Gens PSD-95 and GSK-3ß expression improved by hair follicular stem cells-conditioned medium enhances synaptic transmission and cognitive abilities in the rat model of vascular dementia.

INTRODUCTION: Vascular dementia (VaD) is a common type of dementia. The aim of this study was to investigate the cellular and molecular mechanism of conditioned medium (CM) in VaD. MATERIAL AND METHODS: The rats were divided into four groups of control (n = 9), sham-operation (n = 10), VaD with vehicle (n = 9), and VaD with CM (n = 12) that received CM on days 4, 14, and 24 after 2VO. Before sacrificing the rats, cognitive performance was assessed through the open-field (OP), passive-avoidance, and Morris-water maze. The field-potential recording was used to investigate basal synaptic transmission (BST) and long-term potentiation (LTP). Subsequently, the hippocampus was dissected, and real-time PCR was used to quantify the expression levels of ß1-catenin, insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-ß), glycogen synthase kinase-3ß (GSK-3ß), postsynaptic density protein 95 (PSD-95), and NR2B genes. RESULTS: The results indicated impaired performance in behavioral tests in 2VO rats, coupled with reductions in BST and LTP induction. The expression levels of ß1-catenin, IGF-1, PSD-95, and TGF-ß genes decreased, whereas NR2B and GSK-3ß expression increased. Treatment with CM restores the expression of PSD-95 and GSK-3ß as well as fear-memory, spatial learning, and grooming number without a positive effect on memory retrieval, time spent on the periphery and center of OP. The BST recovered upon administration of CM but, the LTP induction was still impaired. CONCLUSION: The recovery of BST in VaD rats appears to be the most important outcome of this study which is caused by the improvement of gene expression and leads to the restoration of fear memory.

Cerebral venous thrombosis: a practical review.

The evolution of the Coronavirus Disease-2019 pandemic and its vaccination raised more attention to cerebral venous thrombosis (CVT). Although CVT is less prevalent than arterial stroke, it results in larger years of life lost. CVT is more common in women and young patients. Predisposing factors are categorized as transient factors such as pregnancy, puerperium, oral contraceptive pills, trauma, and dehydration; and permanent factors such as neoplastic, vasculitic, thrombophilic, hematologic conditions, infectious causes such as severe acute respiratory syndrome coronavirus-2 infection and HIV. The most common manifestations are headache, seizures, focal neurologic deficits, altered level of consciousness, and cranial nerve palsies. The most common syndromes are stroke-like, raised-intracranial-pressure (ICP), isolated-headache, and encephalopathy, which may have overlaps. Diagnosis is mostly based on computed tomography, magnetic resonance imaging, and their respective venous sequences, supported by blood results abnormalities such as D-dimer elevation. Treatment includes the prevention of propagation of current thrombus with anticoagulation (heparin, or low molecular weight heparinoids and then warfarin, or direct oral anticoagulants), decreasing ICP (even by decompressive craniotomy), and treatment of specific underlying diseases.

Combination Therapy with Platelet-Rich Plasma and Epidermal Neural Crest Stem Cells Increases Treatment Efficacy in Vascular Dementia.

This study aimed to evaluate the efficacy and treatment mechanism of platelet-rich plasma (PRP) and neural crest-derived epidermal stem cells (ESCs) in their administration alone and combination in vascular dementia (VaD) model by two-vessel occlusion (2VO). Methods. Sixty-six rats were divided into six groups: the control, sham, 2VO + vehicle, 2VO + PRP, 2VO + ESC, and 2VO + ESC + PRP. The treated groups received 1 million cells on days 4, 14, and 21 with or without 500 µl PRP (twice a week) after 2VO. The memory performance and anxiety were evaluated by behavioral tests including open field, passive avoidance, and Morris water maze. The basal-synaptic transmission (BST) and long-term potentiation (LTP) were assessed through field-potential recordings of the CA1. The mRNA expression levels of IGF-1, TGF-ß1, PSD-95, and GSk-3ß were measured in the rat hippocampus by quantitative reverse transcription polymerase chain reaction. Results. The results demonstrated impaired learning, memory, and synaptic plasticity in the 2VO rats, along with a significant decrease in the expression of IGF-1, TGF-ß1, PSD-95, and upregulation of GSK-3ß. Treatment with ESC alone and ESC + PRP showed similar improvements in spatial memory and LTP induction, with associated upregulation of PSD-95 and downregulation of GSK-3ß. However, only the ESC + PRP group showed recovery in BST. Furthermore, combination therapy was more effective than PRP monotherapy for LTP and memory. Conclusions. The transplantation of ESC showed better effects than PRP alone, and combination therapy increased the treatment efficacy with the recovery of BST. This finding may be a clue for the combination therapy of ESC and PRP for VaD.

Combined use of hair follicle stem cells and CEPO (carbamylated erythropoietin)-Fc in a rat model of chronic cerebral hypoperfusion: A behavioral, electrophysiological, and molecular study.

BACKGROUND: In dementia, synaptic dysfunction appears before neuronal loss. Stem cell therapy could potentially provide a promising strategy for the treatment of dementia models. The carbamylated erythropoietin fusion protein (CEPO-Fc) has shown synaptotrophic effects. This study aimed to determine the efficiency of the combined use of hair follicle stem cells (HFSC) and CEPO-Fc in the basal synaptic transmission (BST) and long-term plasticity (LTP) of chronic cerebral hypoperfusion (CCH) rats. METHODS: We divided 64 adult rats into control, sham, CCH+vehicle, CCH+CEPO, CCH+HFSC, and CCH+HFSC+CEPO groups. The CEPO-Fc was injected three times/week for 30 days. HFSC transplantation was done on days 4, 14, and 21 after surgery. The Morris water maze test and passive avoidance were used to assess memory. BST and LTP were assessed by a field-potential recording of the CA1 region. The hippocampal mRNA expression of IGF-1, TGF-ß1, ß1-Catenine, NR2B, PSD-95, and GSk-3ß was evaluated by quantitative RT-PCR. RESULTS: Following combination therapy, spatial memory retention, and BST showed significant improvement relative to HFSC and CEPO-Fc groups. These effects were also confirmed by recovered mRNA expression of ß1-catenin, TGF-ß1, and NR2B. GSK-3ß expression was downregulated in all treatment groups. The upregulated PSD-95 was identified in HFSC and combination groups compared to the vehicle group. CONCLUSIONS: These findings indicate that the combined use of HFSC and CEPO-Fc may be more advantageous for treating memory disruption in the CCH model than CEPO-Fc or HFSC alone. This type of combination therapy may hopefully lead to a new approach to treatment for dementia.

The hospitalization rate and clinical characteristics of mucormycosis prior and during COVID-19 pandemic: A single-center study.

INTRODUCTION: There have been some reports of the association between SARS-CoV-2 infection and mucormycosis. This study aims to compare the hospitalization rates and clinical characteristics of mucormycosis before and during the COVID-19 pandemic. METHODOLOGY: In this retrospective study, we compared the hospitalization rate of mucormycosis patients in Namazi hospital in Southern Iran for two periods of 40 months. We defined July 1st, 2018 to February 17th, 2020, as the pre-COVID-19 period and February 18th, 2020, to September 30th, 2021, as the COVID-19 period. In addition, a quadrupled group of hospitalized patients with age and sex-matched SARS-COV-2 infection without any sign of mucormycosis was selected as the control group for COVID-associated mucormycosis. RESULT: In the total of 72 mucormycosis patients in the COVID period, 54 patients had a clinical history and a positive RT-PCR, which confirms the diagnosis of SARS-COV2 infection. The hospitalization rate of mucormycosis showed an increase of + 306% (95% CI: + 259%, + 353%) from a monthly average value of 0.26 (95% confidence interval (CI): 0.14, 0.38) in the pre-COVID period to 1.06 in the COVID period. The use of corticosteroids prior to the initiation of hospitalization (p ≤ 0.01), diabetes (DM) (p = 0.04), brain involvement (p = 0.03), orbit involvement (p = 0.04), and sphenoid sinus invasion (p ≤ 0.01) were more common in patients with mucormycosis during the COVID period. CONCLUSIONS: In high-risk patients, especially diabetics, special care to avoid the development of mucormycosis must be taken into account in patients with SARS-COV-2 infection considered for treatment with corticosteroids.

Short-term beneficial effects of human dental pulp stem cells and their secretome in a rat model of mild ischemic stroke.

Although cell therapy has been applied in regenerative medicine for decades, recent years have seen greatly increased attention being given to the use of stem cell-based derivatives such as cell-free secretome. Dental pulp stem cells (DPSCs) are widely available, easily accessible, and have high neuroprotective and angiogenic properties. In addition, DPSC-derived secretome contains a rich mixture of trophic factors. The current investigation evaluated the short-term therapeutic effects of human DPSCs and their secretome in a rat model of mild ischemic stroke. Mild ischemic stroke was induced by 30 min middle cerebral artery occlusion, and hDPSCs or their secretome was administered intra-arterially and intranasally. Neurological function, infarct size, spatial working memory, and relative expression of seven target genes in two categories of neurotrophic and angiogenic factors were assessed three days after stroke. In the short-term, all treatments reduced the severity of neurological and histological deficits caused by ischemic stroke. Moreover, transient middle cerebral artery occlusion led to the striatal and cortical over-expression of BDNF, NT-3, and angiogenin, while NGF and VEGF expression was reduced. Almost all interventions were able to modulate the expression of target genes after stroke. The obtained data revealed that single intra-arterial administration of hDPSCs or their secretome, single intranasal transplantation of hDPSCs, or repeated intranasal administration of hDPSC-derived secretome was able to ameliorate the devastating effects of a mild stroke, at least in the short-term.

Mechanism of action and therapeutic potential of dimethyl fumarate in ischemic stroke.

Dimethyl fumarate (DMF) is an immunomodulatory drug currently approved for the treatment of multiple sclerosis and psoriasis. Its benefits on ischemic stroke outcomes have recently come to attention. To date, only tissue plasminogen activators (tPAs) and clot retrieval methods have been approved by the FDA for the treatment of ischemic stroke. Ischemic conditions lead to inflammation through diverse mechanisms, and recanalization can worsen the state. DMF and the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway it regulates seem to be important in postischemic inflammation, and animal studies have demonstrated that the drug improves overall stroke outcomes. Although the exact mechanism is still unknown, studies indicate that these beneficial impacts are due to the modulation of immune responses, blood-brain barrier permeability, and hemodynamic adjustments. One major component evaluated before, during, and after tPA therapy in stroke patients is blood pressure (BP). Recent studies have found that DMF may impact BP. Both hypotension and hypertension need correction before treatment, which may delay the appropriate intervention. Since BP management is crucial in managing stroke patients, it is important to consider DMF's role in this matter. That being said, it seems further investigations on DMF may lead to an alternative approach for stroke patients. In this article, we discuss the mechanistic roles of DMF and its potential role in stroke based on previously published literature and laboratory findings.

Transverse Myelitis as a Rare Neurological Complication of Coronavirus Disease 2019: A Case Report and Literature Review.

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is primarily a respiratory virus. However, an increasing number of neurologic complications associated with this virus have been reported, e.g., transverse myelitis (TM). We report a case of a 39-year-old man admitted to Namazi Hospital affiliated with Shiraz University of Medical Sciences, Shiraz, Iran. In December 2020, the patient was infected with Coronavirus Disease 2019 (COVID-19). During hospitalization, the patient suffered from sudden onset of paraplegia, and urinary retention, and had a T6-T7 sensory level. TM was diagnosed and an extensive workup was performed to rule out other etiologies. Eventually, para-infectious TM associated with COVID-19 was concluded. The patient received pulse methylprednisolone therapy of 1 g/day for 10 consecutive days followed by seven sessions of plasma exchange without a favorable response. The patient then underwent regular physical rehabilitation and tapering oral administration of prednisolone 1 mg/Kg. As a result, weakness in the lower extremities improved slightly after six months. Overall, we suspect a correlation between COVID-19 and TM, however, further studies are required to substantiate the association.

From Hair to the Brain: The Short-Term Therapeutic Potential of Human Hair Follicle-Derived Stem Cells and Their Conditioned Medium in a Rat Model of Stroke.

The short-term therapeutic impacts of stem cells and their derivatives were frequently reported in preclinical investigations of ischemic stroke (IS); however, several drawbacks including accessibility, abundancy, and ethical concerns limited their clinical application. We describe here for the first time the therapeutic potential of human hair follicle-derived stem cells (hHFSCs) and their conditioned medium (CM) in a rat model of IS. Furthermore, we hypothesized that a combination of cell therapy with repeated CM administration might enhance the restorative efficiency of this approach compared to each treatment alone. Middle cerebral artery occlusion was performed for 30 min to induce IS. Immediately after reperfusion, hHFSCs were transplanted through the intra-arterial route and/or hHFSC-CM administered intranasally. The neurological outcomes, short-term spatial working memory, and infarct size were evaluated. Furthermore, relative expression of seven target genes in three categories of neuronal markers, synaptic markers, and angiogenic markers was assessed. The hHFSCs and hHFSC-CM treatments improved neurological impairments and reduced infarct size in the IS rats. Moreover, molecular data elucidated that IS was accompanied by attenuation in the expression of neuronal and synaptic markers in the evaluated brain regions and the interventions rescued these expression changes. Although there was no considerable difference between hHFSCs and hHFSC-CM treatments in the improvement of neurological function and decrement of infarct size, combination therapy was more effective to reduce infarction and elevation of target gene expression especially in the hippocampus. These findings highlight the curative potential of hHFSCs and their CM in a rat model of IS.

The impacts of anesthetic regimens on the middle cerebral artery occlusion outcomes in male rats.

The middle cerebral artery occlusion (MCAO) model was introduced more than 3 decades ago to simulate human stroke. Till now, it is the most common platform to investigate stroke-induced pathological changes as well as to discover new drugs and treatments. Induction of general anesthesia is mandatory to induce this model, and different laboratories are using various anesthetic drugs, which might affect MCAO results. Therefore, the present study was designed to compare the impacts of several widely used anesthetic regimens on the MCAO outcomes. Here, adult male rats were anesthetized by isoflurane inhalation, intraperitoneal injection of chloral hydrate (CH), intraperitoneal injection of ketamine-xylazine, or subcutaneous administration of ketamine-xylazine, then subjected to 30 min MCAO. Survival rate, body weight change, infarct size, as well as cognitive and neurological performance were evaluated up to 3 days after the surgery. Our findings revealed CH caused the highest, whereas subcutaneous ketamine-xylazine led to the lowest mortality. Meanwhile, there were no significant differences in the body weight loss, infarct size, cognitive impairments, and neurological deficits among the experimental groups. Based on the current results, we proposed that subcutaneous injection of ketamine-xylazine could be an effective anesthetic regimen in the rat model of MCAO with several advantages such as low mortality, cost-effectiveness, safety, ease of administration, and not requiring specialized equipment.

Exploring the Paradox of COVID-19 in Neurological Complications with Emphasis on Parkinson's and Alzheimer's Disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronavirus (HCoV) that has created a pandemic situation worldwide as COVID-19. This virus can invade human cells via angiotensin-converting enzyme 2 (ACE2) receptor-based mechanisms, affecting the human respiratory tract. However, several reports of neurological symptoms suggest a neuroinvasive development of coronavirus. SARS-CoV-2 can damage the brain via several routes, along with direct neural cell infection with the coronavirus. The chronic inflammatory reactions surge the brain with proinflammatory elements, damaging the neural cells, causing brain ischemia associated with other health issues. SARS-CoV-2 exhibited neuropsychiatric and neurological manifestations, including cognitive impairment, depression, dizziness, delirium, and disturbed sleep. These symptoms show nervous tissue damage that enhances the occurrence of neurodegenerative disorders and aids dementia. SARS-CoV-2 has been seen in brain necropsy and isolated from the cerebrospinal fluid of COVID-19 patients. The associated inflammatory reaction in some COVID-19 patients has increased proinflammatory cytokines, which have been investigated as a prognostic factor. Therefore, the immunogenic changes observed in Parkinson's and Alzheimer's patients include their pathogenetic role. Inflammatory events have been an important pathophysiological feature of neurodegenerative diseases (NDs) such as Parkinson's and Alzheimer's. The neuroinflammation observed in AD has exacerbated the Aß burden and tau hyperphosphorylation. The resident microglia and other immune cells are responsible for the enhanced burden of Aß and subsequently mediate tau phosphorylation and ultimately disease progression. Similarly, neuroinflammation also plays a key role in the progression of PD. Several studies have demonstrated an interplay between neuroinflammation and pathogenic mechanisms of PD. The dynamic proinflammation stage guides the accumulation of α-synuclein and neurodegenerative progression. Besides, few viruses may have a role as stimulators and generate a cross-autoimmune response for α-synuclein. Hence, neurological complications in patients suffering from COVID-19 cannot be ruled out. In this review article, our primary focus is on discussing the neuroinvasive effect of the SARS-CoV-2 virus, its impact on the blood-brain barrier, and ultimately its impact on the people affected with neurodegenerative disorders such as Parkinson's and Alzheimer's.

Early and mid-term outcomes of carotid angioplasty and stent placement in 579 patients.

BACKGROUND AND PURPOSE: Carotid angioplasty and stenting (CAS) could be considered for preventing stroke in patients with carotid artery stenosis. This study aimed to determine the incidence and the risk factors of the early and mid-term complications associated with CAS. METHODS: This is a retrospective cohort study conducted at Shiraz University of Medical Sciences from March 2011 to March 2019. Patients at high risk and standard risk for carotid endarterectomy were included. The primary composite outcome was defined as stroke, myocardial infarction (MI), and death in the first 30 days after CAS. All-cause mortality, vascular mortality, and stroke were investigated during mid-term follow-up. RESULTS: A total of 579 patients (618 CAS) were recruited (mean age: 71.52 years). Overall, 394 (68.40%), 211 (36.63%), 179 (31.07%), and 96 (16.72%) patients had hypertension, dyslipidemia, diabetes mellitus, or were cigarette smokers, respectively. Primary composite outcomes were observed in 2.59% of patients (1.55% stroke, 0.69% MI, and 1.72% death). Atrial fibrillation was a predictor of primary composite outcome in multivariate logistic regression (p = .048). The presence of total occlusion in the contralateral carotid artery was significantly associated with the risk of stroke in univariate logistic regression (p = .041). The patients were followed for a period ranging from 1 to 83 months. The overall survival rate for all-cause mortality was 93.48% at 1 year, 77.24% at 5 years, and 52.92% at 8 years. All-cause mortality was significantly higher among patients with symptomatic carotid stenosis (p = .014). CONCLUSION: CAS provides acceptable short-term and mid-term outcomes in a unique population of high- and standard-surgical-risk, symptomatic and asymptomatic, octogenarian, and nonoctogenarian patients.

Therapeutic potential of hair follicle-derived stem cell intranasal transplantation in a rat model of ischemic stroke.

BACKGROUND: Stem cell-based therapy has received considerable attention as a potential candidate in the treatment of ischemic stroke; however, employing an appropriate type of stem cells and an effective delivery route are still challenging. In the present study, we investigated the therapeutic effect of safe, noninvasive, and brain-targeted intranasal administration of hair follicle-derived stem cells (HFSCs) in a rat model of ischemic stroke. METHODS: Stem cells were obtained from the adult rat hair follicles. In experiment 1, stroke was induced by 30 min middle cerebral artery occlusion (MCAO) and stem cells were intranasally transplanted immediately after ischemia. In experiment 2, stroke was induced by 120 min MCAO and stem cells were administered 24 h after cerebral ischemia. In all experimental groups, neurological performance, short-term spatial working memory and infarct volume were assessed. Moreover, relative expression of major trophic factors in the striatum and cortex was evaluated by the quantitative PCR technique. The end point of experiment 1 was day 3 and the end point of experiment 2 was day 15. RESULTS: In both experiments, intranasal administration of HFSCs improved functional performance and decreased infarct volume compared to the MCAO rats. Furthermore, NeuN and VEGF expression were higher in the transplanted group and stem cell therapy partially prevented BDNF and neurotrophin-3 over-expression induced by cerebral ischemia. CONCLUSIONS: These findings highlight the curative potential of HFSCs following intranasal transplantation in a rat model of ischemic stroke.

The Hospitalization Rate of Cerebral Venous Sinus Thrombosis before and during COVID-19 Pandemic Era: A Single-Center Retrospective Cohort Study.

OBJECTIVES: There are several reports of the association between SARS-CoV-2 infection (COVID-19) and cerebral venous sinus thrombosis (CVST). In this study, we aimed to compare the hospitalization rate of CVST before and during the COVID-19 pandemic (before vaccination program). MATERIALS AND METHODS: In this retrospective cohort study, the hospitalization rate of adult CVST patients in Namazi hospital, a tertiary referral center in the south of Iran, was compared in two periods of time. We defined March 2018 to March 2019 as the pre-COVID-19 period and March 2020 to March 2021 as the COVID-19 period. RESULTS: 50 and 77 adult CVST patients were hospitalized in the pre-COVID-19 and COVID-19 periods, respectively. The crude CVST hospitalization rate increased from 14.33 in the pre-COVID-19 period to 21.7 per million in the COVID-19 era (P = 0.021). However, after age and sex adjustment, the incremental trend in hospitalization rate was not significant (95% CrI: -2.2, 5.14). Patients > 50-year-old were more often hospitalized in the COVID-19 period (P = 0.042). SARS-CoV-2 PCR test was done in 49.3% out of all COVID-19 period patients, which were positive in 6.5%. Modified Rankin Scale (mRS) score ≥3 at three-month follow-up was associated with age (P = 0.015) and malignancy (P = 0.014) in pre-COVID period; and was associated with age (P = 0.025), altered mental status on admission time (P<0.001), malignancy (P = 0.041) and COVID-19 infection (P = 0.008) in COVID-19 period. CONCLUSION: Since there was a more dismal outcome in COVID-19 associated CVST, a high index of suspicion for CVST among COVID-19 positive is recommended.

Intranasal application of stem cells and their derivatives as a new hope in the treatment of cerebral hypoxia/ischemia: a review.

Intranasal delivery of stem cells and conditioned medium to target the brain has attracted major interest in the field of regenerative medicine. In pre-clinical investigations during the last ten years, several research groups focused on this strategy to treat cerebral hypoxia/ischemia in neonates as well as adults. In this review, we discuss the curative potential of stem cells, stem cell derivatives, and their delivery route via intranasal application to the hypoxic/ischemic brain. After intranasal application, stem cells migrate from the nasal cavity to the injured area and exert therapeutic effects by reducing brain tissue loss, enhancing endogenous neurogenesis, and modulating cerebral inflammation that leads to functional improvements. However, application of this administration route for delivering stem cells and/or therapeutic substances to the damaged sites requires further optimization to translate the findings of animal experiments to clinical trials.

Safety and efficacy of remote ischemic preconditioning in patients with severe carotid artery stenosis before carotid artery stenting: A proof-of-concept, randomized controlled trial.

Background: Remote ischemic preconditioning (RIPC) has been proposed as a possible potential treatment for ischemic stroke. This study aimed to investigate the frequency of micro-embolic brain infarcts after RIPC in patients with stroke who underwent elective carotid artery stenting (CAS) treatment. Methods: This study was managed at Shiraz University of Medical Sciences in southwest Iran. Patients undergoing CAS were randomly allocated into RIPC and control groups. Patients in the RIPC group received three intermittent cycles of 5-minute arm ischemia followed by reperfusion using manual blood cuff inflation/deflation less than 30 minutes before CAS treatment. Afterward, stenting surgery was conducted. Magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC), was acquired within the first 24 hours after CAS. Results: Seventy-four patients were recruited (79.7% men, age: 72.30 ± 8.57). Both groups of RIPC and control had no significant difference in baseline parameters (P > 0.05). Fifteen patients (40.5%) in the RIPC group and 19 (54.1%) patients in the control group developed restricted lesions in DWI MRI. In DWI+ patients, there were no significant differences according to the number of lesions, lesion surface area, largest lesion diameter, cortical infarcts percent, and ipsilateral and bilateral infarcts between the two groups. Conclusion: Although RIPC is a safe and non-invasive modality before CAS to decrease infarcts, this study did not show the advantage of RIPC in the prevention of infarcts following CAS. It may be because of the small sample size.

The Beneficial Potential of Genetically Modified Stem Cells in the Treatment of Stroke: a Review.

The last two decades have witnessed a surge in investigations proposing stem cells as a promising strategy to treat stroke. Since growth factor release is considered as one of the most important aspects of cell-based therapy, stem cells over-expressing growth factors are hypothesized to yield higher levels of therapeutic efficiency. In pre-clinical studies of the last 15 years that were investigating the efficiency of stem cell therapy for stroke, a variety of stem cell types were genetically modified to over-express various factors. In this review we summarize the current knowledge on the therapeutic efficiency of stem cell-derived growth factors, encompassing techniques employed and time points to evaluate. In addition, we discuss several types of stem cells, including the recently developed model of epidermal neural crest stem cells, and genetically modified stem cells over-expressing specific factors, which could elevate the restorative potential of naive stem cells. The restorative potential is based on enhanced survival/differentiation potential of transplanted cells, apoptosis inhibition, infarct volume reduction, neovascularization or functional improvement. Since the majority of studies have focused on the short-term curative effects of genetically engineered stem cells, we emphasize the need to address their long-term impact.

The neuroprotective properties and therapeutic potential of epidermal neural crest stem cells transplantation in a rat model of vascular dementia.

INTRODUCTION: The incidence rate of senile dementia is rising, and there is no definite cure for it yet. Cell therapy, as a new investigational approach, has shown promising results. Hair bulges with abundant easily accessible neural stem cells permit autologous implantation in irreversible neurodegenerative disorders. METHODS: Fifty rats were randomly divided into 5 groups of control, sham-operation, two-common carotid vessel-occlusion rats that received vehicle (2VO + V), 2VO rats that received 1 × 106 epidermal stem cells (2VO + ESC1), and 2VO rats that received 2.5 × 106 epidermal stem cells (2VO + ESC2) in 300 µl PBS intravenously on days 4, 9, and 14 after surgery. The epidermal neural crest stem cells (EPI-NCSCs) were isolated from hair follicles of rat whiskers. The open-field, passive avoidance, and Morris water maze were used as behavioral tests. The basal-synaptic transmission, long-term potentiation (LTP), and short-term synaptic plasticity were evaluated by field-potential recording of the CA1 hippocampal area. RESULTS: 30 days after the first transplantation in the 2VO + ESC1 group, functional recovery was prominent in anxiety and fear memory compared to the 2VO + ESC2 group, while LTP induction was recovered in both groups of grafted animals without improvement in basal synaptic transmission. These positive recoveries may be related to the release of different neurotrophic factors from grafted cells that can stimulate endogenous neurogenesis and synaptic plasticity. CONCLUSIONS: Our results showed that EPI-NCSCs implantation could rescue LTP and cognitive disability in 2VO rats, while transplantation of 1 million cells showed better performance relative to 2.5 million cells.

Aspirin impacts on stem cells: Implications for therapeutic targets.

Despite the regenerative potential of stem cell therapy in pre-clinical investigations, clinical translation of cell-based therapy has not been completely clarified. In recent years, the importance of lifestyle, patient comorbidities, and prescribed medication has attracted more attention in the efficacy of cell therapy. As a nonsteroidal anti-inflammatory drug, aspirin is one of the most prevalent prescribed medications in the clinic for various disorders. Hence, aspirin treatment might affect the efficacy of stem cell therapy. In this regard, the current review focused on the impacts of aspirin on the viability, proliferation, differentiation, and immunomodulatory properties of stem cells in vitro as well as in experimental animal models.

Therapeutic Potential of Vital Transcription Factors in Alzheimer's and Parkinson's Disease With Particular Emphasis on Transcription Factor EB Mediated Autophagy.

Autophagy is an important cellular self-digestion and recycling pathway that helps in maintaining cellular homeostasis. Dysregulation at various steps of the autophagic and endolysosomal pathway has been reported in several neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington disease (HD) and is cited as a critically important feature for central nervous system (CNS) proteostasis. Recently, another molecular target, namely transcription factor EB (TFEB) has been explored globally to treat neurodegenerative disorders. This TFEB, is a key regulator of autophagy and lysosomal biogenesis pathway. Multiple research studies suggested therapeutic potential by targeting TFEB to treat human diseases involving autophagy-lysosomal dysfunction, especially neurodegenerative disorders. A common observation involving all neurodegenerative disorders is their poor efficacy in clearing and recycle toxic aggregated proteins and damaged cellular organelles due to impairment in the autophagy pathway. This dysfunction in autophagy characterized by the accumulation of toxic protein aggregates leads to a progressive loss in structural integrity/functionality of neurons and may even result in neuronal death. In recent years TFEB, a key regulator of autophagy and lysosomal biogenesis, has received considerable attention. It has emerged as a potential therapeutic target in numerous neurodegenerative disorders like AD and PD. In various neurobiology studies involving animal models, TFEB has been found to ameliorate neurotoxicity and rescue neurodegeneration. Since TFEB is a master transcriptional regulator of autophagy and lysosomal biogenesis pathway and plays a crucial role in defining autophagy activation. Studies have been done to understand the mechanisms for TFEB dysfunction, which may yield insights into how TFEB might be targeted and used for the therapeutic strategy to develop a treatment process with extensive application to neurodegenerative disorders. In this review, we explore the role of different transcription factor-based targeted therapy by some natural compounds for AD and PD with special emphasis on TFEB.