Electromagnetic Fields and Stem Cell Fate: When Physics Meets Biology.

Controlling stem cell (SC) fate is an extremely important topic in the realm of SC research. A variety of different external cues mainly mechanical, chemical, or electrical stimulations individually or in combination have been incorporated to control SC fate. Here, we will deconstruct the probable relationship between the functioning of electromagnetic (EMF) and SC fate of a variety of different SCs. The electromagnetic (EM) nature of the cells is discussed with the emphasis on the effects of EMF on the determinant factors that directly and/or indirectly influence cell fate. Based on the EM effects on a variety of cellular processes, it is believed that EMFs can be engineered to provide a controlled signal with the highest impact on the SC fate decision. Considering the novelty and broad applications of applying EMFs to change SC fate, it is necessary to shed light on many unclear mechanisms underlying this phenomenon.

Nitric oxide pathway presumably does not contribute to antianxiety and memory retrieval effects of losartan.

Nitric oxide (NO) and angiotensin (AT) receptors have demonstrated well-established interactions in various physiological phenomena. AT1 receptors can play a part in stress-induced activation of the hypothalamic-pituitary-adrenal axis; also, angiotensinergic neurotransmission plays a pivotal role in stress-evoked physiological responses. On the basis of the stress-modulating characteristics of NO, AT1, and AT2 receptors, the present study evaluated the roles of NO and AT1 receptors in the attenuation of stress-induced anxiety-like behaviors after administration of losartan, an AT1 antagonist. Male Wistar rats were exposed to the communication stress box, using a novel method to induce physical or emotional stress, and losartan (10 mg/kg), losartan+L-NG-nitroargininemethyl ester (L-NAME), L-NAME (1, 10, and 100 mg/kg), and normal saline-treated groups were compared. Losartan had reduced behavioral changes induced by both types of stressor and enhanced memory retrieval. Anxiety-like behaviors were significantly attenuated by administration of losartan, to a greater extent in the emotional rather than physical stress group. None of the injected dosages of L-NAME reversed the antianxiety and memory retrieval effects of losartan. Our results indicate that losartan probably improves memory retrieval and lessens anxiety-like behaviors through mechanisms other than the NO pathway.

Oral consumption of α-linolenic acid increases serum BDNF levels in healthy adult humans.

BACKGROUND AIMS: Dietary omega-6 and omega-3 fatty acids have remarkable impacts on the levels of DHA in the brain and retina. Low levels of DHA in plasma and blood hamper visual and neural development in children and cause dementia and cognitive decline in adults. The level of brain-derived neurotrophic factors (BDNF) changes with dietary omega-3 fatty acid intake. BDNF is known for its effects on promoting neurogenesis and neuronal survival. METHODS: In this study, we examined the effect of the oral consumption of α-Linolenic acid (ALA) on blood levels of BDNF and Malondialdehyde (MDA) in healthy adult humans. 30 healthy volunteers, 15 men and 15 women, were selected randomly. Each individual served as his or her own control. Before consuming the Flaxseed oil capsules, 5cc blood from each individual was sampled in order to measure the plasma levels of BDNF and MDA as baseline controls. During the experiment, each individual was given 3 oral capsules of flaxseed oil, containing 500mg of alpha linolenic acid, daily for one week. Then, plasma levels of BDNF and MDA were tested. RESULTS: The plasma levels of BDNF and MDA significantly (P < 0.05) increased in individuals who received the oral capsules of ALA. Plasma levels of BDNF increased more in the women in comparison with the men. CONCLUSION: ALA treatment could be a feasible approach to reduce size of infarcts in stroke patients. Thus, ALA could be used in adjunction with routine stroke therapies to minimize brain lesions caused by stroke.

Four novel p.N385K, p.V36A, c.1033-1034insT and c.1417-1418delCT mutations in the sphingomyelin Phosphodiesterase 1 (SMPD1) gene in patients with types A and B Niemann-Pick disease (NPD).

BACKGROUND: Types A and B Niemann-Pick disease (NPD) are autosomal-recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. METHODS: In order to determine the prevalence and distribution of SMPD1 gene mutations, the genomic DNA of 15 unrelated Iranian patients with types A and B NPD was examined using PCR, DNA sequencing and bioinformatics analysis. RESULTS: Of 8 patients with the p.G508R mutation, 5 patients were homozygous, while the other 3 were heterozygous. One patient was heterozygous for both the p.N385K and p.G508R mutations. Another patient was heterozygous for both the p.A487V and p.G508R mutations. Two patients (one homozygous and one heterozygous) showed the p.V36A mutation. One patient was homozygous for the c.1033-1034insT mutation. One patient was homozygous for the c.573delT mutation, and 1 patient was homozygous for the c.1417-1418delCT mutation. Additionally, bioinformatics analysis indicated that two new p.V36A and p.N385K mutations decreased the acid sphingomyelinase (ASM) protein stability, which might be evidence to suggest the pathogenicity of these mutations. CONCLUSION: with detection of these new mutations, the genotypic spectrum of types A and B NPD is extended, facilitating the definition of disease-related mutations. However, more research is essential to confirm the pathogenic effect of these mutations.

A newly identified c.1824_1828dupATACG mutation in exon 13 of the GAA gene in infantile-onset glycogen storage disease type II (Pompe disease).

Pompe disease or glycogen storage disease type II is a glycogen storage disorder associated with malfunction of the acid α-glucosidase enzyme (GAA; EC.3.2.1.3) leading to intracellular aggregations of glycogenin muscles. The infantile-onset type is the most life-threatening form of this disease, in which most of patients suffer from cardiomyopathy and hypotonia in early infancy. In this study, a typical case of Pompe disease was reported in an Iranian patient using molecular analysis of the GAA gene. Our results revealed a new c.1824_1828dupATACG mutation in exon 13 of the GAA gene. In conclusion, with the finding of this novel mutation, the genotypic spectrum of Iranian patients with Pompe disease has been extended, facilitating the definition of disease-related mutations.

Feasibility of clinoptilolite application as a microporous carrier for pH-controlled oral delivery of aspirin.

Clinoptilolite is a natural zeolite which due to high surface area/volume ratio has found many applications in industries and medicine. Aspirin is a non-steroidal anti-inflammatory drug which is currently used as an anticoagulant, antinociceptive, antipyretic, and anti-inflammatory drug. It is an acidic drug which induces gastric irritation due to inhibition of cyclooxygenase I located in gastric mucosa. In the present work, adsorption and desorption of aspirin on Iranian clinoptilolite micronized particles were studied in acidic and relatively alkaline pHs. Effect of particle size of clinoptilolite was also investigated on adsorption and desorption of aspirin. Specific surfaces, particle sizes, and zeta potentials of clinoptilolite particles were also determined. Scanning electron micrograph was used to study the morphology and crystallinity of clinoptilolite particles. The results showed that adsorption and desorption of aspirin on clinoptilolite are particle size- and pH-dependent. The present work proposes clinoptilolite as an inexpensive, efficient, and non-toxic natural available microporous material for aspirin oral delivery.

Four novel ARSA gene mutations with pathogenic impacts on metachromatic leukodystrophy: a bioinformatics approach to predict pathogenic mutations.

Metachromatic leukodystrophy (MLD) disorder is a rare lysosomal storage disorder that leads to severe neurological symptoms and an early death. MLD occurs due to the deficiency of enzyme arylsulfatase A (ARSA) in leukocytes, and patients with MLD excrete sulfatide in their urine. In this study, the ARSA gene in 12 non-consanguineous MLD patients and 40 healthy individuals was examined using polymerase chain reaction sequencing. Furthermore, the structural and functional effects of new mutations on ARSA were analyzed using SIFT (sorting intolerant from tolerant), I-Mutant 2, and PolyPhen bioinformatics software. Here, 4 new pathogenic homozygous mutations c.585G>T, c.661T>A, c.849C>G, and c.911A>G were detected. The consequence of this study has extended the genotypic spectrum of MLD patients, paving way to a more effective method for carrier detection and genetic counseling.

Understanding biophysical behaviours of microfluidic-synthesized nanoparticles at nano-biointerface.

Encapsulating drugs in nanoparticles (NPs) provide some advantages over free drugs; for example the probability of distribution in off-target tissues decreases and drugs remain safe from environment degrading factors. Upon entering the bioenvironment, NPs establish a number of interactions with their surroundings based on their physicochemical properties. Here we demonstrate how the size-surface charge interplay of chitosan NPs affects the protein corona formation and endocytosis pathway in the HeLa cells at non-toxic concentrations. Generally, large NPs (102 and 161nm) with low surface charge (+6.7 and +3.6mV) exhibited weaker tendency for endocytosis compared with smaller ones (63 and 83nm with 10 and 9.3mV surface charge, respectively). This is mainly because the interactions of larger NPs with the plasma membrane were too weak to release enough free energy required for cellular internalization. Furthermore, we tested the upright and inverted cell culture configurations to better understand the impact of the sedimentation and diffusion velocities of NPs on the resulting cellular uptake pattern in both serum free and serum containing culture medias. Considering the different particokinetics, the amount of internalized NPs in upright and inverted positions differed in all cases by a factor of approximately three (for 161nm particles), or less for smaller ones. Ultimately, our results offer a paradigm for analyzing the biobehavior of NPs under the precise control of their physicochemical characteristics.

The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Aß neurotoxicity.

It was demonstrated that treatment with beta amyloid (Aß) led to extreme alterations in the intrinsic electrophysiological properties of CA1 pyramidal neurons. Also, malfunction of the cholinergic system is correlated to the memory and cognitive impairments. Several new studies have suggested that Berberis vulgaris can act as a cholinesterase inhibitor. The present study aimed to investigate the effects of berberine (BER) on the Aß-induced impairments in learning and memory. The male Wistar rats were divided into 4 groups of Sham, BER, Aß and Aß+BER. The administration of BER or its vehicle started immediately after the injection of Aß and followed by 13 days. Then, the animals were tested for learning and memory performance using the Morris water maze (MWM) and passive avoidance tests. Then, they were sacrificed for the whole cell patch clamp recording. The results of the MWM and passive avoidance tasks indicated that administration of the BER in the Aß+BER group prevented the memory impairment induced by Aß. The results of the whole cell patch clamp also showed that administration of the BER restored the Aß-induced impairments in the firing frequency, half-width and rebound action potential. These results suggested that administration of the BER could ameliorate neurotoxicity induced by Aß. However, this neuroprotection impact could be resulted from the balance effect of the Ca(2+) entry. The optimal level of Ca(2+) entry by BER could be a major factor that modified the function of the Ca(2+)-activated K(+) channels and decreased the half-width in the Aß treated rats.

Generation of eye field/optic vesicle-like structures from human embryonic stem cells under two-dimensional and chemically defined conditions.

Despite the enormous progress in studying retinal cell differentiation from human embryonic stem cells (hESCs), none of the reported protocols have produced a cost-effective eye field cells with the capability to further differentiate into retinal derivatives. In this study, by drawing chemicals on our four-step differentiation strategy, we demonstrated the ability of hESCs in assembling such qualifications to follow human retinogenesis in a serum- and feeder-free adherent condition. Two-dimensional (2D) populations of eye field cells arose within early forebrain progeny upon hESCs differentiation. Gene expression analysis showed that the treatment of hESCs with a combination of selected small molecules (SMs) gave rise to the higher expressions of eye field-specific genes, PAX6, RX, and SIX3. Thereafter, a subset of cells gained the transient features of advancing retinal differentiation, including optic vesicle (OV)-like structures, which expressed MITF and CHX10 in a manner imitated in vivo human retinal development. The competency of derived cells in differentiation to retinal derivatives was further investigated. The gene analysis of the cells showed more propensity for generating retinal pigment epithelial (RPE) than neural retina (NR). The generation of OV-like structures in 2D cultures can shed light on molecular events governing retinal specification. It can also facilitate the study of human retinal development.

Human pluripotent stem cell-derived retinal pigmented epithelium in retinal treatment: from bench to bedside.

The generation of retinal pigment epithelial (RPE) cells from pluripotent stem cells is a topic of interest over the past few years as dysfunctional RPE cells are a primary cause of ocular diseases. However, a number of obstacles need to be overcome before these cells can be used in clinical trials. This review aims to provide an overview of the latest reports on the generation of RPE cells from human pluripotent stem cells. Challenges that need to be addressed in future studies for their therapeutic applications are discussed. Proposed research goals for this fast growing field are highlighted.

Two novel tyrosinase (TYR) gene mutations with pathogenic impact on oculocutaneous albinism type 1 (OCA1).

Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.

Combination of stem cell mobilized by granulocyte-colony stimulating factor and human umbilical cord matrix stem cell: therapy of traumatic brain injury in rats.

OBJECTIVES: Clinical studies of treating traumatic brain injury (TBI) with autologous adult stem cells led us to examine the impression of a combination therapy. This was performed by intravenous injection of human umbilical cord matrix stem cell (hUCMSC-Wharton(,)s jelly stem cell) with bone marrow cell mobilized by granulocytecolony stimulating factor (G-CSF) in rats injured with cortical compact device. MATERIALS AND METHODS: Adult male Wistar rats (n= 50) were injured with controlled cortical impact device and divided into five groups. All injections were performed 1 day after injury into the tail veins of rats. Neurological functional evaluation of animals was performed before and after injury using modified neurological severity scores (mNSS). Animals were sacrificed 42 days after TBI and brain sections were stained by Brdu immunohistochemistry. RESULTS: Statistically significant improvement in functional outcome was observed in treatment groups when compared with control (P< 0.01). mNSS showed no significant differences among the hUCMSC and G-CSF treated groups at any time point (end of trial). Rats with hUCMSC + G-CSF treatment had a significant improvement on mNSS at 5 and 6 week compared to other treatment group (P< 0.01). CONCLUSION: Histological analysis in G-CSF+ hUCMSC treated traumatic rats exhibited significant increase in numbers of Brdu immunoreactive cells in their traumatic core compared with other labeled group.

Comparison of transplantation of bone marrow stromal cells (BMSC) and stem cell mobilization by granulocyte colony stimulating factor after traumatic brain injury in rat.

BACKGROUND: Recent clinical studies of treating traumatic brain injury (TBI) with autologous adult stem cells led us to compare effect of intravenous injection of bone marrow mesenchymal stem cells (BMSC) and bone marrow hematopoietic stem cell mobilization, induced by granulocyte colony stimulating factor (G-CSF), in rats with a cortical compact device. METHODS: Forty adult male Wistar rats were injured with controlled cortical impact device and divided randomly into four groups. The treatment groups were injected with 2 × 106 intravenous bone marrow stromal stem cell (n = 10) and also with subcutaneous G-CSF (n = 10) and sham-operation group (n = 10) received PBS and "bromodeoxyuridine (Brdu)" alone, i.p. All injections were performed 1 day after injury into the tail veins of rats. All cells were labeled with Brdu before injection into the tail veins of rats. Functional neurological evaluation of animals was performed before and after injury using modified neurological severity scores (mNSS). Animals were sacrificed 42 days after TBI and brain sections were stained by Brdu immunohistochemistry. RESULTS: Statistically, significant improvement in functional outcome was observed in treatment groups compared with control group (P<0.01). mNSS showed no significant difference between the BMSC and G-CSF-treated groups during the study period (end of the trial). Histological analyses showed that Brdu-labeled (MSC) were present in the lesion boundary zone at 42nd day in all injected animals. CONCLUSION: In our study, we found that administration of a bone marrow-stimulating factor (G-CSF) and BMSC in a TBI model provides functional benefits.