Immunoregulatory Effect of Calcitriol on Experimental Autoimmune Encephalomyelitis (EAE) Mice.

Previous studies noted an imbalance in T helper (Th) 17 and regulatory T cells (Tregs) in experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis animal model. calcitriol, vitamin D's active form, was found to ameliorate EAE symptoms by favoring Tregss over Th17 cells, suggesting immunomodulatory effects. This study aimed to assess calcitriol's impact on EAE manifestations and cytokine profile in mice. In this study, we recruited twenty-eight C57BL/6 mice and divided them into 4 groups: healthy controls, EAE, EAE with calcitriol treatment, and healthy mice with calcitriol treatment. CD4+ T cells were isolated from splenocytes using magnetic-activated cell sorting. Real-time polymerase chain reaction was employed to quantify the genes associated with Th9 cells (i.e., SPI1 encoding PU.1 and IL9 encoding interleukin [IL]-9). Moreover, the levels of IL-17 and transforming growth factor beta (TGF-ß) were evaluated through enzyme-linked immunosorbent assay in the supernatant of CD4+ T cell culture stimulated by anti-CD3 and anti-CD28 antibodies for 72 hours. In the supernatant of CD4+ T cell cultures, the levels of interleukin-17 (IL-17) were significantly increased, while the levels of transforming growth factor beta (TGF-ß) were decreased in the EAE Group compared to the healthy control group. Calcitriol treatment reversed these changes and attenuated EAE symptoms, as confirmed in hematoxylin and eosin, and luxol fast blue stains. Notably, calcitriol increased IL9 gene expression in both EAE and healthy mice.  This study provides further evidence of the anti-inflammatory effects of calcitriol and its role in attenuating EAE.

Route exposure and adverse effects monitoring of Aflatoxin B1 in the workers of wet waste management, the role of body redox system modulation.

Exposure to dust, containing different fungi metabolites such as aflatoxins is a risk factor for developing liver and kidney health abnormalities. Occupational evaluation of the aflatoxin's exposure-induced health abnormalities should include the monitoring of bioaerosols in the workplace and personal air, and applying of appropriate blood biomarkers to assess Aflatoxin B1 (AFB1) detrimental effects on a worker's health. However, to the best of our knowledge, these appropriate methods, especially determining the associated-adverse effects on health, following exposure, haven't been well documented in the literature at the wet waste handling sites. In the current study, the AFB1 quantity in the area, personal, and settled dust in wet household waste handling samples and AFB1-Albumin levels in the serum of workers in comparison with the control group were determined using high-pressure liquid chromatography with a fluorescent detector (HPLC-FLD) methods. Moreover, the adverse effects of AFB1 on the liver and kidney biochemical profiles of the exposed workers and its relation to antioxidant capacity in the household wet waste sorting were recorded in a consolidated investigation. The results demonstrated that the average airborne dust concentration and its associated AFB1 content were significantly higher in wet waste management sections as compared to the control place, corresponding to the serum AFB1-Albumin levels of workers. Furthermore, AFB1-induced changes in the serum biochemicals evaluating liver and kidney function tests and antioxidant profiles of workers in wet waste handling sections were indicative of their function abnormalities. The results imply AFB1-induced adverse effects on the liver and kidney functions may be mediated through the body redox system modulation.

The Effect of bisphenol A and Photobiomodulation Therapy on Autophagy-Related Genes Induction in Adipose Tissue-Derived Stem Cells.

Introduction: As adipose tissue-derived stem cells (ADSCs) can divide rapidly and be prepared non-invasively, they have extensively been used in regenerative medicine. On the other hand, a new method of therapy, known as photobiomodulation (PHT), has been used to treat many diseases, such as inflammatory conditions, wound healing and pain. Besides, exposure to chemical substances such as bisphenol A (BPA), at low levels, can lead to autophagy. This study investigated the effects of BPA and PHT on the expression of autophagy-related genes, including LC3, NRF2, P62, in rat ADSCs as a model. Methods: ADSCs isolation and purification were confirmed by immunocytochemistry (ICC). The cells were then treated with different concentrations of BPA and also subjected to PHT. Reverse transcription polymerase chain reaction (RT-PCR) was used for the evaluation of LC3, NRF2 and P62 gene expressions. Oil red O staining was used for adipogenic vacuole formation. Result: ICC showed that the isolated cells were CD 49-positive but CD 31 and CD 34-negative. The viability test indicated that the number of live cells after 24 hours in the BPA groups at concentrations of 0, 1, 50, 100 and 200 µM was 100%, 93%, 81%, 72%, and 43% respectively. The difference in cell viability between groups 50, 100 and 200 µM was significant as compared with the control groups (P < 0.05). Moreover, in the group with 1 µM concentration of BPA, the expressions of LC3, NRF2 and P62 genes were upregulated. However, in the treatment group at the concentration of 200 µM of BPA, the LC3 gene was expressed, but NRF2 and P62 genes were downregulated. Conclusion: BPA and PHT induce autophagy and adiposeness in ADSCs in a dose-dependent manner.

A systematic review and meta-analysis of recent studies reporting hormone levels related to thyroid gland function in migraineurs, until April 2020.

PURPOSE: The purpose of the current study was to evaluate thyroid function in terms of serum thyroid-stimulating hormone (TSH, also known as thyrotropin), 3,5,3'-triiodo-L-thyronine (T3), and 3,5,3',5'-tetraiodo-L-thyronine (T4, also known as thyroxine) levels in migraineurs in comparison with non-migraineurs using a systematic review of literature and a meta-analysis. METHODS: This is a systematic review of case-control studies on serum TSH, T3, and T4 concentrations of migraineurs in comparison with non-migraineurs. After extracting the data from the finally included studies, the weighted overall standardized mean difference (SMD) was calculated. RESULTS: The weighted overall SMD for the impact of TSH, T3, and T4 blood levels for migraineurs in comparison with non-migraineurs was as follows: 0.804 (95% CI, 0.045-1.564), - 0.267 (95% CI, - 0.660-0.125), 0.093 (95% CI, - 0.077-0.263), respectively. It is noteworthy that only the p value for the significance of the overall SMD for serum TSH level was statistically significant (p = 0.038), as examined by the z-test. CONCLUSIONS: The results of the current study point to an association between migraine pathogenesis and changing TSH levels in comparison with those of controls.

Association between ABCC8 Ala1369Ser Polymorphism (rs757110 T/G) and Type 2 Diabetes Risk in an Iranian Population: A Case-Control Study.

OBJECTIVE: Glucose metabolism increases ATP/ADP ratio within the ß-cells and causes ATP-sensitive K+ (KATP) channel closure and consequently insulin secretion. The enhanced activity of the channel may be a mechanism contributing to the reduced first-phase of insulin secretion observed in T2DM. There is no study to date in the Kurdish ethnic group regarding the relationship between SNP Ala1369Ser (rs757110 T/G) of SUR1 gene and T2DM, and additionally, the results of this association in other populations are inconsistent. Therefore, our aim in this study was to explore the possible association between SNP Ala1369Ser and type 2 diabetes in an Iranian Kurdish ethnic group. METHODS: In this study, we checked out the frequency of alleles and genotypes of SNP Ala1369Ser in T2DM individuals (207 patients; men/women: 106/101) and non-T2DM subjects (201 controls; men/women: 97/104), and their effects on anthropometric, clinical, and biochemical parameters. Genomic DNA was extracted from the leukocytes of blood specimens using a standard method. We amplified the ABCC8 rs757110 polymorphic site (T/G) using a polymerase chain reaction (PCR) method and a designed primer pair. To perform the PCR-RFLP method, the amplicons were subjected to restriction enzymes and the resulting fragments separated by gel electrophoresis. RESULTS: The frequency of the G-allele of Ala1369Ser polymorphism was significantly (0.01) higher in the case group than the control group (19% vs. 9%, respectively). In the dominant model (TT vs. TG+GG), there was a significant relationship between this SNP and an increased risk of T2DM (P = 0.00). T2DM patients with TG+GG genotypes had significantly higher fasting plasma insulin and HOMA-IR than those who had the TT genotype (P = 0.02 and 0.01, respectively). CONCLUSION: Our study is the first study to investigate the association between Ala1369Ser ABCC8 genetic variation and T2DM in the Kurdish population of western Iran. The obtained results clearly show that Ala1369Ser polymorphism of ABCC8 is associated with an increased risk of T2DM in this population.

Serum vascular endothelial growth factor (VEGF) levels in ischemic stroke patients: a systematic review and meta-analysis of case-control studies.

Serum VEGF level is regarded to be a biomarker for the diagnosis of stroke. Even though there have been published plethora of original articles describing higher blood VEGF concentrations since the 1970s, however, there is no any meta-analysis report for serum VEGF levels in the field of evidence-based medicine yet. A systematic review was performed by searching the online biomedical databases including retrieving 14 case-control studies including within-article subgroups after fulfilling the inclusion and exclusion criteria without the beginning date restriction, until 2020 for ischemic stroke patients. The Q quantity and I2% statistic index showed a high heterogeneity (84.895 and 84.687, respectively) and the random-effects model of meta-analysis was applied for further analyses. The meta-analysis on a total number of 769 stroke subjects and 621 controls found that the weighted pooled SMD for overall serum VEGF levels on different days of testing was 1.92 (95% CI, - 4.059-0.219, p value = 0.079) and the pooled SMD for overall serum VEGF levels on day 1 of testing was - 1.083 (95% CI, - 4.229-2.063, p value = 0.500). The meta-regression results demonstrated that different days of testing do not significantly affect serum VEGF concentrations in ischemic patients and actually their serum levels are time-independent. Based on the recently published studies, this meta-analysis showed that serum VEGF levels were not significantly associated with an ischemic stroke diagnosis. Thus, researchers may concern another ideal serum or cerebrospinal fluid-derived biomarker for stroke diagnosis.

Liver and kidney serum profile abnormalities in workers exposed to aflatoxin B1 in urban solid waste management centers.

Many workers are exposed to health problems arising from molds, fungi, and their toxins during waste processing. Aflatoxin B1 (AFB1) level in airborne and settled dust, aflatoxin B1-albumin (AFB1-Alb) adduct in serum, liver and kidney biochemical tests, and body redox change of workers in municipal dry waste-processing sites were investigated. The surface, personal, and area air dust and the blood of workers' samples were collected from the plastic and bread waste-sorting sections in three recycling municipal dry waste sites. Digestion (only for serum samples), passed through SPE cartridge, elution, and collection with methanol, immune-affinity column clean-up, and HPLC system equipped with post-column derivatization method and fluorescence detection were performed for determination of AFB1 and AFB1-Alb levels in the samples. The mean level of dust and AFB1 in the personal and area air, and in the settled dust and the AFB1-Alb in the serum of workers in the bread waste sorting, was higher than plastic waste-sorting samples, in all of the sites. The differences in the biochemical profiles of subjects exposed to aflatoxin B1 as compared to the control group especially in liver and kidney function parameters as well as antioxidant factors of the serum were significant. The workers in handling of municipal waste may be exposed to potentially hazardous levels of aflatoxin B1. The adverse effects of AFB1 on the kidney and liver may be caused by changes in the redox system.

Immunomodulatory Effects of Calcitriol through DNA Methylation Alteration of FOXP3 in the CD4+ T Cells of Mice.

Vitamin D plays a variety of physiological functions, such as regulating mineral homeostasis. More recently, it has emerged as an immunomodulator player, affecting several types of immune cells, such as regulatory T (Treg) cells. It has been reported that vitamin D exerts some mediatory effects through an epigenetic mechanism. In this study, the impacts of calcitriol, the active form of vitamin D, on the methylation of the conserved non-coding sequence 2 (CNS2) region of the forkhead box P3 (Foxp3) gene promoter, were evaluated. Fourteen C57BL/6 mice were recruited in this study and divided into two intervention and control groups. The CD4+ T cells were isolated from mice splenocytes. The expression of Foxp3, IL-10, and transforming growth factor-beta (TGF-ß1) genes were relatively quantified by real-time PCR technique, and the DNA methylation percentage of every CpG site in the CNS2 region was measured individually by bisulfite-sequencing PCR. Vitamin D Intervention significantly (p<0.05) could increase the expression of Foxp3, IL-10, and TGF-ß1 gene in the CD4+ T cells of mice comparing with the control group. Meanwhile, methylation of the CNS2 region of Foxp3 promoter was significantly decreased in three of ten CpG sites in the vitamin D group compared to the control group. The results of this study showed that vitamin D can engage the methylation process to induce Foxp3 gene expression and probably Treg cytokines profile. Further researches are needed to discover the precise epigenetic mechanisms by which vitamin D modulates the immune system.

Evidence for hyperprolactinemia in migraineurs: a systematic review and meta-analysis.

BACKGROUND: One of the hypothalamus-pituitary axis hormones which may play a crucial role in pathophysiology of migraine is prolactin which is secreted from anterior pituitary gland and synthesized by various immune system cells as well. Whether prolactin blood levels can affect the migraine pathogenesis is an open question. Therefore, investigating prolactin circulatory levels in migraineurs may pave the way to underpin the mechanisms of migraine pathophysiology at biochemical levels. In the current investigation, the prolactin blood levels in the migraine subjects were investigated using systematic review and meta-analysis. METHODS: Using online and specialized biomedical databases including Google Scholar, Medline, Pubmed, Pubmed Central, Embase, and Scopus, without the beginning date restriction until Feb 2019, the systematic review retrieved 11 publications in this systematic review after fulfilling for the inclusion and exclusion criteria. For heterogeneity, extent calculation statistical testing was applied. In the present study, the levels of circulatory prolactin in migraineurs assessed using standardized mean difference (SMD) as the effect size. RESULTS: Q quantity and I2% statistic index showed a high heterogeneity in the 13 selected publications (188.370 and 92.568, respectively) and random-effects model was chosen for further analyses. The meta-analysis on a total number of 460 migraineurs and 429 healthy controls found that the weighted pooled SMD for the effects of prolactin blood concentrations on migraine pathogenesis was as follows: SMD = 1.435 (95% confidence interval, 0.854-2.015). CONCLUSION: The current investigation presents evidence that prolactin blood levels are higher in migraineurs than healthy subjects.

Leptin, adiponectin, and resistin blood adipokine levels in migraineurs: Systematic reviews and meta-analyses.

INTRODUCTION: Migraine comorbidity with obesity is not new and studies have focused on how adipose tissue-derived substances such as adipokines might be involved in the migraine pathophysiology. Quantification of the nature and magnitude of the association between each adipokine including leptin, adiponectin and resistin with migraine pathophysiology is the objective of the current study. METHODS: Using systematic reviews and meta-analyses and standardized mean difference as effect size, the levels of three adipokines, leptin, adiponectin and resistin, have been investigated in migraineur subjects in the case-control studies. RESULTS: Using random-effects models, the final analyses demonstrated the standardized mean differences of leptin, adiponectin and resistin as 0.534 (95% confidence interval, 0.169-0.898), 0.439 (95% confidence interval, 0.132-0.746) and 0.194 (95% confidence interval, -0.158-0.546), respectively. The p-value for test of significance for each pooled standardized mean difference was examined by the z-test and calculated as 0.004, 0.005 and 0.281 for leptin, adiponectin and resistin (clearly considered as statistically significant, significant and non-significant), respectively. CONCLUSION: Based on the findings, the blood levels of leptin and adiponectin, but not resistin, of the migraineurs are associated with disease pathogenesis.

Intra-articular ozone therapy efficiently attenuates pain in knee osteoarthritic subjects: A systematic review and meta-analysis.

OBJECTIVES: Ozone (O3) gas is being used for chronic pain relief in knee osteoarthritis (KOA). However, there are controversies whether this gas can be medically useful in KOA pain treatments. The aim of this study was to evaluate the effectiveness of intra-articular ozone therapy for pain relief in KOA subjects using a systematic review and meta-analysis and standardized mean difference (SMD) as the effect size. METHOD: Using specialized biomedical online databases of Pubmed Central, Pubmed, Medline, Google scholar, Scopus and Embase databases without the beginning date restriction until July 2018, the systematic review retrieved 10 studies for meta-analysis after fulfilling the inclusion and exclusion criteria. RESULTS: Analysis of Q and I2% indices showed a high heterogeneity in the selected studies (2600.330 and 99.654, respectively), thus, the random-effects model was chosen for SMD calculation. The primary analysis for the main hypothesis found that the weighted pooled effect size for the impact of intra-articular ozone therapy for pain reduction was as follows: SMD= -28.551 (95% confidence interval, -32.553 to -24.549). The P-value for the significance of the combined SMD examined by the z-test was 0.000 and thus, it was clearly considered statistically significant. CONCLUSION: This meta-analysis presents evidence that intra-articular ozone therapy is an effective way for chronic pain management in KOA.

17 ß-Estradiol Oxidative Stress Attenuation and Autophagy-Induced Dopaminergic Neuroprotection.

OBJECTIVE: Degeneration of dopaminergic neurons in the substantia nigra of the brain stem is the main pathological aspect of Parkinson's disease (PD). 17 ß-estradiol (E2) has neuroprotective effects on substantia nigra, however, the underlined mechanism is not well-known. In this study, we evaluated the neuroprotective effects of E2 in the ovariectomized 6-hydroxydopamine- (6-OHDA) rat model of PD. MATERIALS AND METHODS: In this experimental study, all animals were ovariectomized to avoid any further bias in E2 levels and then these ovariectomized rats were randomly assigned into three experimental groups (10 rats in each group): ovariectomized control group (OCG), ovariectomized degeneration group receiving 25 µg of 6-OHDA into the left corpus striatum (ODG), and ovariectomized E2 pretreatment group pretreated with 0.1 mgkg-1 of 17 ß-estradiol for three days prior to the destruction of corpus striatum with 6-OHDA (OE2PTG). The apomorphine behavioral test and Nissl staining were performed in all experimental groups. The expressions of Sequestosome-1 (P62), Unc- 51 like autophagy activating kinase (Ulk1), and microtubule-associated proteins 1A/1B light chain 3B (Lc3) genes were evaluated using reverse transcriptionpolymerase chain reaction (RT-PCR). RESULTS: E2 administration reduced the damages to the dopaminergic neurons of the substantia nigra. The motor behavior, the number of rotations, and histological tests in the treatment group showed the cell survival improvement in comparison with the control groups indicating that E2 can inhibit the neurodegeneration. P62 and Lc3 were expressed in all experimental groups while Ulk1 was not expressed in ODG group. Moreover, Ulk1 was expressed after the treatment with E2 in OE2PTG group. CONCLUSION: E2 prevents neurodegeneration in dopaminergic neurons of the midbrain by over-expression of Ulk1 gene and augmenting the induction of autophagy.

Elevated blood apelin levels in type 2 diabetes mellitus: A systematic review and meta-analysis.

AIMS: Apelin is a circulatory blood peptide acting as a ligand for the orphan G protein-coupled receptor known as APJ. Whether apelin blood levels can affect the pathogenesis of type 2 diabetes mellitus is an open question. In the present study, we aimed to assess the levels of circulatory apelin peptide in the type 2 diabetic subjects using systematic review and meta-analysis under random-effects model and standardized mean difference (SMD) as the effect size. For heterogeneity testing, Q and I2% statistic indices as well as meta-regression were applied. METHODS: Using specialized biomedical online databases of Pubmed, Pubmed Central, Medline, Google scholar, Scopus and Embase databases without the beginning date restriction until July 2018, the systematic review retrieved nine studies for meta-analysis after fulfilling the inclusion and exclusion criteria. RESULTS: Analysis of Q and I2% statistic indices as well as meta-regression showed a high heterogeneity in the 16 selected studies (737.578 and 96.475, respectively), thus, the random-effects model was chosen. The primary analysis for the main hypothesis on a total number of 1102 cases and 1078 healthy control subjects found that the weighted pooled SMD for the impact of apelin blood concentration in type 2 diabetes mellitus was as follows: SMD = 2.136 (95% confidence interval, 1.580-2.693). The P-value for the significance of the combined SMD examined by the z-test was 0.000 and thus, it was clearly significant. CONCLUSIONS: This meta-analysis presents evidence that apelin circulatory levels are higher in type 2 diabetic subjects than normal controls.

Frequency of CD8+ regulatory T cells in the multiple sclerosis patients: a systematic review and meta-analysis.

Multiple sclerosis (MS) is a neuro-immunological demyelinating disease. From the immunological aspects, it is well accepted that T cells play a pivotal role in the etiology of the disease. T helper (Th) 1 and Th17 cells are thought to be the main pathogenic T cells in the pathogenesis of MS and are known as effector T cells. As the self-reactive T lymphocytes can escape clonal deletion in the thymus and subsequently are released into the periphery, there is an urgent need for peripheral tolerance, which is executed by the specialized regulatory T (Treg) cells. Interestingly, CD8+ regulatory T (Treg) cells have also been identified among lymphocyte subtypes. The peripheral CD8+ Treg cells frequency in MS subjects in comparison with healthy controls is the objective of the current study using the systematic review and meta-analysis. A systematic literature search was carried out using specialized biomedical databases of Pubmed, Pubmed Central, Medline, Google Scholar, Embase and SCOPUS databases without the beginning date restriction until January 2018 in English language. The results were as follows: OR 15.548 (95% confidence interval 1.954-123.742) using the random-effects model. The P value for test of significance of the total OR was examined by the z test and calculated as 0.010 (clearly considered as statistically significant). Based on our findings, the number of CD8+ Treg cells in the blood of MS subjects is significantly different as compared to healthy controls.

C/EBP homologous protein investigation in the serum and cerebro-spinal fluid of relapsing-remitting multiple sclerosis patients.

The exact determination of endoplasmic reticulum (ER) stress-associated proteins is not completely elucidated in the multiple sclerosis (MS) patients. We measured CHOP concentrations in the serum and cerebro-spinal fluid (CSF) of relapsing-remitting MS (RRMS) patients (n = 20) in comparison with the non-MS control group (n = 20) to determine whether this marker could be detected in the body fluids of RRMS patients. CHOP marker was not detectable in all harvested CSF samples. However, its levels were detectable in all serums harvested from both non-MS and RRMS patients and its levels in the latter group were not significantly higher than those of the non-MS control group (P value = 0.265). CHOP was not detectable in the CSF of RRMS patients in spite of the recent reports on the RRMS autopsies. Additionally, there were not any significant correlations (Spearman's correlation) between both of EDSS score and age with CHOP serum concentrations in all subjects.

Trehalose Neuroprotective Effects on the Substantia Nigra Dopaminergic Cells by Activating Autophagy and Non-canonical Nrf2 Pathways.

Trehalose, as a natural disaccharide, is known as an autophagy inducer. The neuroprotective effects of trehalose in the rat model of Parkinson's disease were the aim of the present study. Parkinson's disease model was induced by injecting 6-hydroxydopamine (6-OHDA) in the striatum of male Wistar rats. Apomorphine-induced behavior and substantia nigra neuronal counts were applied to evaluate the neuroprotective effects of trehalose. The autophagy was studied using the expression of p62 and LC3II/LC3I ratio. In addition, the antioxidant effects of trehalose were assessed by analyzing the levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and also glutathione reductase (GR), glutathione peroxidase (GPx) and Catalase (CAT) enzymes. Moreover, the levels of 3, 4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) were assessed.The behavioral test showed that trehalose in the treatment group reduced the damage to the substantial nigra dopaminergic neurons, which was characterized by improved motor and reduced rotations in the treatment group as compared with the lesion group. In the histological examinations of the treatment group, trehalose prevented the destruction of dopaminergic neurons. Trehalose treatments increased autophagy (high LC3II/LC3I ratio) and the expression of the p62 protein as well. Through p62-dependent manner, it led to increased nuclear translocation of Nrf2 transcription factor and elevated expression of downstream antioxidant enzymes, such as GR, GPx, and CAT, restoring DA and DOPAC contents of the cells. In the current study, trehalose simultaneously protects substantia nigra dopaminergic cells by activating both non-canonical p62/SQSTM1-Keap1-Nrf2 and autophagy pathways.

Stem cell transplantation and functional recovery after spinal cord injury: a systematic review and meta-analysis.

Spinal cord injury is a significant cause of motor dysfunctions. There is no definite cure for it, and most of the therapeutic modalities are only symptomatic treatment. In this systematic review and meta-analysis, the effectiveness of stem cell therapy in the treatment of the spinal cord injuries in animal models was studied and evaluated. A systematic search through medical databases by using appropriate keywords was conducted. The relevant reports were reviewed in order to find out cases in which inclusion and exclusion criteria had been fulfilled. Finally, 89 articles have been considered, from which 28 had sufficient data for performing statistical analyses. The findings showed a significant improvement in motor functions after cell therapy. The outcome was strongly related to the number of transplanted cells, site of injury, chronicity of the injury, type of the damage, and the induction of immune-suppression. According to our data, improvements in functional recovery after stem cell therapy in the treatment of spinal cord injury in animal models was noticeable, but its outcome is strongly related to the site of injury, number of transplanted cells, and type of transplanted cells.

SMER28 Attenuates Dopaminergic Toxicity Mediated by 6-Hydroxydopamine in the Rats via Modulating Oxidative Burdens and Autophagy-Related Parameters.

Parkinson's disease is the second most common neurodegenerative disease that occurs due to cellular autophagy deficiency and the accumulation of alpha-synuclein in the dopaminergic neurons of the substantia nigra pars compacta (SNc) of the brainstem. The SMER28 (also known as 6-Bromo-N-prop-2-enylquinazolin-4-amine) is an autophagy inducer. In this study, the neuroprotective effects of SMER28 were evaluated on autophagy induction, antioxidant system activation, and microgliosis attenuation. The Parkinson's disease model was developed in the male Wistar rats by injection of 6-OHDA into the left striatum. Apomorphine-induced behavior assessment test and SNc cell counting were performed to investigate the neuroprotective effects of SMER28. This study examined the pharmacological roles of SMER28, especially by focusing on the autophagy (p62/ SQSTM1 and LC3II/LC3I ratio where LC3 is microtubule-associated protein 1A/1B-light chain 3), inhibiting free radicals, and activating the antioxidant system. The levels of malondialdehyde (MDA), reactive oxygen species (ROS), glutathione (GSH), GSH/glutathione peroxidase (GPX), superoxide dismutase (SOD) activity and nuclear factor-erythroid 2-related factor-2 (Nrf2) were measured to evaluate the antioxidant activity of SMER28. Moreover, Iba-1 (ionized calcium binding adaptor molecule, indicating microgliosis) and tyrosine hydroxylase immunoreactivities were evaluated in the SNc. In the behavioral assessment, SMER28 (50 µg/kg) attenuated damages to the SNc dopaminergic neurons, characterized by improved motor function. The tissue observations revealed that SMER28 prevented the destruction of SNc neurons and attenuated microgliosis as well. It also reduced MDA and ROS production and increased GSH, GPX, SOD, and Nrf2 activities by inducing autophagy (decreasing p62 and increasing LC3II/LC3I ratio). Consequently, possibly with further studies, it can be considered as a drug for neurodegenerative diseases with proteinopathy etiology.

Human wild-type superoxide dismutase 1 gene delivery to rat bone marrow stromal cells: its importance and potential future trends.

OBJECTIVES: Human superoxide dismutase 1 (SOD1) is the cytosolic form of this enzyme it detoxifies superoxide anions and attenuates their toxicities and concomitant detrimental effects on the cells. It is believed that the amount of these enzymes present in the oxidative stress-induced diseases is crucial for preventing disease progression. Transfection of rat bone marrow stromal cells (BMSCs) by a constructed vector carrying the human wild-type SOD1 gene, a non-viral gene transfer method, was the main aim of this study. MATERIALS AND METHODS: For this purpose, the rat BMSCs were transfected with the vector using Turbofect reagent and then stabilized. Western-blot and real-time PCR were also used for evaluation of SOD1 expression. RESULTS: Data analysis from RT-PCR and Western-blot techniques revealed that the stable transfected cells could secrete human wild-type SOD1 in the supernatant. Also, the total activity of SOD1 was about 0.5±0.09 U/ml and 0.005±0.002 U/ml in the supernatants of the transfected and not-transfected of rat BMSCs, respectively. CONCLUSION: This study showed that expansion of the stable transfected rat BMSCs by a constructed vector carrying the human wild-type SOD1 gene is capable of secreting the active SOD1 enzyme under ex-vivo conditions. The recommendation of this study is that the same experiment would be applicable for expression of the other form of this enzyme, SOD3, as well. More valuable information could probably be provided about the variety of the diseases caused by superoxide anions toxicities by intervention and application of the non-viral method for expressions of SOD1 and SOD3 enzymes.