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Spinal cord injury (SCI) is a sensory-motor injury. Today, combined treatments such as cell therapy along with drug therapy and their interactions are of interest. Morphine is an opioid drug used to relieve intolerable pain. This study aims to evaluate the impact of an antinociceptive dose of morphine (with minimal tolerance/dependence but effective pain relief) on cell therapy in SCI. The antinociceptive dose of morphine was determined in rats with SCI through the Hargreaves and naloxone-induced morphine withdrawal tests. The rats were then allocated to 5 groups: laminectomy, SCI, SCI + Morphine, SCI + cell therapy, SCI + Morphine + cell therapy. The antinociceptive dose (5 mg/kg) was administered on days 1, 4, 10, and 13 (i.p.) post-SCI. On day 7, Neural-like stem cells derived from adipose tissue were transplanted intraspinally into the injured animals, and they were monitored for 12 weeks. The outcomes were assessed using the BBB test, somatosensory evoked potential (SSEP), and histology. The BBB test indicated that morphine significantly hindered functional recovery post-cell transplantation compared to animals receiving only cell therapy (p < 0.05). In the SSEP test, the analysis of amplitude and latency of waves did not reveal a significant difference (p > 0.05). The histological results showed that cell therapy reduced the cavity size post-SCI, while morphine had no significant impact on it. Morphine at the antinociceptive dose significantly impairs motor recovery despite cell therapy. Nonetheless, there was no significant difference between groups in terms of sensory pathway outcomes., Competing Interests: Declarations. Ethics Approval: All experiments were conducted according to the Helsinki guidelines for the use of laboratory animals, and the ethical committee at Tarbiat Modares University approved the procedures with the ethical code: IR.TMU.REC.1395.488 (Declaration of Helsinki). Consent to Participate: Not applicable Consent for Publication: Not applicable Competing Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Cell transplantation with hydrogel-based carriers is one of the advanced therapeutics for challenging diseases, such as spinal cord injury. Electrically conductive hydrogel has received much attention for its effect on nerve outgrowth and differentiation. Besides, a load of neuroprotective substances, such as lithium chloride can promote the differentiation properties of the hydrogel., Methods: In this study, alginate/collagen/reduced graphene oxide hydrogel loaded with lithium chloride (AL/CO/rGO Li+) was prepared as an injectable cell delivery system for neural tissue regeneration. After determining the lithium-ion release profile, an MTT assay was performed to check neural viability. In the next step, real-time PCR was performed to evaluate the expression of cell adhesion and neurogenic markers., Results: Our results showed that the combination of collagen fibers and rGO with alginates increased cell viability and the gene expression of collagen-binding receptor subunits such as integrin α1, and β1. Further, rGO contributed to the controlled release of lithium-ion hydrogel in terms of its plenty of negatively charged functional groups. The continuous culture of NSCs on AL/CO/rGO Li+ hydrogel increased neurogenic genes' expressions of nestin (5.9 fold), NF200 (36.8 fold), and synaptophysin (13.2 fold), as well as protein expression of NF200 and synaptophysin after about 14 days., Conclusion: The simultaneous ability of electrical conduction and lithium-ion release of AL/CO/rGO Li+ hydrogel could provide a favorable microenvironment for NSCs by improving their survival, maintaining cell morphology, and expressing the neural marker. It may be potentially used as a therapeutic approach for stem cell transplantation in a spinal cord injury., Competing Interests: The authors declare no potential conflicts of interest., (© 2023 The Author(s).)

The developing brain is susceptible to the neurotoxic effects of lead. Exposure to lead has main effects on the cholinergic system and causes reduction of cholinergic neuron function during brain development. Disruption of the cholinergic system by chemicals, which play important roles during brain development, causes of neurodevelopmental toxicity. Differentiation of stem cells to neural cells is recently considered a promising tool for neurodevelopmental toxicity studies. This study evaluated the toxicity of lead acetate exposure during the differentiation of bone marrow-derived mesenchyme stem cells (bone marrow stem cells, BMSCs) to CCholinergic neurons. Following institutional animal care review board approval, BMSCs were obtained from adult rats. The differentiating protocol included two stages that were pre-induction with β-mercaptoethanol (BME) for 24 h and differentiation to cholinergic neurons with nerve growth factor (NGF) over 5 days. The cells were exposed to different lead acetate concentrations (0.1-100 μm) during three stages, including undifferentiated, pre-induction, and neuronal differentiation stages; cell viability was measured by MTT assay. Lead exposure (0.01-100 μg/ml) had no cytotoxic effect on BMSCs but could significantly reduce cell viability at 50 and 100 μm concentrations during pre-induction and neuronal differentiation stages. MAP2 and choline acetyltransferase (ChAT) protein expression were investigated by immunocytochemistry. Although cells treated with 100 μm lead concentration expressed MAP2 protein in the differentiation stages, they had no neuronal cell morphology. The ChAT expression was negative in cells treated with lead. The present study showed that differentiated neuronal BMSCs are sensitive to lead toxicity during differentiation, and it is suggested that these cells be used to study neurodevelopmental toxicity.

Valproic acid (VPA) usage in high dose is teratogen with low bioavailability. Hence to improve its efficacy and reduce its side effect it was encapsulated by the Nano liposomes and stabilized by the chitosan at different concentrations. The cellular uptake, biocompatibility, loading and encapsulation efficiency of the six-different formulations (1:1, 2:1, and 4:1 of chitosan-phospholipids: VPA), PC12 differentiation to neuron cells assays (gene-expression level by qRT-PCR) were conducted for the efficacy assessment of the Nano carriers. The encapsulation efficiency (EE) results revealed that the encapsulation of the VPA corresponds to the phospholipids dose, where 2:1 formulations showed higher encapsulating rate (64.5% for non-coated and 80% for coated by chitosan). The time monitored released of VPA also showed that the chitosan could enhance its controlled release too. The cellular uptake exhibited similar uptake behavior for both the coated and the non-coated Nano carriers and cytoplasmic distribution. We witnessed no toxicity effects, at different concentrations, for both formulations. Moreover, the results indicated that the gene expression level of SOX2, NeuroD1, and Neurofilament 200 increased from 1 to 5 folds for different genes. The qRT-PCR data were confirmed by the immunofluorescence antibodies staining, where Neurofilament 68 and SOX2 cell markers were modulated during differentiation of PC12 cells. Finally, our findings suggest promising potential for the Lip-VPA-Chit Nano carrier in inducing the differentiation of PC12 into neuron for treating neurodegenerative disorders., (Copyright © 2022. Published by Elsevier B.V.)