RESUMEN
Central nervous system (CNS) disorders are one of the leading health problems today, accounting for a large proportion of global morbidity and mortality. Most these disorders are characterized by high levels of oxidative stress and intense inflammatory responses in degenerated neuronal tissues. While extensive research has been conducted on CNS diseases, but few breakthroughs have been made in treatment methods. To date, there are no disease-modifying drugs available for CNS treatment, underscoring the urgent need for finding effective medications. Bee venom (BV), which is produced by honeybee workers' stingers, has been a subject of interest and study across various cultures. Over the past few decades, extensive research has focused on BV and its therapeutic potentials. BV consists a variety of substances, mainly proteins and peptides like melittin and phospholipase A2 (PLA2). Research has proven that BV is effective in various medical conditions, including pain, arthritis and inflammation and CNS disorders such as Multiple sclerosis, Alzheimer's disease and Parkinson's disease. This review provides a comprehensive overview of the existing knowledge concerning the therapeutic effects of BV and its primary compounds on various CNS diseases. Additionally, we aim to shed light on the potential cellular and molecular mechanisms underlying these effects.
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BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) with inflammation and immune dysfunction. OBJECTIVES: We compared the remyelination and immunomodulation properties of mesenchymal stem cells (MSCs) with their conditioned medium (CM) in the cuprizone model. METHODS: Twenty-four C57BL/ 6 mice were divided into four groups. After cuprizone demyelination, MSCs and their CM were injected into the right lateral ventricle of mice. The expression level of IL-1ß, TNF-α, and BDNF genes was evaluated using the qRT-PCR. APC antibody was used to assess the oligodendrocyte population using the immunofluorescent method. The remyelination and axonal repair were studied by specific staining of the LFB and electron microscopy techniques. RESULTS: Transplantation of MSCs and CM increased the expression of the BDNF gene and decreased the expression of IL-1ß and TNF-α genes compared to the cuprizone group, and these effects in the cell group were more than CM. Furthermore, cell transplantation resulted in a significant improvement in myelination and axonal repair, which was measured by luxol fast blue and transmission electron microscope images. The cell group had a higher number of oligodendrocytes than other groups. CONCLUSIONS: According to the findings, injecting MSCs intraventricularly versus cell-conditioned medium can be a more effective approach to improving chronic demyelination in degenerative diseases like MS.
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Cuprizona , Enfermedades Desmielinizantes , Modelos Animales de Enfermedad , Inflamación , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Ratones Endogámicos C57BL , Animales , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones , Células Madre Mesenquimatosas/metabolismo , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Medios de Cultivo Condicionados/farmacología , Inflamación/patología , Inflamación/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Oligodendroglía/metabolismo , Remielinización , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/inducido químicamente , Factor de Necrosis Tumoral alfa/metabolismo , Masculino , Vaina de Mielina/metabolismoRESUMEN
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by inflammation and demyelination of CNS neurons. Up to now, there are many therapeutic strategies for MS but they are only being able to reduce progression of diseases and have not got any effect on repair and remyelination. Stem cell therapy is an appropriate method for regeneration but has limitations and problems. So recently, researches were used of exosomes that facilitate intercellular communication and transfer cell-to-cell biological information. MicroRNAs (miRNAs) are a class of short non-coding RNAs that we can used to their dysregulation in order to diseases diagnosis. The miRNAs of microvesicles obtained stem cells may change the fate of transplanted cells based on received signals of injured regions. The miRNAs existing in MSCs may be displayed the cell type and their biological activities. Current studies show also that the miRNAs create communication between stem cells and tissue-injured cells. In the present review, firstly we discuss the role of miRNAs dysregulation in MS patients and miRNAs expression by stem cells. Finally, in this study was confirmed the relationship of microRNAs involved in MS and miRNAs expressed by stem cells and interaction between them in order to find appropriate treatment methods in future for limit to disability progression.
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Exosomas , MicroARNs , Esclerosis Múltiple , Células Madre , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Exosomas/metabolismo , Esclerosis Múltiple/terapia , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Animales , Células Madre/metabolismoRESUMEN
Exosomes are nano-sized membrane extracellular vesicles which can be released from various types of cells. Exosomes originating from inflammatory or injured cells can have detrimental effects on recipient cells, while exosomes derived from stem cells not only facilitate the repair and regeneration of damaged tissues but also inhibit inflammation and provide protective effects against various diseases, suggesting they may serve as an alternative strategy of stem cells transplantation. Exosomes have a fundamental role in communication between cells, through the transfer of proteins, bioactive lipids and nucleic acids (like miRNAs and mRNAs) between cells. This transfer significantly impacts both the physiological and pathological functions of recipient cells. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is able to mitigate damage caused by oxidative stress and inflammation through various signaling pathways. The positive effects resulting from the activation of the Nrf2 signaling pathway in different disorders have been documented in various types of literature. Studies have confirmed that exosomes derived from stem cells could act as Nrf2 effective agonists. However, limited studies have explored the Nrf2 role in the therapeutic effects of stem cell-derived exosomes. This review provides a comprehensive overview of the existing knowledge concerning the role of Nrf2 signaling pathways in the impact exerted by stem cell exosomes in some common diseases.
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Exosomas , MicroARNs , Humanos , Exosomas/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Células Madre/metabolismo , Inflamación/metabolismoRESUMEN
One of the major causes of long-term disability and mortality is ischemic stroke that enjoys limited treatment approaches. On the one hand, oxidative stress, induced by excessive generation of reactive oxygen species (ROS), plays a critical role in post-stroke inflammatory response. Increased ROS generation is one of the basic factors in the progression of stroke-induced neuroinflammation. Moreover, intravenous (IV) thrombolysis using recombinant tissue plasminogen activator (rtPA) as the only medication approved for patients with acute ischemic stroke who suffer from some clinical restrictions it could not cover the complicated episodes that happen after stroke. Thus, identifying novel therapeutic targets is crucial for successful preparation of new medicines. Recent evidence indicates that the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) contributes significantly to regulating the antioxidant production in cytosol, which causes antiinflammatory effects on neurons. New findings have shown a relationship between activation of the Nrf2 and glial cells, nuclear factor kappa B (NF-κB) pathway, the nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, and expression of inflammatory markers, suggesting induction of Nrf2 activation can represent a promising therapeutic alternative as the modulators of Nrf2 dependent pathways for targeting inflammatory responses in neural tissue. Hence, this review addresses the relationship of Nrf2 signaling with inflammation and Nrf2 activators' potential as therapeutic agents. This review helps to improve required knowledge for focused therapy and the creation of modern and improved treatment choices for patients with ischemic stroke.
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Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Activador de Tejido Plasminógeno/metabolismo , Transducción de Señal , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Inflamación/tratamiento farmacológico , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib's mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Calidad de Vida , Estaciones del AñoRESUMEN
Microglia are the primary immune cells of the central nervous system (CNS) that comprise about 5-12% of all cells in the brain. These cells are the first line of defense that protects the CNS from damage and attacking pathogens. Microglia originate from yolk sac macrophages and migrate to the brain before the blood-brain barrier formation. Microglia show key roles in healthy CNS including promoting neurogenesis, synaptic sculpting, and maintaining homeostasis but in pathological conditions of CNS, microglial activation may exacerbate diseases. Thus, microglial depletion of the CNS is a novel approach that could be a useful tool to understand the microglial functions in neurodegenerative and neuroinflammatory diseases. There are methods for microglial ablation and reduction such as genetic tools and pharmacological inhibitors. In this study, we review recent studies that used different microglial ablation models for microglial reduction and repopulation after depletion in pathological states of CNS. Recently, studies showed that microglial depletion as a potential therapeutic application has benefits (such as inflammatory factors reduction, increase synaptogenesis, astrogliosis preventation) in CNS. For these reasons, the inhibition of microglia with these models was considered a therapeutic approach for neurodegenerative disease treatment.
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Microglía , Enfermedades Neurodegenerativas , Humanos , Microglía/patología , Enfermedades Neurodegenerativas/patología , Sistema Nervioso Central/patología , Encéfalo/patología , Macrófagos/patologíaRESUMEN
TP53 is the most frequently mutated gene in human cancer. It encodes the tumor suppressor protein p53, which suppresses tumorigenesis by acting as a critical transcription factor that can induce the expression of many genes controlling a plethora of fundamental cellular processes, including cell cycle progression, survival, apoptosis, and DNA repair. Missense mutations are the most frequent type of mutations in the TP53 gene. While these can have variable effects, they typically impair p53 function in a dominant-negative manner, thereby altering intra-cellular signaling pathways and promoting cancer development. Additionally, it is becoming increasingly apparent that p53 mutations also have non-cell autonomous effects that influence the tumor microenvironment (TME). The TME is a complex and heterogeneous milieu composed of both malignant and non-malignant cells, including cancer-associated fibroblasts (CAFs), adipocytes, pericytes, different immune cell types, such as tumor-associated macrophages (TAMs) and T and B lymphocytes, as well as lymphatic and blood vessels and extracellular matrix (ECM). Recently, a large body of evidence has demonstrated that various types of p53 mutations directly affect TME. They fine-tune the inflammatory TME and cell fate reprogramming, which affect cancer progression. Notably, re-educating the p53 signaling pathway in the TME may be an effective therapeutic strategy in combating cancer. Therefore, it is timely to here review the recent advances in our understanding of how TP53 mutations impact the fate of cancer cells by reshaping the TME.
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Neoplasias , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Genes p53 , Neoplasias/genética , Neoplasias/patología , Carcinogénesis/genética , Transformación Celular Neoplásica/metabolismo , Microambiente Tumoral/genéticaRESUMEN
Spinal cord injury (SCI) is a traumatic injury with sensory and motor deficits that more than 1 million patients worldwide suffer from disability due to it. Many pharmacological therapies help reduce SCI-related injury and protect CNS from more damage but no current therapy could improve the axonal repair. In this regard, stem cell therapy is considered a regenerative method for SCI patient treatment. The neurotrophic and immunomodulatory factor secretion, differentiation, neuroprotecting, and remyelinating properties have made mesenchymal stem cells (MSCs) principally useful in this field. There are studies on the role of MSCs in patients suffering from SCI. However, low number of SCI patients and the lack of control groups in these studies, the cell transplantation appropriate methods, including cell source, dose, route of delivery, and transplantation timing, are various in trials. This study reviews the beneficial effects of MSC transplantation in SCI clinical studies with a special focus on the MSC properties and limitations of MSC transplantation.
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Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Traumatismos de la Médula Espinal , Axones , Diferenciación Celular , Humanos , Trasplante de Células Madre Mesenquimatosas/métodos , Médula Espinal , Traumatismos de la Médula Espinal/terapiaRESUMEN
Motor neuron diseases such as spinal cord injuries and amyotrophic lateral sclerosis are known as the most common disorders worldwide. Using stem cells (e.g., human umbilical cord blood mesenchymal stem cells) is currently a potent medical approach for modulating the impact of neural damages and regeneration of spinal cord injuries. MicroRNAs (miRNA) are taken into account as principal regulators during differentiation. The miRNAs play a significant role in stem cell self-renewal and fate determination. There are few studies on how miRNAs regulate neural differentiation in stem cells. The purpose of this study is to explore miRNA profiles of CB-MSCs during differentiation into motor neuron-like cells. Human CB-MSCs were isolated and characterized using flow cytometry. Cell differentiation has been induced by combining retinoic acid (RA) and sonic hedgehog (Shh) in a two-step protocol for 14 days. Then, cell differentiation was confirmed by immunocytochemistry and flow cytometry. The miRNA was analyzed using Illumina/Solexa sequencing platform. In this regard, three libraries were prepared to investigate the effect of these two biological morphogens on the miRNA profile of the differentiating cells. These libraries were Control (non-treated CB-MSCs), Test 1 (RA + /Shh +), and Test 2 (RA-/Shh-). Quantitative RT-PCR was employed to verify miRNA expression. CB-MSCs were spindle-shaped in morphology, and they did not express hematopoietic markers. After differentiation, the cells expressed motor neuron markers (i.e., Islet-1, SMI-32, and ChAT) at the protein level after 14 days. The analysis of miRNA sequencing demonstrated a significant up-regulation of miR-9-5p and miR-324-5p in Test 1 (RA + /Shh +). Also, there is a considerable down-regulation of mir-137 and let-7b in Test 2 (RA-/Shh-). These results have been obtained by comparing them with the Control library. Indeed, they were responsible for neuron and motor neuron differentiation and suppression of proliferation in neural progenitor cells. Furthermore, significant up-regulation was detected in some novel microRNAs involved in cholinergic, JAK-STAT, and Hedgehog and MAPK signaling pathways. CB-MSCs are potent to express motor neuron markers. This procedure has been performed by developing a two-week protocol and employing Shh and RA. The miRNA profile analysis showed a significant up-regulation in the expression of some miRs involved in neuron differentiation and motor neuron maturation. MiR-9-5p and miR-324-5p were up-regulated at the early stage of differentiation. Also, miR-137 and miR-let-7b were downregulated in the absence of RA and Shh. Furthermore, several novel miRNAs involved in cholinergic, Hedgehog, MAPK, and JAK-STAT signaling pathways have been detected. However, further studies are still necessary to validate their functions during motor neuron generation and maturation.
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Células Madre Mesenquimatosas , MicroARNs , Traumatismos de la Médula Espinal , Diferenciación Celular , Colinérgicos/metabolismo , Sangre Fetal/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , MicroARNs/metabolismo , Neuronas Motoras/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Tretinoina/metabolismo , Tretinoina/farmacologíaRESUMEN
Multiple sclerosis (MS), which is an autoimmune disease, is characterized by symptoms such as demyelination, axonal damage, and astrogliosis. As the most abundant type of glial cells, astrocytes play an important role in MS pathogenesis. Mesenchymal stem cells (MSCs) are a subset of stromal cells that have the potential for migration, immune-modulation, differentiation, remyelination, and neuroregeneration. Therefore, the present study evaluates the effects of MSC transplantation on A1 reactive astrocytes and the remyelination process in the cuprizone mouse model. The study used 30 male C57BL/6 mice, which were randomly distributed into three subgroups (n = 10), i.e., control, cuprizone, and transplanted MSCs groups. In order to generate a chronic demyelination model, the mice in the cuprizone group received food mixed with 0.2% cuprizone powder for 12 weeks. Then, 2 µl of DMEM containing approximately 3 × 105 DiI labeled cells was injected with a 4-min interval into the right lateral ventricle using a 10-µl Hamilton syringe. After 2 weeks of cell transplantation, we used the rotarod test to evaluate the behavioral deficits, while the remyelination process was assessed by transmission electron microscopy (TEM) and Luxol Fast Blue (LFB) staining. We assessed the population of A1 astrocytes and oligodendrocytes using specific markers, such as C3, GFAP, and Olig2, using the immunefleurocent method. The pro-inflammatory and trophic factors were assessed by a real-time polymerase chain reaction. According to our data, the specific marker of A1 astrocytes (C3) decreased in the MSCs group, while the number of oligodendrocytes significantly increased in this group compared to the cuprizone mice. Additionally, MSC was able to enhance the remyelination process after cuprizone usage, as shown by LFB and TEM images. The molecular results showed that MSCs could reduce pro-inflammatory factors, such as IL-1 and TNF-α, through the secretion of BDNF and TGF-ß as trophic factors. The obtained results indicated that MSC could reduce demyelination and inflammation by decreasing A1 neurotoxic reactive astrocytes and neurotrophic and immunomodulatory factors secretion in the chronic cuprizone demyelination model.
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Enfermedades Desmielinizantes , Células Madre Mesenquimatosas , Esclerosis Múltiple , Animales , Astrocitos/patología , Biomarcadores , Cuprizona , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/terapia , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/patología , OligodendroglíaRESUMEN
Multiple sclerosis is a kind of autoimmune and demyelinating disease with pathological symptoms such as inflammation, myelin loss, astrocytosis, and microgliosis. The colony stimulating factor 1 receptor (CSF1R) is an essential factor for the microglial function, and PLX3397 (PLX) is its specific inhibitor. In this wstudy, we assessed the effect of different doses of PLX for microglial ablation on glial cell population and remyelination process. Sixty male C57BL/6 mice (8 weeks old) were divided into 6 groups. The animals were fed with 0.2% cuprizone diet for 12 weeks. For microglial ablation, PLX (290 mg/kg) was added to the animal food for 3, 7, 14 and 21 days. Glial cell population was measured using immunohistochemistry. The rate of remyelination was evaluated using electron microscopy and Luxol Fast Blue staining. The expression levels of all genes were assessed by qRT-PCR method. Data were analysed using GraphPad Prism and SPSS software. The results showed that the administration of different doses of PLX significantly reduced microglial cells (p ≤ .001). PLX administration also significantly increased oligodendrocytes population (p ≤ .001) and remyelination compared to the cuprizone mice, which was aligned with the results of LFB and TEM. Gene results showed that PLX treatment reduced CSF1R expression. According to the results, the administration of PLX for 21 days enhanced remyelination by increasing oligodendrocytes in the chronic demyelination model. These positive effects could be related to the reduction of microglia.
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Aminopiridinas/farmacología , Esclerosis Múltiple/patología , Vaina de Mielina/efectos de los fármacos , Neuroglía/efectos de los fármacos , Pirroles/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Remielinización/efectos de los fármacos , Animales , Cuprizona , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/patología , Neuroglía/patologíaRESUMEN
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system with symptoms such as neuroinflammation, astrocytosis, microgliosis, and axonal degeneration. Mesenchymal stem cells (MSCs) with their immunomodulation, differentiation, and neuroprotection abilities can influence the remyelination process. The goal of this study is to investigate the impact of microglial ablation and MSCs transplantation on remyelination processes in the corpus callosum (CC) of the cuprizone demyelination model. For the induction of a chronic demyelination model, C57BL6 mice were fed with chow containing 0.2% cuprizone (wt/wt) for 12 weeks. For the depletion of microglia, PLX3397 was used as a colony-stimulating factor 1 receptor inhibitor for 21 days. MSCs were injected to the right lateral ventricle and after 2 weeks, the mice were killed. We assessed glial cells using specific markers such as APC, Iba-1, and GFAP using the immunohistochemistry method. Remyelination was evaluated by Luxol fast blue (LFB) staining and transmission electron microscope (TEM). The specific genes of microglia and MSCs were evaluated by a quantitative real-time polymerase chain reaction. According to the results of the study, 21 days of PLX3397 treatment significantly reduced microglial cells, and MSCs transplantation decreased the number of astrocytes, whereas the oligodendrocytes population increased significantly in PLX + MSC group in comparison with the cuprizone mice. Furthermore, PLX and MSC treatment elevated levels of remyelination compared with the cuprizone group, as confirmed by LFB staining and TEM analysis. The molecular results showed that MSC transplantation significantly decreased the number of microglia through the CX3CL1/CX3CR1 axis. These results revealed that PLX3397 treatment and MSCs injection reduced microgliosis and astrocytosis. It also increased the oligodendrocytes population by enhancing remyelination in the CC of the cuprizone model of MS.
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Enfermedades Desmielinizantes/terapia , Trasplante de Células Madre Mesenquimatosas , Microglía/patología , Aminopiridinas/administración & dosificación , Aminopiridinas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Biomarcadores/metabolismo , Receptor 1 de Quimiocinas CX3C/metabolismo , Proteínas de Unión al Calcio/metabolismo , Quimiocina CX3CL1/metabolismo , Cuerpo Calloso/patología , Cuerpo Calloso/ultraestructura , Cuprizona , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía/metabolismo , Inyecciones Intraventriculares , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , Microglía/efectos de los fármacos , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Pirroles/administración & dosificación , Pirroles/farmacologíaRESUMEN
Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) with symptoms such as neuroinflammation and axonal degeneration. Existing drugs help reduce inflammatory conditions and protect CNS from demyelination and axonal damage; however, these drugs are unable to enhance axonal repair and remyelination. In this regard, cell therapy is considered as a promising regenerative approach to MS treatment. High immunomodulatory capacity, neuro-differentiation and neuroprotection properties have made Mesenchymal Stem Cells (MSCs) particularly useful for regenerative medicine. There are scant studies on the role of MSCs in patients suffering from MS. The low number of MS patients and the lack of control groups in these studies may explain the lack of beneficial effects of MSC transplantation in cell therapies. In this review, we evaluated the beneficial effects of MSC transplantation in clinical studies in terms of immunomodulatory, remyelinating and neuroprotecting properties of MSCs.
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Diferenciación Celular/fisiología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Esclerosis Múltiple/terapia , Animales , Modelos Animales de Enfermedad , Humanos , Trasplante de Células Madre Mesenquimatosas/métodos , Remielinización/fisiologíaRESUMEN
BACKGROUND: The increase of oxidant compounds is the most well-known reasons for the tolerance to the analgesic properties of Morphine. Additionally, the production of proxy-nitrite impairs receptors, proteins and enzymes involved in the signaling pathways of analgesia, apoptosis and necrosis. Also, we revised all patents relating to opioid tolerance control methods. OBJECTIVE: The aim of this study was to assess the effects of Alpha-tocopherol as an anti-oxidant agent to reduce Morphine tolerance. METHOD: Forty male rats randomly divided into four groups. 10 mg/kg of morphine was injected subcutaneously to create the desired level of tolerance. After modeling, 70 mg/kg Alpha- Tocopherol was injected intraperitoneal. Also, the hot plate recorded pain threshold alterations was used to evaluate the behavioral test. All tissue samples were extracted from the spinal cord, thalamus and frontal cortex for molecular and gene expression evaluations. Also, the effect of Alpha- Tocopherol on the apoptosis and necrosis parameters was analyzed using nissl staining and tunel test. RESULTS: The time latency results showed that there were no significant differences in the different days in groups treated with Morphine plus Alpha-Tocopherol. However, our data highlighted that the pain threshold and their time latency in respond to it had substantially increased in comparison with the control group. Furthermore, we found that the Alpha-Tocopherol obviously decreased c-fos gene expression, especially in the spinal cord. CONCLUSION: Thus, co-administration of Alpha-Tocopherol with Morphine can decrease the adverse effects of nitrite proxy, which is released due to repeated injections of Morphine.
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Analgésicos Opioides/farmacología , Antioxidantes/farmacología , Tolerancia a Medicamentos/genética , Genes fos , Morfina/farmacología , Dolor/tratamiento farmacológico , alfa-Tocoferol/farmacología , Animales , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Expresión Génica/efectos de los fármacos , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Masculino , Dolor/genética , Dolor/metabolismo , Dolor/fisiopatología , Patentes como Asunto , Ratas , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Tálamo/efectos de los fármacos , Tálamo/metabolismoRESUMEN
Microglial cells have an essential role in neurodegenerative disorders, such as multiple sclerosis. They are divided into two subgroups: M1 and M2 phenotypes. Mesenchymal stem cells (MSC), with neuroprotective and immunomodulating properties, could improve these diseases. We evaluate the immunomodulating effects of MSC on microglial phenotypes and the improvement of demyelination in a cuprizone (CPZ) model of multiple sclerosis (MS). For inducing the chronic demyelination model, C57BL6 mice were given a diet with 0.2% CPZ (w/w) for 12 weeks. In the MSC group, cells were transplanted into the right lateral ventricle of mice. The expression of targeted genes was assessed by real-time polymerase chain reaction. M1 and M2 microglial phenotypes were assessed by immunohistochemistry of inducible nitric oxide synthase (iNOS) and Arg-1, respectively. Remyelination was studied by luxal fast blue (LFB) staining and electron microscopy (EM). We found that MSC transplantation reduced the expression level of M1-specific messenger RNA (mRNA; iNOS and CD86) but increased the expression level of M2 specific genes (CD206, Arg-1, and CX3CR1) in comparison to the CPZ group. Moreover, cell therapy significantly decreased the M1 marker (iNOS+ cells), but M2 marker (Arg-1+ cells) significantly increased in comparison with the CPZ group. In addition, MSC treatment significantly increased the CX3CL1 expression level in comparison with the CPZ group and led to improvement in remyelination, which was confirmed by LFB and EM images. The results showed that MSC transplantation increases the M2 and decreases the M1 phenotype in MS. This change was accompanied by decrease in demyelination and axonal injury and indicated that MSCs have a positive effect on MS by modification of microglia cells.
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Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Células Madre Mesenquimatosas/patología , Microglía/patología , Animales , Receptor 1 de Quimiocinas CX3C/metabolismo , Quimiocina CX3CL1/metabolismo , Cuerpo Calloso/patología , Cuerpo Calloso/ultraestructura , Cuprizona , Modelos Animales de Enfermedad , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Fenotipo , Remielinización , Transducción de SeñalRESUMEN
Mesenchymal stem cells (MSCs) have a notable potential to modulate immune responses and protect the central nervous system (CNS), mostly by secreting factors that affect inflammation. MSCs have the ability to improve several autoimmune diseases in animal models including multiple sclerosis (MS). MS is a disease of the CNS among adult humans and it is characterized by demyelination, neuroinflammation and gliosis. In this study, we first induced chronic demyelination by cuprizone, followed by intraventricular injection of MSC. Our results showed that MSC significantly decreased microgliosis and astrocytosis by secreting cytokines that have neuroprotective activity including TGF-ß and CX3CL1. Also, downregulation of IL-1ß and TNF-α as inflammatory chemokines was seen along with decreased astrocytes and microglia activation. Finally, these results showed that trophic factors secreted by MSC can increase oligodendrocyte population and remyelination rate by reducing pro-inflammatory factors. These findings demonstrate that MSC could decrease inflammation, gliosis and demyelination with neuroprotective and immunomodulating properties in chronic cuprizone demyelination model. Therefore MSC transplantation can be considered as a suitable approach for enhancing myelination and reducing inflammation in diseases such as MS.
Asunto(s)
Enfermedades Desmielinizantes/metabolismo , Células Madre Mesenquimatosas , Neuroglía/metabolismo , Animales , Quimiocina CX3CL1/metabolismo , Cuprizona , Citocinas/metabolismo , Enfermedades Desmielinizantes/inducido químicamente , Masculino , Ratones , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system (CNS). Despite introducing multiple immunomodulatory approaches for MS, there are still major concerns about possible ways for improving remyelination in this disease. Microglia exert essential roles in regulation of myelination processes, and interaction between colony-stimulating factor 1 (CSF1) with its receptor CSF1R is considered as a key regulator of microglial differentiation and survival. The aim of this study was to investigate possible roles for a CSF1R inhibitor PLX3397 in recovery of central myelination processes. Chronic demyelination was induced in mice by addition of 0.2% cuprizone to the chow for 12 weeks. Next, animals were undergoing a diet containing 290 mg/kg PLX3397 to induce microglial ablation. The PLX3397 treatment caused a significant decrease in the rate of expression for the CSF1/CSF1R axis, and a reduction in the protein expressions for the microglial marker Iba-1 and for the oligodendrocyte marker Olig-2. Findings from Luxol fast blue (LFB) staining and transmission electron microscopy (TEM) showed an increase in the rate of myelination for the mice receiving PLX3397. The rate of destruction in the nerve fibers and the extent of the gaps formed between layers of myelin sheaths was also reduced after the treatment with PLX3397. In addition, animals experienced an improvement in recovery of motor deficit after receiving PLX3397 (for all P < 0.05). It could be concluded that PLX3397 could retain myelination in the MS model possibly through regulation of the myelin environment.
Asunto(s)
Aminopiridinas/farmacología , Cuerpo Calloso/efectos de los fármacos , Enfermedades Desmielinizantes/tratamiento farmacológico , Vaina de Mielina/efectos de los fármacos , Pirroles/farmacología , Animales , Cuerpo Calloso/patología , Cuprizona/toxicidad , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Indoles , Factor Estimulante de Colonias de Macrófagos/genética , Factor Estimulante de Colonias de Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/patología , Microglía/fisiología , Microscopía Electrónica de Transmisión , Esclerosis Múltiple/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
BACKGROUND: Spermatogonial stem cells are the foundation of spermatogenesis and male fertility. So, their maintenance and culture are very important. OBJECTIVE: In this study, we assessed protective effects of the Calligonum on in vitro viability and apoptotic and antiapoptotic genes expression of spermatogonial stem cells. MATERIALS AND METHODS: After 24 hr of culture, the spermatogonial stem cells were treated with 30 µM dose of H2O2 and then 10 µg/ml the Calligonum extract was added for 3 wks. Viability was assessed by Trypan blue, apoptosis using PI-Annexin and finally Bax, Bcl-2 and P53 genes expression by Real-Time Polymerase chain reaction. RESULTS: After 3 wk of treatment, viability in the Calligonum extract+H2O2 group was significantly higher than H2O2 group alone (p=0.001). In the Calligonum extract+H2O2 group, apoptosis, as well as expression of apoptotic genes (Bax and P53), was significantly lower than the group treated with H2O2 alone. CONCLUSION: The results of this study showed that 30 µM H2O2 increased apoptosis but decreased viability in spermatogonial stem cells. Calligonum has antioxidant properties that can reduce apoptosis, Bax and P53 expression and increase the viability and Bcl-2 expression.