditions, these particles can affect the progression of inflammatory responses following the onset of pathologies. The existence of several uptake exosomal mechanisms, such as receptor-mediated endocytosis, and high penetration capacity into the deep layers of the brain makes Exo promising bio-shuttles for the alleviation of pathological conditions. Like astrocytes, stem cells can release Exo into the surrounding niche with neuroprotective properties regenerative potential. Whether and how Exo can initiate the essential signals required for neurogenesis has not been fully understood. In this review, we will try to elaborate on the putative therapeutic role of Exo in the dynamic activity of neuronal cells.

Ischemic stroke is characterized by extensive neuronal loss, glial scar formation, neural tissue degeneration that leading to profound changes in the extracellular matrix, neuronal circuitry, and long‐lasting functional disabilities. Although transplanted neural stem cells (NSCs) can recover some of the functional deficit after stroke, retrieval is not complete and repair of lost tissue is negligible. Therefore, the current challenge is to use the combination of NSCs with suitably enriched biomaterials to retain these cells within the infarct cavity and accelerate the formation of a de novo tissue. This study aimed to test the regenerative potential of polylactic‐co‐glycolic acid‐polyethylene glycol (PLGA‐PEG) micelle biomaterial enriched with Reelin and embryonic NSCs on photothrombotic stroke model of mice to gain appropriate methods in tissue engineering. For this purpose, two sets of experiments, either in vitro or in vivo models, were performed. In vitro analyses exhibited PLGA‐PEG plus Reelin‐induced proliferation rate (Ki‐67+ NSCs) and neurite outgrowth (axonization and dendritization) compared to PLGA‐PEG + NSCs and Reelin + NSCs groups (p

Dysfunction in mitochondrial activity may have profound role in ischemic stroke-induced neuronal death, hence maintaining the mitochondrial function seems to be valuable for neuronal viability and neurological improvement.C57BL/6J mice were allocated into sham and stroke groups. Mice in the stroke groups underwent photothrombosis-induced stroke in the medial prefrontal cortex (mPFC) and were divided into the following subgroups; RB, Mito 85, Mito 170, and Mito 340, and received their respective treatments via intra-nasal route every other day (3 days per week) for one week. A battery of behavioral tests including social interaction, passive avoidance, and the Lashley III maze was used to investigate social, contextual, and spatial memories. Moreover, changes in mitochondrial function, including reactive oxygen species (ROS) and ATP levels, and mitochondrial membrane potential, were assessed in mPFC. The expression of growth-associated protein 43 (GAP-43), post-synaptic density-95 (PSD-95), and synaptophysin (SYP) was detected by western blotting.Behavioral results revealed that mitotherapy alleviated ischemia-induced memory impairment. Also, transplantation of exogenous mitochondria lowered ROS, restored ATP generation, and improved mitochondrial membrane potential. Induction of ischemia decreased the levels of synaptic markers in mPFC while exogenous mitochondria (170 and 340µg) significantly upregulated the expression of GAP-43 and PSD-95 after ischemic stroke.Our research highlighted the importance of mitotherapy in regulating synaptic markers expression and mitochondria function, which could represent a potential strategy for improving cognitive and memory deficits following stroke.

During the last decades, numerous basic and clinical studies have been conducted to assess the delivery efficiency of therapeutic agents into the brain and spinal cord parenchyma using several administration routes. Among conventional and in-progress administrative routes, the eligibility of stem cells, viral vectors, and biomaterial systems have been shown in the delivery of NTFs. Despite these manifold advances, the close association between the delivery system and regeneration outcome remains unclear. Herein, we aimed to discuss recent progress in the delivery of these factors and the pros and cons related to each modality.

Background: Photothrombotic (PT) stroke model is a novel method to induce ischemic stroke in the target site using excitation of photosensitive agents such as Rose Bengal (RB) dye after light illumination. Here, we performed a PT-induced brain ischemic model using green laser and photosensitive agent RB and confirmed its efficiency through cellular, histological and neurobehavioral approaches.Methods: Mice were randomly allocated into RB; Laser irradiation; and RB + Laser irradiation groups. Mice were exposed to green laser at a wavelength of 532 nm and intensity 150 mW in a mouse model after injection of RB under stereotactic surgery. The pattern of Hemorrhagic and ischemic changes were evaluated throughout the study. The volume of the lesion site was calculated using unbiased stereological methods. For investigation of neurogenesis, we performed double - (BrdU/NeuN) immunofluorescence (IF) staining on day 28 following the last- BrdU injection. To assess the effect and quality of ischemic stroke on neurological behavior, the Modified neurological severity score (mNSS) test was done on days 1, 7, 14, and 28 days after stroke induction.Results: Laser irradiation plus RB induced hemorrhagic tissue and pale ischemic changes over the 5 days. On the next days, microscopic staining revealed neural tissue degeneration, demarcated necrotic site, and neuronal injury. BrdU staining showed a significant number of proliferating cells in the periphery of the lesion site in the Laser irradiation plus RB group compared to the group (pConclusion: Our study revealed that the PT could induce neuropathological alterations and neurobehavioral deficits. Moreover, our findings indicated that the undesirable microenvironment and inflammatory conditions could affect the neurogenesis concomitantly with functional deficits. Taken together, this method of PT introduces a focal, reproducible, noninvasive and accessible stroke model with a distinctive demarcation similar to human stroke conditions.

DNA methylation, as an epigenetic mechanism, occurs by adding a methyl group of cytosines in position 5 by DNA methyltransferases and has essential roles in cellular function, especially in the transcriptional regulation of embryonic and adult stem cells. Hypomethylation and hypermethylation cause either the expression or inhibition of genes, and there is a tight balance between regulating the activation or repression of genes in normal cellular activity. Abnormal methylation is well-known hallmark of cancer development and progression and can switch normal stem cells into cancer stem cells. Cancer Stem Cells (CSCs) are minor populations of tumor cells that exhibit unique properties such as self-regeneration, resistance to chemotherapy, and high ability of metastasis. The purpose of this paper is to show how aberrant DNA methylation accumulation affects self-renewal, differentiation, multidrug-resistant, and metastasis processes in cancer stem cells.

Direct astrocyte reprogramming to neural progenitor cells and promotion of neurogenesis is considered as an alternative approach to replace the lost neurons in the spinal cord injury(SCI). Herein, we used the human amniotic fluid mesenchymal stem cells (hAF-MSCs) and their conditioned medium (CM), to investigating their ability to reprogramming astrocytes to neuroblasts following SCI. 54 adult rats were randomly divided into 9 groups (n = 6), included: Control, SCI, (SCI + DMEM), (SCI + CM), (SCI + MSCs), (SCI + Astrocyte), (SCI + Astrocyte + DMEM), (SCI + Astrocyte + CM) and SCI + Astrocyte + MSCs). Following laminectomy and SCI induction, DMEM, CM, MSCs and Astrocytes were injected. Wester-blot was performed to explore the levels of the Sox2 protein in the MSCs-CM. The immunofluorescence staining against DCX and GFAP was done. Finally, Basso-Beattie-Brenham (BBB) locomotor test was conducted to assess the neurological outcomes. Our results showed that the MSCs through juxtacrine and paracrine mechanisms induced the promotion of the endogenous neuroblasts and the decline of astrocytes. Moreover, in the present research, MSCs and CM could convert the transplanted human astrocytes to neuroblasts in the spinal cord injury. Taken together, our data indicate the MSCs via juxtacrine and paracrine pathways could direct the spinal cord endogenous neural stem cells(NSCs) to the neuroblasts lineage rather than astrocytes as well as induce reprogramming. Ultimately, MSCs could reverse the neurobehavioral deficit in the SCI. The striking output in our study was the capability of the MSCs in the reprogramming of the astrocytes to neuroblasts via juxtacrine and paracrine pathways in the In-vivo condition.

One of the most important natural extracellular constituents is hyaluronic acid (HA) with the potential to develop a highly organized microenvironment. In the present study, we enriched HA hydrogel with tenascin-C (TN-C) and examined the viability and survival of mouse neural stem cells (NSCs) using different biological assays. Following NSCs isolation and expansion, their phenotype was identified using flow cytometry analysis. Cell survival was measured using MTT assay and DAPI staining after exposure to various concentrations of 50, 100, 200, and 400 nM TN-C. Using acridine orange/ethidium bromide staining, we measured the number of live and necrotic cells after exposure to the combination of HA and TN-C. MTT assay revealed the highest NSCs viability rate in the group exposed to 100 nM TN-C compared to other groups, and a combination of 1% HA + 100 nM TN-C increased the viability of NSCs compared to the HA group after 24 hours. Electron scanning microscopy revealed the higher attachment of these cells to the HA + 100 nM TN-C substrate relative to the HA substrate. Epifluorescence imaging and DAPI staining of loaded cells on HA + 100 nM TN-C substrate significantly increased the number of NSCs per field over 72 hours compared to the HA group ( P < 0.05). Live and dead assay revealed that the number of live NSCs significantly increased in the HA + 100 TN-C group compared to HA and control groups. The enrichment of HA substrate with TN-C promoted viability and survival of NSCs and could be applied in neural tissue engineering approaches and regenerative medicine.

The COVID-19 pandemic has profoundly influenced public health and contributed to global economic divergences of unprecedented dimensions. Due to the high prevalence and mortality rates, it is then expected that the consequence and public health challenges will last for long periods. The rapid global spread of COVID-19 and lack of enough data regarding the virus pathogenicity multiplies the complexity and forced governments to react quickly against this pandemic. Stem cells represent a small fraction of cells located in different tissues. These cells play a critical role in the regeneration and restoration of injured sites. Because of their specific niche and a limited number of stem cells, the key question is whether there are different anti-viral mechanisms against viral infection notably COVID-19. Here, we aimed to highlight the intrinsic antiviral resistance in different stem cells against viral infection. These data could help us to understand the possible viral infections in different stem cells and the activation of specific molecular mechanisms upon viral entrance., Tabriz University of Medical Sciences

Background Photothrombotic (PT) stroke model is a novel method to induce ischemic stroke in the target site using excitation of a photosensitive agent such as Rose Bengal dye after light illumination. Here, we performed a photothrombotic-induced brain ischemic model using green laser and photosensitive agent Rose Bengal (RB) and its efficiency evaluated through cellular, histological, and neurobehavioral approaches.Methods Mice were randomly allocated into RB; Laser irradiation; and RB + Laser irradiation groups. Mice were exposed to green laser at a wavelength of 532 nm and intensity 150 mW in a mouse model after injection of RB. Four circular polarizers were applied to control output beam intensity. The laser was illuminated on the target region under stereotactic surgery. Mice were euthanatized after 28 days. We assessed ischemic stroke outcomes using multiple approaches including macroscopic, microscopic (H&E and Cresyl violet staining). The volume of lesion sites was calculated using unbiased stereological assay and Cavalier’s principle. We performed double immunofluorescence staining for NeuN and BrdU on day 28. To assess the quality of ischemic stroke, neurological behavior, and functional deficits were done on days 1, 7, 14, and 28. Results Laser irradiation plus RB promoted pale ischemic changes after 7 days. Microscopic staining revealed neural tissue degeneration and demarcated necrotic site and neuronal injury plus prominent astrogliosis in the periphery of irradiated sites on day 28. NeuN+/BrdU+ staining showed a significant number of proliferating cells in Laser irradiation plus RB group compared to the group (p+ cells reduced. Neurological behavior and functional deficits were detected in mice from Laser irradiation plus the RB group. No histological or functional deficits were detected in RB and Laser irradiation groups. Conclusion Our study revealed that the PT although increased the cell proliferating in the periphery of the lesion site, but due to undesirable microenvironment the neurogenesis decreased concomitantly with functional deficits. This method of PT introduces a reliable, reproducible, noninvasive, and accessible stroke model similar to human stroke condition.

Herein, we investigated the effect of electrospun polycaprolactone fumarate (PCLF) nanofibers on neural stem cell (NSC) behavior in the in vitro setting. Murine NSCs were isolated from adult mice subventricular zone and immunophenotyped by flow cytometry assay and immunofluorescence staining. Cells were cultured on the plastic surface, laminin-coated surface, and electrospun PCLF nanofibers. Cell morphology, attachment, and spreading were evaluated by scanning electron microscopy analysis. Cell viability and proliferation rates were evaluated by MTT assay. The proliferation of plated cells was investigated by monitoring Ki-67-positive cells using flow cytometry analysis. The protein levels of Map-2 and GFAP were detected by using immunofluorescence staining to show neural and astrocyte differentiation capacity. Scanning electron microscopy images revealed an extensive distribution, morphological adaptation, and cell-to-cell connectivity in NSCs upon culture on the PCLF surface. MTT analysis showed that the NSCs had more survival rates on the PCLF surface compared to the laminin and control groups over time (p < 0.05). In contrast to the laminin group, Ki-67 analysis showed a decrease of proliferating cells in the PCLF group. Immunofluorescence staining revealed the prominent increase of Map-2 and GFAP reduction in NSCs from the PCLF group compared to the laminin and control groups, showing the stimulatory effect of PCLF on targeted maturation of NSCs (p < 0.05). In brief, PCLF based construct promotes NSCs morphological adaptation and neuronal differentiation, suggesting PCLF as an appropriate and applicable substrate in neural tissue engineering.

Purpose: Application of Mummy material for treatment of different diseases such as bone fracture, cutaneous wounds and joint inflammation has been advised since hundred years ago in Persian traditional medicine. Due to the claims of indigenous people and advice of traditional medicine for application of this material in healing of bone fractures, this study has been designed to evaluate whether Mummy material can promote the differentiation of mesenchymal stem cells into osteoblasts and enhance the expression of bone specific genes and proteins. Methods: Adipose derived stem cells (ASCs) at fourth cell passage were divided into control, osteogenesis group (received osteogenic medium), Mummy group (received Mummy at concentration of 500 µg/ml). ASCs in the fourth group were treated with both osteogenic medium and Mummy (500µg/ml). Cells in all groups were harvested on days 7, 14 and 21 days for further evaluation through Real time RT-PCR, Von kossa staining, Immunocytochemistry and flowcytometery. Results: Treatment of ASCs with Mummy at concentration of 500µg/ml promotes the expression level of Osteocalcin, RUNX-2 and β1-integrin genes in different time points but that of the Osterix did not changed. Furthermore the expression of Osteocalcin protein enhanced significantly in ASCs treated with Mummy detected by Immunocytochemistry and flowcytometery technique compared to the control groups. The results of this study also showed that treatment of ASCs with Mummy resulted in formation of mineral deposits which was evaluated by Von Kossa staining method. Conclusion: Obtained data from this study reveals that Mummy is a potent enhancer for differentiation of ASCs into osteoblasts in in vitro system, probably through increasing the level of bone specific genes and proteins.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by a spectrum of clinicopathologic signs and a complex etiology. PD results from the degeneration of dopaminergic (DAergic) neurons in the substantia nigra. Current therapies for PD are only able to alleviate symptoms without stopping disease progression. In addition, the available therapeutic strategies do not have long-lasting effects. Furthermore, these therapies cause different ranges of adverse side effects. There is great interest in neurotrophic factors (NTFs) due to their ability to promote the survival of different neural cells. These factors are divided into four families: neurotrophins, neurokines, the glial cell line-derived NTF family of ligands, and the newly recognized cerebral DA NTF/mesencephalic astrocyte-derived NTF family. The protective and therapeutic effects of these factors on DAergic neurons make them suitable for the prevention of progressive cell loss in PD. Based on the above premise, we focus on the protective effects of NTFs, especially CDNF and MANF, on nigrostriatal DAergic neurons in PD.

Spinal cord injury (SCI) is a debilitating condition within the neural system which is clinically manifested by sensory-motor dysfunction, leading, in some cases, to neural paralysis for the rest of the patient’s life. In the current study, mesenchymal stem cells (MSCs) were isolated from the human amniotic fluid, in order to study their juxtacrine and paracrine activities. Flow cytometry analysis was performed to identify the MSCs. A conditioned medium (CM) was collected to measure the level of BDNF, IL-1β, and IL-6 proteins using the ELISA assay. Following the SCI induction, MSCs and CM were injected into the lesion site, and also CM was infused intraperitoneally in the different groups. Two weeks after SCI induction, the spinal cord samples were examined to evaluate the expression of the doublecortin (DCX) and glial fibrillary acid protein (GFAP) markers using immunofluorescence staining. The MSCs’ phenotype was confirmed upon the expression and un-expression of the related CD markers. Our results show that MSCs increased the expression level of the DCX and decreased the level of the GFAP relative to the injury group (p &lt, 0.001). Additionally, the CM promoted the DCX expression rate (p &lt, 0.001) and decreased the GFAP expression rate (p &lt, 0.01) as compared with the injury group. Noteworthily, the restorative potential of the MSCs was higher than that of the CM (p &lt, 0.01). Large-scale meta-analysis of transcriptomic data highlighted PAK5, ST8SIA3, and NRXN1 as positively coexpressed genes with DCX. These genes are involved in neuroactive ligand–receptor interaction. Overall, our data revealed that both therapeutic interventions could promote the regeneration and restoration of the damaged neural tissue by increasing the rate of neuroblasts and decreasing the astrocytes.

Synapses are touted as the main structural and functional components of neural cells within in the nervous system, providing tissue connectivity and integration via the formation of perineuronal nets. In the present study, we evaluated the synaptogenic activity of electrospun PLGA and PLGA-PEG nanofibers on human SH-SY5Y cells after 14 days in vitro. Electrospun PLGA and PLGA-PEG nanofibers were fabricated and physicochemical properties were examined using the HNMR technique. The cells were classified into three random groups, i.e., control (laminin-coated surface), PLGA, and PLGA-PEG. Scaffolds’ features, cell morphology, attachment, and alignment were monitored by SEM imaging. We performed MTT assay to measure cell survival rate. To evaluate neurite formation and axonal outgrowth, cells were stained with an antibody against β-tubulin III using immunofluorescence imaging. Antibodies against synapsin-1 and synaptophysin were used to explore the impact of PLGA and PLGA-PEG scaffolds on synaptogenesis and functional activity of synapses. According to SEM analysis, the PLGA-PEG scaffold had less thick nanofibers compared with the PLGA scaffold. Cell attachment, expansion, neurite outgrowth, and orientation were promoted in the PLGA-PEG group in comparison with the PLGA substrate (p

Acute lymphoblastic leukemia (ALL) is an aggressive cancer in children and adults which possess higher CD47 expression than normal cells. ALL chemotherapy has a lot of side effects and in most cases is ineffective. However arrival of Natural killer (NK) cell immunotherapy raised hopes for successful treatment of cancers, tailoring NK cells to meet clinical requirements is still under investigation. Of note, CD16

Natural killer (NK) cells have significant capability in tumor immune-surveillance. The ability of lyse transformed cells immediately in an antigen-independent manner make them an attractive candidate for cancer cell therapy. Despite employment of NK cells in cancer immunotherapy, clinical trials are faced with serious limitations such as trouble with the penetration of NK cells in tumor sites, limited in vivo persistence, and tumor microenvironment interference. Taken together, the NK-cell cancer therapy is still infant scenario that has a long way to be translated in clinic. Current article first reviews characteristic features of NK lymphocytes. Then, it discusses about important disruptive barriers and motivator in the developmental stages of NK cells like as tumor microenvironment. Finally, some revolutionary approaches are highlighted utilizing of NK cells in cancer therapy.

Acute lymphoblastic leukemia (ALL) is an aggressive cancer in children and adults which possess higher CD47 expression than normal cells. ALL chemotherapy has a lot of side effects and in most cases is ineffective. However arrival of Natural killer (NK) cell immunotherapy raised hopes for successful treatment of cancers, tailoring NK cells to meet clinical requirements is still under investigation. Of note, CD16+ (FCγIIIa) NK cells eliminate tumor cells with antibody dependent cell cytotoxicity (ADCC) mechanism. Therefore, we evaluated ADCC effect of cord blood stem cell derived CD16+ NK cells with using anti CD47 blocking antibody. CD16+ NK cells generated efficiently from CD34 positive cord blood cells in vitro using IL-2, IL-15 and IL-21 cytokines, although it was not dose dependent. CD16+ cells derived from CD34+ cells in day 14 of culture efficiently increased apoptosis in ALL cells, produced INFγ and increased CD107-a expression when used anti CD47 antibody (increased around 30-40%). Interestingly, CD16+ NK cell cytotoxicity slightly increased in combination with macrophages against ALL cells (around 10%). Taken together, our findings induced this hope that cord blood stem cell derived CD16+ NK cells exploit antitumor immune response in cancer therapy with using anti-CD47 antibody.

Background The brain development during the prenatal period is affected by various factors, including the mother's metabolic condition. It has been revealed that diabetes in pregnancy is associated with structural and functional alterations in offspring’s hippocampus. Hippocampus, as a critical region with well-known roles in learning and memory consolidation, is vulnerable to changes in glucose level. This study was designed to investigate the effects of maternal diabetes during the pregnancy period and insulin therapy on the neuronal density and the volume of different subfields of the hippocampus in rat offspring at postnatal day 14 (P14). Methods Wistar female rats were randomly divided into diabetics (STZ-D), diabetes treated with insulin (STZ-INS) group, and controls (CON). The animals in all groups were mated by non-diabetic male rats. Two weeks after birth, male pups from each group were sacrificed. The Cavalieri method was carried out to estimate the total volume, and the numerical density of the neurons in the hippocampus and its sub regions was measured by the optical dissector technique. Results Bilateral hippocampal volume decreased in the diabetic group, mainly in the CA1, dentate gyrus (DG) and subiculum areas (P ≤ 0.05), when compared to control and insulin-treated diabetic animals. In all hippocampus sub-regions, maternal diabetes resulted in a significant decrease in the number of cells in comparison with two other groups (P ≤ 0.05 each). Conclusion These data indicate that diabetes during pregnancy has a negative impact on the development of the hippocampus in the rats. These changes in the volume of hippocampal CA1, DG, and subiculum areas might be at the core of underlying neurocognitive and neurobehavioral impairments observed in the children of diabetic mothers.

The decline in neurogenesis is a very critical problem in Alzheimer disease. Different biological activities have been reported for medicinal application of quercetin. Herein, we investigated the neurogenesis potential of quercetin in a rat model of Alzheimer's disease induced by amyloid-beta injection. Rats were randomly divided into Control, Alzheimer + Saline and Alzheimer + Quercetin groups. Following the administration of Amyloid-beta, rats in the Alzheimer + Quercetin group received 40 mg/kg/day quercetin orally for one month. Our data demonstrated amyloid-β injection could impair learning and memory processing in rats indicated by passive avoidance test evaluation. We noted that one-month quercetin treatment alleviated the detrimental effects of amyloid-β on spatial learning and memory parameters using Morris water maze analysis. Quercetin was found to increase the number of proliferating neural stem/progenitor cells. Notably, quercetin increased the number of DCX-expressing cells, indicating the active dynamic growth of neural progenitor cells in the dentate gyrus of the hippocampus. We further observed that the quercetin improved the number of BrdU/NeuN positive cells contributed to enhanced adult neurogenesis. Based on our results, quercetin had the potential to promote the expression of BDNF, NGF, CREB, and EGR-1 genes involved in regulating neurogenesis. These data suggest that quercetin can play a valuable role in alleviating Alzheimer's disease symptoms by enhancing adult neurogenesis mechanism.

Background: Dementia as a major cognitive neurological disorder is defined as impairment in one or more cognitive territories compared with the former level of performance. This disorder disrupts patient's independence, and the patient would need others aid in order of doing daily and complex activities. The aim of this study was to evaluate the efficacy of Rosa damascena extract in the improvement of cognitive function in patients with dementia. Methods: This study is a randomized double-blind, placebo-controlled clinical trial on 40 patients older than 55 years with dementia referred to Specialized Elderly Patients Clinic in 2015–2016. Patients were divided randomly into two groups (control and intervention). The intervention group used donepezil and R. damascena capsules, and in control group, placebo capsule instead of R. damascena added on donepezil. Four test was filled three times at the study initiation, after month one and also after month three: Mini–Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination Revised (ACE-R) were used for cognition evaluation, for depression assessment, Geriatric Depression Scale was administered, and checklist of memory and behavioral disorders were filled. Results: The results showed add-on donepezil and R. damascena versus placebo improved cognitive impairment based on MMSE with P = 0.002, ACE-R with total P = 0.001, depression (P = 0.012), behavioral disorders (P < 0.001), and daily activity (P < 0.001). Conclusions: The R. damascena extract affected cognitive impairment of dementia patients significantly and also have significant effects on improving depression and behavioral problems.

The science of gene therapy has experienced a controversial history. At first, the initial concept that various disorders become curable by gene transferring was very exciting and challengeable. However, the problems and difficulties related to emerging techniques and unwanted side effects seen in some patients who have undergone gene therapy make some questions against the safety of novel molecular medicine approach. In line with this statement, discovery and developing a good bio-vector possessing low toxicity and high efficiency rate are the most important issues in gene therapy field. Introducing exosomes as vectors for gene delivery gives us a new opportunity in gene-based therapy. Exosomes, ranging from 30 to 120 nm in diameter, have unique lipid and protein composition. These nanostructures participate in cell-to-cell cross-talk, regulation of immune system, and the transport of genetic material. Besides the inherent potency of exosomes in gene therapy, a better understanding of their biology, characteristics, production, targeting, and cargo loading still need to be elucidated. In the current review, we exclusively focused on the various facets of exosomes and their importance as a bio-shuttle in gene therapy.

Objective: For a long time there was a central dogma that new neurons are not generated in the adult mammalian brain. But nowadays, it is well accepted that new neurons are continuously generated in discrete neurogenic regions of the brain throughout adult life. Neurological disorders are characterized by neuronal cell death, glial scar formation, axonal damage and deterioration of the cerebral cytoarchitecture and neuronal circuitry which result in functional deficits. Since the promising strategy for regenerating the damaged central nervous system (CNS), is the activation and recruitment of the endogenous regenerative capacity, therefore we investigated the neurogenesis potential of endogenous neural stem cells in an adult mouse brain. Methods and Materials : Since the some documented experimental studies have shown that the long-term injection of the BrdU induces cell senescence and astroglial differentiation, in the present study, BrdU intraperitoneal injection was applied in a short period of time. The number of animals sacrificed for evaluation of the proliferation of neural stem and progenitor cells and 4 weeks following the last BrdU injection, the rest of the animals was used for investigation of adult neurogenesis. Results : Findings showed that the neural stem and progenitor cells produce in the subgranular zone (SGZ) of the dentate gyrus and after 4 weeks differentiate into mature neurons. Also, this experiment showed that the possibility of the evaluation of adult neurogenesis mechanism will be provided with BrdU injection in a short time. Conclusion : The generation and integration of new neurons is a continuous physiological process that occurs in the brain. Therefore, the use of endogenous neural stem cells is a promising approach for neural tissue regeneration in the neurological conditions.

The number of older people who are suffering from memory impairment is increasing among populations throughout the world. Alzheimer's disease (AD) affects about 5% of people over 65 years old. The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage in the early stages of AD. Emerging evidence suggests that loss of neurons and synapses are correlated with dementia in this devastating disease. Therefore, neurogenesis and synaptogenesis in adulthood could serve as a preventive as well as a therapeutic target for AD. This study investigated the effect of Rosa damascena extract on neurogenesis and synaptogenesis in an animal model of AD. Molecular, cellular, and behavioral experiments revealed that this treatment could induce neurogenesis and synaptic plasticity and improve memory in AD. Our study suggests that R. damascena is a promising treatment for mild memory impairments and AD.

In this research, nanocomposite poly (lactide-co-glycolide)-Graphene (PLGA-Gr) microribbons were developed for neural tissue engineering. Moreover, the effects of Gr concentration (0, 0.1, 0.5 and 1 wt %) on the chemical and physical structure, mechanical properties, thermal stability and biological properties were evaluated. Our findings proved that incorporation of Gr nanosheets in the PLGA matrix resulted in the formation of aligned groove-shaped roughness on the surface of microribbons. In addition, Gr nanosheets could significantly promote the electrical conductivity and hydrophilicity of PLGA microribbons. In addition, the tensile strength and elastic modulus of the PLGA-Gr microribbons significantly promoted (upon 2 times and more than 3 times, respectively) compared to PLGA microribbons. The results demonstrated enhanced differentiation rate of SH-SY5Y cells to mature neurons on PLGA-Gr compared to PLGA. In summary, our findings discovered that aligned PLGA-Gr microribbons presented appropriate chemical, physical and mechanical properties to promote neuroblastoma cells. It is anticipated that the offered PLGA-Gr scaffolds might have great potential to develop a favorable construct for central nerve regeneration. However, further biological in vivo studies are required to assess the role of PLGA-Gr microribbons on the nerve regeneration.