A new insight into the role of pericytes in ischemic stroke.

The functional structure of the blood-brain barrier (BBB) deteriorates after stroke by developing diffuse microvascular and neurovascular dysfunction and loss of white matter integrity. This causes nervous tissue injury and causes sensory and motor disabilities in stroke patients. Improving the integrity of the BBB and neurovascular remodeling after stroke can promote post-stroke injury conditions. Pericytes are contractile cells abundant in the BBB and sandwiched between astrocytes and endothelial cells of the microvessels. Stroke could lead to the degeneration of pericytes in the BBB. However, recent evidence shows that promoting pericytes enhances BBB integrity and neurovascular remodeling. Furthermore, pericytes achieve multipotent properties under hypoxic conditions, allowing them to transdifferentiate into the brain resident cells such as microglia. Microglia regulate immunity and inflammatory response after stroke. The current review studies recent findings in the intervening mechanisms underlying the regulatory effect of pericytes in BBB recovery after stroke.

Designing Potent Anticancer Peptides by Aurein 1.2 Key Residues Mutation and Catenate Cell-Penetrating Peptide.

Purpose: Aurein 1.2 (Aur) peptide is known for possessing anticancer characteristics devoid of conventional therapeutics side effects. For improving Aur peptide anticancer functionality, different anticancer peptides were constructed based on Aur peptide through targeting two separate strategies, including (1) sequence-based mutations and (2) adding a cell-penetrating peptide linker. Methods: The study was approached by designing three different analogs of Aur, including (a) Aur mutant (Aurm), (b) Aur with N-terminal polyarginine linker (R5-Aur), and (c) Aurm with R5 (R5-Aurm). Computational molecular dynamics simulations clearly showed higher structural stability of R5-Aur and R5-Aurm compared to Aur, solely. The α-helical properties of R5-Aur and R5-Aurm were protected during 500 ns simulations in water solution while no such structural conservation was seen for Aur in silico. Results: The results of the current study highlight response to one of the main challenges of cancer therapy through selective invasion of Aur to cancer cells without significant involvement of normal cells. This issue was confirmed by different assays, including: MTT assay, flow cytometry, qPCR, and nuclei morphological observations. Furthermore, this study intensifies exploiting in silico approaches for adjusting drug delivery. The results of different assessments on designed peptides reveal an anticancer activity pattern rising from Aur toward Aurm, and R5- Aur, consecutively. Conclusion: The designed structure of Aur shows improved anticancer activity through molecular changes which makes it suggestable for anticancer therapies.

Probiotic immunonutrition impacts on colon cancer immunotherapy and prevention.

The important role of the immune system in treating cancer has attracted the attention of researchers to the emergence of oncology research. Immunotherapy has shown that the immune system is important in the fight against cancer. The challenge has led researchers to analyze the impact of immunotherapy on improving the status of the immune system, modifying the resulting safety response, reducing toxicity, and improving the results. This study aimed to discuss the potential mechanisms of probiotics in preventing colon cancer. The mechanisms include the change in intestinal microbiota, the metabolic activity of microbiota, the binding and degradation of the carcinogenic compounds present in the lumen of the intestine, the production of compounds with anticancer activity, immune system modification, intestinal dysfunction, changes in host physiology, and inhibition of cell proliferation and induction of apoptosis in cancerous cells. By contrast, very few reports have shown the harmful effects of oral probiotic supplements. According to available evidence, further studies on probiotics are needed, especially in identifying bacterial species with anticancer potential, studying the survival of the strains after passing the digestive tract, reviewing potential side effects in people with a weak immune system, and ultimately consuming and repeating its use. This study emphasizes that the nutritional formula can modulate inflammatory and immune responses in cancer patients. This effect reduces acute toxicity, although the pathways and measurement of this immune response are unclear. Nutrition safety is an emerging field in oncology, and further research is required.

Classical music restored fertility status in rat model of premature ovarian failure.

BACKGROUND: The restorative effect of classical music was assessed on the cyclophosphamide-induced animal model of premature ovarian failure (POF). METHODS: Mozart's piano classical music (K.448) was used for up to 4 and 8 weeks. Rats were exposed to music 6 h every day using a stereo system with a volume of 65-70 dB. Sera and ovarian tissue samples were collected for the evaluation of FSH, LH, and E2 and histopathological examination. At the same time points, samples were taken from the hypothalamus and hippocampus to monitor the expression of Ntrk2, Crh, and Pomc using real-time PCR. Mating trial was performed to evaluate the fertility status of POF rats. RESULTS: Histopathological examination revealed a significant increase (p < 0.05) in the numbers of morphologically normal follicles at all the developmental stages in POF rats after music therapy compared to the POF group (p < 0.05). Music therapy decreased FSH and LH levels to near-to-normal levels conidied with elevation of E2 (p < 0.05). Ntrk2, Crh, and Pomc expressions were down-regulated in POF rats. Music therapy increasaed the expression of Ntrk2 in the hypothalamus of POF rats (p < 0.05). In contrast, Crh and Pomc failed to reach the detection limit before intervention and four weeks after the intervention however, these genes were expressed eight weeks after music therapy. Fertility status was increased (p < 0.05) in terms of litter size in POF rats after being exposed to music compared to the non-treated POF control group (p < 0.05). CONCLUSION: Results showed that music can exert therapeutic effects on POF rats via the alteration of sex-related hormones.

Metformin-dependent variation of microglia phenotype dictates pericytes maturation under oxygen-glucose deprivation.

Blood-brain barrier resident cells are in the frontline of vascular diseases. To maintain brain tissue homeostasis, a series of cells are integrated regularly to form the neurovascular unit. It is thought that microglia can switch between M1/M2 phenotypes after the initiation of different pathologies. The existence of transition between maturity and stemness features in pericytes could maintain blood-brain barrier functionality against different pathologies. In the current study, the effect of metformin on the balance of the M1/M2 microglial phenotype under oxygen-glucose deprivation conditions and the impact of microglial phenotype changes on pericyte maturation have been explored. Both microglia and pericytes were isolated from the rat brain. Data showed that microglia treatment with metformin under glucose- and oxygen-free conditions suppressed microglia shifting into the M2 phenotype (CD206+ cells) compared to the control (p < .01) and metformin-treated groups (p < .05). Incubation of pericytes with microglia-conditioned media pretreated with metformin under glucose- and oxygen-free conditions or normal conditions increased pericyte maturity. These changes coincided with the reduction of the Sox2/NG2 ratio compared to the control pericytes (p < .05). Data revealed the close microglial-pericytic interplay under the ischemic and hypoxic conditions and the importance of microglial phenotype acquisition on pericyte maturation.

Biomaterials patterning regulates neural stem cells fate and behavior: The interface of biology and material science.

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.

Static and dynamic culture of human endothelial cells encapsulated inside alginate-gelatin microspheres.

This study aimed to explore the angiogenesis potential of human endothelial cells encapsulated inside alginate-gelatin microspheres under static and dynamic culture systems after 7 days. Human umbilical vein endothelial cells were encapsulated inside alginate (1%) and gelatin (1.2%) using an electrostatic encapsulation method. Cells were incubated for 7 days in vitro. The cell survival rate was measured using the MTT assay. The expression of VEGFR-2 and von Willebrand factor genes was studied by real-time PCR assay. Using western blot analysis, we monitored the protein contents of VEGFR-2, vWF, and Caspase 3. The levels of SOD and GPx enzymes were calculated using biochemical kits. Angiogenesis potential was assessed using in vitro Matrigel assay. Data showed an increased survival rate in encapsulated cells cultured under the static condition compared to the conventional 2D condition (p < 0.05). The culture of encapsulated cells under a dynamic bioreactor system did not alter cell viability. Compared to the dynamic culture system, the incubation of encapsulated cells in the static culture system swelled the microspheres (p < 0.05). Both dynamic and static culture models increased the expression of VEGFR-2 and von Willebrand factor in encapsulated cells compared to 2D culture (p < 0.05), showing enhanced functional maturation. Data showed a significant increase of vWF and reduction of apoptosis marker Caspase in the dynamic culture system (p < 0.05). The levels of SOD and GPx were significantly increased in dynamic and static culture models as compared to the control 2D group (p < 0.05). In vitro tubulogenesis assay showed significant induction of angiogenesis in dynamic encapsulated HUVECs indicated with a large number of vascular tubes and arborized ECs compared to the control and static encapsulated HUVECs (p < 0.05). The current study suggests a bioreactor dynamic system is a reliable approach, similar to a static condition, for the expansion of encapsulated human ECs in a 3D milieu.

CTRP9: An emerging potential anti-aging molecule in brain.

C1q/tumor necrosis factor (TNF)-related proteins (CTRPs) particularly CTRP9, have been established to be as adiponectin (APN) highly conserved paralogs which assemble several APN regulatory functions. Recently, growing body of evidences drawn significant attention to evaluate metabolic and cardiovascular effect of CTRP9. However, the potential role of CTRP9 in brain tissue has not yet fully illustrated. Here, we aimed to uncover latest advances regarding the CTRP9 related signaling pathways and during brain aging process.

Modulatory effect of photobiomodulation on stem cell epigenetic memory: a highlight on differentiation capacity.

Differentiation potential of stem cells into various lineages makes these cells as promising sources to treat multiple diseases. In this regard, the use of different strategies and protocols to increase differentiation capacity is highly demanded. Low-level laser therapy, a relatively noninvasive technique, has the capacity to accelerate the healing of numerous injuries and a portion of restorative capacity could be correlated with the stem cell activation and differentiation. Several mechanisms have been diagnosed to participate in orientation of stem cells to functional mature cells. Among them, the status of DNA methylation orchestrates the maintenance of tissue-specific gene expression during the differentiation procedure. DNA methylation is a momentous event in embryogenesis and functional maturation. This review article highlighted the potency of laser irradiation (low-level intensities) in the differentiation of stem cells by modulation of methylation. The analysis of these modalities could help us to understand the underlying mechanisms participating in the therapeutic effects of photobiomodulation.

Targeting pericytes for neurovascular regeneration.

Pericytes, as a key cellular part of the blood-brain barrier, play an important role in the maintenance of brain neurovascular unit. These cells participate in brain homeostasis by regulating vascular development and integrity mainly through secreting various factors. Pericytes per se show different restorative properties after blood-brain barrier injury. Upon the occurrence of brain acute and chronic diseases, pericytes provoke immune cells to regulate neuro-inflammatory conditions. Loss of pericytes in distinct neurologic disorders intensifies blood-brain barrier permeability and leads to vascular dementia. The therapeutic potential of pericytes is originated from the unique morphological shape, location, and their ability in providing vast paracrine and juxtacrine interactions. A subset of pericytes possesses multipotentiality and exhibit trans-differentiation capacity in the context of damaged tissue. This review article aimed to highlight the critical role of pericytes in restoration of the blood-brain barrier after injury by focusing on the dynamics of pericytes and cross-talk with other cell types.

Dual thermo-and pH-sensitive injectable hydrogels of chitosan/(poly(N-isopropylacrylamide-co-itaconic acid)) for doxorubicin delivery in breast cancer.

In this work, dual thermo- and pH-responsive hydrogels were developed and loaded with doxorubicin (DOX) with potential therapy of breast cancer. Hydrogels were engineered by blending synthesized poly(N-isopropylacrylamide-co-itaconic acid) (PNIAAm-co-IA) with chitosan (CS) through ionic crosslinking using glycerophosphate (GP). The synthesized copolymer and hydrogels were characterized by means of various techniques such as FT-IR, 1H NMR, scanning electron microscopy (SEM) and energy dispersive X-ray (EDX). Lower critical solution temperature (LCST) of the copolymer was determined around 39 °C using UV-Vis spectroscopy. Swelling studies of hydrogels and their morphology implied the porous structure, high water content with rapid swelling/deswelling rate in response to abrupt changes of pH and temperature. The release investigation of DOX at different concentration, temperature and pH values confirmed the accelerated release of DOX in lower concentration and acidic condition at 37 °C as compared to neutral pH and the temperature of 40 °C. The MTT cytotoxicity study revealed that the hydrogels are cytocompatible and exert no/negligible cytotoxicity on MCF-7 cells. The proliferation of MCF-7 cells on the prepared hydrogel and DOX-loaded hydrogel was evaluated by 4',6-diamidino-2-phenylindole (DAPI) staining which further demonstrated the potential of developed hydrogels for local therapy of breast cancer.

Wnt lipidation: Roles in trafficking, modulation, and function.

The Wnt signaling pathway consists of various downstream target proteins that have substantial roles in mammalian cell proliferation, differentiation, and development. Its aberrant activity can lead to uncontrolled proliferation and tumorigenesis. The posttranslational connection of fatty acyl chains to Wnt proteins provides the unique capacity for regulation of Wnt activity. In spite of the past belief that Wnt molecules are subject to dual acylation, it has been shown that these proteins have only one acylation site and undergo monounsaturated fatty acylation. The Wnt monounsaturated fatty acyl chain is more than just a hydrophobic coating and appears to be critical for Wnt signaling, transport, and receptor activation. Here, we provide an overview of recent findings in Wnt monounsaturated fatty acylation and the mechanism by which this lipid moiety regulates Wnt activity from the site of production to its receptor interactions.

Intranasal cerebrolysin improves cognitive function and structural synaptic plasticity in photothrombotic mouse model of medial prefrontal cortex ischemia.

Medial prefrontal cortex (mPFC) ischemia affects post-stroke cognitive outcomes. We aimed to investigate the effects of different doses and routes of cerebrolysin (CBL) on the structural synaptic plasticity and cognitive function after mPFC ischemia in mice. Thence, CBL (1, 2.5 ml/kg/i.p./daily) or (1 ml/kg/i.n./daily), were administrated in photothrombotic mouse model of mPFC ischemia for two weeks. Episodic and spatial memories were assessed by the What-Where-Which (WWWhich) and Barnes tasks. Growth-associated protein 43 (GAP-43), postsynaptic density-95 (PSD-95), and synaptophysin (SYN) levels were measured in the lesioned area using western blot analysis. Dendritic arbors, spine densities, and morphology were assessed via Golgi-Cox staining. Treatment with 2.5 ml/kg/i.p. and 1 ml/kg/i.n. doses attenuated mPFC ischemia-induced episodic and spatial memories impairment. Results showed an obvious increase in the GAP-43, PSD-95 and SYN levels and improvement in the structural synaptic indexes in lesioned area induced by the same doses and routes of CBL. In conclusion, we found that specific doses/routes of CBL have positive effects on the structural synaptic plasticity and cognitive outcomes after mPFC ischemia.

The Dynamics of Neurosteroids and Sex-Related Hormones in the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is commonly diagnosed by vast extracellular amyloid deposits and existence of intracellular neurofibrillary tangles. In accordance with the literature, age-related loss of sex steroid hormones in either males or females was found in relation to AD subjects. The dynamics of these hormones have been previously described in both physiological and pathological conditions with the evidence of changes in various intracellular signalings regarding the neurodegenerative disease. The potent protective effects of sex steroid hormones and their synthetic analogs are indicative of the decrease in the accumulated levels of intercellular beta-amyloid (Aß) protein and an increase of specific proteases activity, resulting in the improvement of pathological features. In the current review, we focused on the dynamic of signaling pathway related to sex steroid hormones. It is logical to hypothesize that androgen hormones have regulatory actions on the kinetics of Aß which make them as a promising preventive approach for neurodegenerative diseases in the near future.

Tissue engineering strategies for the induction of angiogenesis using biomaterials.

Angiogenesis is touted as a fundamental procedure in the regeneration and restoration of different tissues. The induction of de novo blood vessels seems to be vital to yield a successful cell transplantation rate loaded on various scaffolds. Scaffolds are natural or artificial substances that are considered as one of the means for delivering, aligning, maintaining cell connection in a favor of angiogenesis. In addition to the potential role of distinct scaffold type on vascularization, the application of some strategies such as genetic manipulation, and conjugation of pro-angiogenic factors could intensify angiogenesis potential. In the current review, we focused on the status of numerous scaffolds applicable in the field of vascular biology. Also, different strategies and priming approaches useful for the induction of pro-angiogenic signaling pathways were highlighted.

Exosomes and their Application in Biomedical Field: Difficulties and Advantages.

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.

Stem Cells as a Promising Tool for the Restoration of Brain Neurovascular Unit and Angiogenic Orientation.

Establishing systemic therapeutics for neuro-inflammatory diseases is a main objective of regenerative medicine, certainly focusing on restoration of BBB dysfunction and neurovascular reconstitution. In this context, the regenerative capacity and therapeutic effects of different stem cells have been recently found to bring hopeful outcomes through trans-differentiation, paracrine interactions, and molecular cross-talk of transplanted stem cells with resident cells of blood-brain barrier. Here, we highlight some of the most recent scientific breakthroughs and discoveries by different authorities. Potency of different types of stem cells on the regulation and maintenance of endothelial and perivascular cells via various microRNAs was also studied.

Paracrine Neuroprotective Effects of Neural Stem Cells on Glutamate-Induced Cortical Neuronal Cell Excitotoxicity.

PURPOSE: Glutamate is a major excitatory neurotransmitter in mammalian central nervous system. Excessive glutamate releasing overactivates its receptors and changes calcium homeostasis that in turn leads to a cascade of intracellular events causing neuronal degeneration. In current study, we used neural stem cells conditioned medium (NSCs-CM) to investigate its neuroprotective effects on glutamate-treated primary cortical neurons. METHODS: Embryonic rat primary cortical cultures were exposed to different concentrations of glutamate for 1 hour and then they incubated with NSCs-CM. Subsequently, the amount of cell survival in different glutamate excitotoxic groups were measured after 24 h of incubation by trypan blue exclusion assay and MTT assay. Hoechst and propidium iodide were used for determining apoptotic and necrotic cell death pathways proportion and then the effect of NSCs-CM was investigated on this proportion. RESULTS: NSCs conditioned medium increased viability rate of the primary cortical neurons after glutamate-induced excitotoxicity. Also we found that NSCs-CM provides its neuroprotective effects mainly by decreasing apoptotic cell death rate rather than necrotic cell death rate. CONCLUSION: The current study shows that adult neural stem cells could exert paracrine neuroprotective effects on cortical neurons following a glutamate neurotoxic insult.