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Purpose: Amyotrophic lateral sclerosis (ALS) is an uncommon and aggressive neurodegenerative disorder that influences the lower and upper motor neurons. There are low eligible drugs for ALS treatment; in this regard, supplemental and replacement treatments are essential. There are relative studies in the field of mesenchymal stromal cells (MSCs) therapy in ALS, but the different methods, differently used medium, and difference in follow-up periods affect the outcome treatment. Methods: The current survey is a single-center, phase I clinical trial to evaluating the efficacy and safety of autologous bone marrow (BM)-derived MSCs through intrathecal administration in ALS patients. MNCs were isolated from BM specimens and cultured. The clinical outcome was evaluated based Revised Amyotrophic Lateral Sclerosis Functional Rating (ALSFRS-R) Scale. Results: Each patient received 15±3×10 6 cells through subarachnoid space. No adverse events (AEs) were detected. Just one patient experienced a mild headache after injection. Following injection, no new intradural cerebrospinal pathology transplant-related was observed. None of the patients' pathologic disruptions following transplantation were detected by magnetic resonance imaging (MRI). The additional analyses have shown the average rate of ALSFRS-R score and forced vital capacity (FVC) reduction have decreased during 10 months following MSCs transplantation versus the pretreatment period, from -5.4±2.3 to -2±3.08 ALSFRS-R points/period ( P =0.014) and -12.6±5.22% to -4.8±14.72%/period ( P <0.001), respectively. Conclusion: These results have shown that autologous MSCs transplantation reduces the disease's progression and has favorable safety. Trial Registration: This study performed as a phase I clinical trial (code IRCT20200828048551N1)., Competing Interests: The authors declare no conflict of interest. All procedure performs in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compare ethical strand., (©2023 The Authors.)

Objective: To assess the patient's satisfaction rate during two distinct registry procedures in the emergency department., Methods: A cross-sectional study was conducted in educational hospitals with a high volume of patient's admission in Tabriz-Iran and Erzurum-Turkey. In this study, we used a Press Ganey questionnaire as a data collection tool that was filled out with patients or their companions before discharging or referred to other areas (wards). Finally, data were analyzed by using SPSS software version 16., Results: The included patients were from three-admission time courses includes morning, evening, and night shifts. The present study results indicated that the total satisfaction score was two scores higher than the classic one ( p <0.001) in the model registry system. Furthermore, the findings of the current study interestingly showed a correlation between satisfaction rate and education level as well as patient's location. Thus, patients with moderate education levels had a higher satisfaction rate in urban regions when compared with rural regions and higher/lower education levels ( p =0.03)., Conclusion: Patients' satisfaction rate with multiple variables can be improved by designing an appropriate registry procedure., Competing Interests: None declared.

Purpose: Oligodendrocytes (OLGs) damage and myelin distraction is considered as a critical step in many neurological disorders especially multiple sclerosis (MS). Cuprizone (cup) animal model of MS targets OLGs degeneration and frequently used to the mechanistic understanding of de- and remyelination. The aim of this study was exploring the effects of metformin on the OLGs regeneration, myelin repair and profile of neurotrophic factors in the mice brain after cup-induced acute demyelination., Methods: Mice (C57BL/6 J) were fed with chow containing 0.2% cup for 5 weeks to induce specific OLGs degeneration and acute demyelination. Next, the cup was withdrawn to allow one-week recovery (spontaneous remyelination). At the end of this period, mature OLGs markers, myelin-associated neurite outgrowth inhibitor protein A (NogoA), premature specific OLGs transcription factor (Olig2), anti-apoptosis marker (survivin), neurotrophic factors, and AMPK activation were monitored in the presence or absence of metformin (50 mg/kg body weight/day) in the corpus callosum (CC)., Results: Our finding indicated that consumption of metformin during the recovery period potentially induced an active form of AMPK (p-AMPK) and promoted repopulation of mature OLGs (MOG + cells, MBP + cells) in CC through up-regulation of BDNF, CNTF, and NGF as well as down-regulation of NogoA and recruitment of Olig2 + precursor cells., Conclusions: This study for the first time reveals that metformin-induced AMPK, a master regulator of energy homeostasis, activation following toxic demyelination could potentially accelerate regeneration and supports spontaneous demyelination. These findings suggest the development of new therapeutic strategies based on AMPK activation for MS in the near future. Graphical abstract An overview of the possible molecular mechanisms of action of metformin-mediated remyelinationa.

The onset of acute myocardial ischemia (MI) is accompanied by a rapid increase in electrical instability and often fatal ventricular arrhythmias. This study investigated that whether oxytocin (OT) can modulate ischemia-induced arrhythmias and considered relationships between the severity of arrhythmia and the electrocardiogram parameters during ischemia. OT (0.0001-1 μg) was administrated intraperitoneally 30 min before ischemia. To examine receptor involved, a selective OT-receptor antagonist, atosiban (ATO), was infused 10 min before OT. OT caused a significant and biphasic dose-dependent reduction in ectopic heart activity and arrhythmia score. OT doses that reduced ventricular arrhythmia elicited significant increase in QT interval. OT attenuated the electrophysiological changes associated with MI and there was significant direct relationship between QRS duration and arrhythmia score. ATO treatment reduced beneficial effects of OT on arrhythmogenesis. Nevertheless, ATO failed to alter OT effects on premature ventricular contractions. We assume that the ability of OT to modulate the electrical activity of the heart may play an important role in the antiarrhythmic actions of OT., Competing Interests: There are no conflicts of interest.

An attractive approach to replace the destroyed insulin-producing cells (IPCs) is the generation of functional β cells from stem cells. Embryonal carcinoma (EC) stem cells are pluripotent cells which can differentiate into all cell types. The present study was carried out to establish a simple nonselective inductive culture system for generation of IPCs from P19 EC cells by 1-2 weeks old mouse pancreas extract (MPE). Since, mouse pancreatic islets undergo further remodeling and maturation for 2-3 weeks after birth, we hypothesized that the mouse neonatal MPE contains essential factors to induce in vitro differentiation of pancreatic lineages. Pluripotency of P19 cells were first confirmed by expression analysis of stem cell markers, Oct3/4, Sox-2 and Nanog. In order to induce differentiation, the cells were cultured in a medium supplemented by different concentrations of MPE (50, 100, 200 and 300 µg/ml). The results showed that P19 cells could differentiate into IPCs and form dithizone-positive cell clusters. The generated P19-derived IPCs were immunoreactive to proinsulin, insulin and insulin receptor beta. The expression of pancreatic β cell genes including, PDX-1, INS1 and INS2 were also confirmed. The peak response at the 100 µg/ml MPE used for investigation of EP300 and CREB1 gene expression. When stimulated with glucose, these cells synthesized and secreted insulin. Network analysis of the key transcription factors (PDX-1, EP300, CREB1) during the generation of IPCs resulted in introduction of novel regulatory candidates such as MIR17, and VEZF1 transcription factors, as well as MORN1, DKFZp761P0212, and WAC proteins. Altogether, we demonstrated the possibility of generating IPCs from undifferentiated EC cells, with the characteristics of pancreatic β cells. The derivation of pancreatic cells from EC cells which are ES cell siblings would provide a valuable experimental tool in study of pancreatic development and function as well as rapid production of IPCs for transplantation.

Background and Purpose: There is growing evidence that stress contributes to cardiovascular disease and triggers the release of oxytocin. Moreover previous studies confirmed oxytocin mimics the protection associated with ischemic preconditioning. The present study was aimed to assess the possible cardioprotective effects of the centrally released oxytocin in response to stress and intracerebroventricular (i.c.v.) administration of exogenous oxytocin in ischemic-reperfused isolated rat heart., Methods and Subjects: Rats were divided in two main groups and all of them were subjected to i.c.v. infusion of vehicle or drugs: unstressed rats [control: vehicle, oxytocin (OT; 100 ng/5 μl), atosiban (ATO; 4.3 μg/5 μl) as oxytocin antagonist, ATO+OT] and stressed rats [St: stress, OT+St, ATO+St]. After anesthesia, hearts were isolated and subjected to 30 min regional ischemia and 60 min reperfusion (IR). Acute stress protocol included swimming for 10 min before anesthesia. Myocardial function, infarct size, coronary flow, ventricular arrhythmia, and biochemical parameters such as creatine kinase and lactate dehydrogenase were measured. Ischemia-induced ventricular arrhythmias were counted during the occlusion period., Results: The plasma levels of oxytocin and corticosterone were significantly elevated by stress. Unexpectedly hearts of stressed rats showed a marked depression of IR injury compared to control group. I.c.v. infusion of oxytocin mimicked the cardioprotective effects of stress, yet did not elevate plasma oxytocin level. The protective effects of both stress and i.c.v. oxytocin were blocked by i.c.v. oxytocin antagonist., Conclusions: These findings suggest that i.c.v. infusion of exogenous oxytocin and centrally released endogenous oxytocin in response to stress could play a role in induction of a preconditioning effect in ischemic-reperfused rat heart via brain receptors., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Selegiline, the irreversible inhibitor of monoamine oxidase B (MAO-B), is currently used to treat Parkinson's disease. However, the mechanism of action of selegiline is complex and cannot be explained solely by its MAO-B inhibitory action. It stimulates gene expression, as well as expression of a number of mRNAs or proteins in nerve and glial cells. Direct neuroprotective and anti-apoptotic actions of selegiline have previously been observed in vitro. Previous studies showed that selegiline can induce neuronal phenotype in cultured bone marrow stem cells and embryonic stem cells. Embryonal carcinoma (EC) cells are developmentally pluripotene cells which can be differentiated into all cell types under the appropriate conditions. The present study was carried out to examine the effects of selegiline on undifferentiated P19 EC cells. The results showed that selegiline treatment had a dramatic effect on neuronal morphology. It induced the differentiation of EC cells into neuron-like cells in a concentration-dependent manner. The peak response was in a dose of selegiline significantly lower than required for MAO-B inhibition. The differentiated cells were immunoreactive for neuron-specific proteins, synaptophysin, and β-III tubulin. Stem cell therapy has been considered as an ideal option for the treatment of neurodegenerative diseases. Generation of neurons from stem cells could serve as a source for potential cell therapy. This study suggests the potential use of combined selegiline and stem cell therapy to improve deficits in neurodegenerative diseases.