RESUMO
This guideline is the first Iranian guideline developed for the diagnosis, management, and treatment of hyperlipidemia in adults. The members of the guideline developing group (GDG) selected 9 relevant clinical questions and provided recommendations or suggestions to answer them based on the latest scientific evidence. Recommendations include the low-density lipoprotein cholesterol (LDL-C) threshold for starting drug treatment in adults lacking comorbidities was determined to be over 190 mg/dL and the triglyceride (TG) threshold had to be >500 mg/dl. In addition to perform fasting lipid profile tests at the beginning and continuation of treatment, while it was suggested to perform cardiovascular diseases (CVDs) risk assessment using valid Iranian models. Some recommendations were also provided on lifestyle modification as the first therapeutic intervention. Statins were recommended as the first line of drug treatment to reduce LDL-C, and if its level was high despite the maximum allowed or maximum tolerated drug treatment, combined treatment with ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, or bile acid sequestrants was suggested. In adults with hypertriglyceridemia, pharmacotherapy with statin or fibrate was recommended. The target of drug therapy in adults with increased LDL-C without comorbidities and risk factors was considered an LDL-C level of <130 mg/dl, and in adults with increased TG without comorbidities and risk factors, TG levels of <200 mg/dl. In this guideline, specific recommendations and suggestions were provided for the subgroups of the general population, such as those with CVD, stroke, diabetes, chronic kidney disease, elderly, and women.
RESUMO
The effects of astaxanthin (AST) were evaluated on oxidative mediators, neuronal apoptosis, and autophagy in functional motor recovery after spinal cord injury (SCI). Rats were divided into three groups of sham, SCI + DMSO (dimethyl sulfoxide), and SCI + AST. Rats in the sham group only underwent a laminectomy at thoracic 8-9. While, the SCI + DMSO and SCI + AST groups had a compression SCI with an aneurysm clip. Then, this groups received an intrathecal (i.t.) injection of 5% DMSO and AST (10 µl of 0.005 mg/kg), respectively. The rat motor functions were assessed weekly until the 28th day using a combined behavioral score (CBS). Total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were measured in spinal tissue to evaluate oxidative stress-related parameters. Besides, autophagy-related proteins (P62, LC3B, and Beclin1) and apoptosis-associated proteins (Bax and Bcl2) were determined using western blotting on the 1st and 7th days after surgery. Hematoxylin-eosin and Fluoro-Jade B staining were performed to detect the histological alterations and neuronal degeneration. As the result, treatment with AST potentially attenuated rat CBS scores (p < 0.001) towards a better motor performance. AST significantly reduced the spinal level of oxidative stress by increasing TAC, SOD, and GPx, while decreasing MDA (p < 0.001). Furthermore, AST treatment remarkably upregulated expression of LC3B (p < 0.001), and Beclin1 (p < 0.05) in the spinal cord, but downregulated P62 (p < 0.05) and the Bax/Bcl2 ratio (p < 0.001). Consequently, AST reduced SCI-induced histological alterations and neuronal degeneration (p < 0.001). In conclusion, AST can improve motor function after SCI by reducing oxidative stress/apoptosis and increasing neuronal autophagy.
Assuntos
Dimetil Sulfóxido , Traumatismos da Medula Espinal , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose , Autofagia , Proteína Beclina-1/metabolismo , Dimetil Sulfóxido/farmacologia , Glutationa Peroxidase/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Superóxido Dismutase/metabolismo , Xantofilas , Proteína X Associada a bcl-2/metabolismoRESUMO
Astaxanthin (AST) is a lipid-soluble carotenoid with antioxidant and anti-inflammatory properties. Previous reports demonstrated the promising effects of AST on spinal cord injury (SCI)-induced inflammation and sensory-motor dysfunction. Macrophage migration inhibitory factor (MIF), as a cytokine, plays a critical role in the inflammatory phase of SCI. The aim of this study was to evaluate the effects of AST on post-SCI levels of MIF in serum and spinal cord. The possible correlation between MIF and mechanical pain threshold was also assessed. Adult male rats were subjected to a severe compression spinal injury and 30 min later were treated with AST (Intrathecal, 2 nmol) or vehicle. Neuropathic pain was assessed by von Frey filaments before the surgery, and then on days 7, 14, 21, and 28 post-SCI. Western blot and ELISA were used to measure the serum level and spinal expression of MIF following SCI in the same time points. AST treatment significantly attenuated the SCI-induced dysregulations in the serum levels and tissue expression of MIF. A negative correlation was observed between mechanical pain threshold and serum MIF level (r = -0.5463, P < 0.001), as well as mechanical pain threshold and spinal level of MIF (r = -0.9562; P < 0.001). AST ameliorates SCI-induced sensory dysfunction, probably through inhibiting MIF-regulated inflammatory pathways.
Assuntos
Fatores Inibidores da Migração de Macrófagos , Traumatismos da Medula Espinal , Animais , Antioxidantes/farmacologia , Lipídeos , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/farmacologia , Masculino , Ratos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Xantofilas/metabolismo , Xantofilas/farmacologiaRESUMO
Nepeta menthoides Boiss. & Buhse and Melissa officinalis are extensively used in Persian medicine for the treatment of depression. Considering the active ingredients and main phenolic compounds of these plants and possible synergistic effects, this study examined the antidepressant and antioxidant activities of aqueous extract of N. menthoides (NM) and M. officinalis (MO) in reserpinized mice alone and combination. Mice were pretreated orally for 1-week with normal saline (10 ml/kg), fluoxetine (20 mg/kg), imipramine (10 mg/kg), NM (50-100-200-400 mg/kg), MO (150-350-550-750 mg/kg), and combination (NM 50 with MO 150 mg/kg). The behavioral changes were evaluated using forced swim, tail suspension, and open field tests, 24 hr after reserpine injection (4 mg/kg) on eighth day. The amounts of active components in the extracts and catalase (CAT) as a brain oxidative stress were measured with enzyme-linked immunosorbent assay. Data showed that this combination produced a synergistic action on behaviors and a significant increase in CAT activity. High-performance liquid chromatography results showed that rosmarinic acid contents in MO and NM were 6.42 ± 1.1 and 11.03 ± 2.16 mg/g of dried extract, respectively. Total flavonoid and phenolic contents of MO were higher than NM. The findings suggest that the present combination produces an antidepressant-like effect, which is possibly triggered by its antioxidant properties.
Assuntos
Melissa , Nepeta , Animais , Antidepressivos/farmacologia , Antioxidantes/análise , Antioxidantes/farmacologia , Melissa/química , Camundongos , Nepeta/química , Fenóis/análise , Extratos Vegetais/química , ReserpinaRESUMO
As a complicated process of forming new blood vessels from the present vasculature endothelium, angiogenesis plays a critical role in the progression of cancer, through developing new blood vessels in tumor cells. Angiogenesis is regulated by proteins known as inhibitor or activator molecules, affected by different medicinal herbs and small molecules. In the present review, the molecular mechanisms of tumor angiogenesis are outlined, focusing on the pharmacological aspects and molecular mechanisms of natural compounds used in chemotherapy and their effects on angiogenesis, focusing on vascular endothelial growth factor (VEGF).Our findings show that a significant number of drugs used in the treatment of cancer are antiangiogenic small molecules and phytochemicals which inhibit VEGF and angiogenesis. Besides, medicinal herbs are potential multi-target agents with more covering mechanisms, lower costs and lower toxicity to develop novel anticancer drugs through targeting the VEGF signaling pathway and receptor tyrosine kinases (RTKs) in the angiogenesis. For this reason, herbal anti-VEGF agents are considered as imperative targets to be used for cancer treatment in clinical applications.The findings reveal a promising perspective for medicinal herbs and natural compounds acting on VEGF and angiogenesis to find new targets and potential therapeutic use in the treatment of cancer.
Assuntos
Plantas Medicinais , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese , Humanos , Neovascularização Patológica/tratamento farmacológico , Fatores de Crescimento do Endotélio VascularRESUMO
Exploring the regulatory effects of estrogen on different body organs via its receptors is largely of interest. Recently, the expression, signaling and the clinical significance of ERα36, the newly identified isoform of ERα, mediating non-genomic signaling of estrogen, have been studied in a wide range of organs and tumors. ERα36 is expressed highly in the CNS and actively involved in neuroprotection. It is also suggested to be an important estrogen receptor involved in preserving bone in postmenopausal women. On the oncological side, although ERα36 has usually been considered to be an oncogenic molecule, results from some studies paradoxically imply its protective role in certain tumors. Collectively, it seems that ERα36 is highly involved in cell type-specific functions of estrogen through its MAPK/ERK signaling, which is dependent on ERα36 expression levels, ligand concentrations and disease stage. The response is also dependent on the levels of ERα66 and ERß. These factors influence the ERK kinetic and determine the ultimate mitogenic or antimitogenic signaling of estrogen, leading to cell survival or cell death. In this review, we summarize the recent organ-specific, cellular and molecular events and the mechanisms involved in estrogen effects mediated through the ERα36/ ERα66 with a particular focus on carcinomas where more clinical information has recently emerged.
Assuntos
Estrogênios/metabolismo , Neoplasias/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Apoptose , Produtos Biológicos/farmacologia , Humanos , Neuroproteção , Isoformas de Proteínas/metabolismo , Receptores de Estrogênio/química , Receptores Acoplados a Proteínas G/metabolismo , Caracteres SexuaisRESUMO
PURPOSE: The regulatory effects of estradiol on pituitary homeostasis have been well documented. However, the expression patterns of ERα66 and ERα36 and their correlations with the clinical course of postoperative prolactinoma tumors remain unclear. METHODS: The expression of ERα36, ERα66, Ki67, p53, and CD31 were determined by immunohistochemistry in 62 prolactinoma patients. Snap-frozen tumors and normal pituitaries were also examined by western blotting for estrogen receptor detection. RESULTS: A broad expression of ERα36 was identified in normal pituitaries. The median scores of ERα36 and ERα66 expression were 8 and 6 in normal pituitaries and 4 and 0 in tumors, respectively. Four phenotypes of ERα36 and ERα66 expression were explored in tumors with regard to sex, invasiveness, dopamine resistance, and recurrence. Low ERα36 expression was associated with tumor invasion and increased Ki67. Low ERα66 expression was associated with tumor invasion, dopamine-agonist resistance, and enhanced tumor size. Multivariable logistic regression analysis showed that low ERα36 expression is an independent risk factor for invasiveness. The significant inverse association of ERα66 with invasiveness, dopamine resistance, and tumor size remained significant after adjustment for sex as a potential confounder. After controlling for sex, the low ERα66/low ERα36 phenotype was 6.24 times more prevalent in invasive tumors than in noninvasive tumors. Although the decreasing trend of CD31 expression from surrounding nontumoral lactotroph adenomas to tumors was similar to that of the estrogen receptors, a significant correlation was not observed here. CONCLUSION: The decreasing trends of ERα36 and ERα66 expression from normal pituitaries to tumors are associated with aggressive clinical behavior.
Assuntos
Biomarcadores/metabolismo , Receptor alfa de Estrogênio/metabolismo , Neoplasias Hipofisárias/metabolismo , Prolactinoma/metabolismo , Isoformas de Proteínas/metabolismo , Adulto , Western Blotting , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prolactinoma/genética , Isoformas de Proteínas/genéticaRESUMO
Astaxanthin (AST) is a potent lipid-soluble keto-carotenoid with auspicious effects on human health. It protects organisms against a wide range of diseases with excellent safety and tolerability. Various imperative biological activities in vitro and in vivo models have been suggested for AST. This review article is focused on the therapeutic potentials, biological activities and benefical health effects of AST. The pharmacological mechanisms of action of AST in the treatment and prevention of the peripheral and central nervous system diseases was also reviewed to provide new insights to researchers. Finally, we suggested a novel hypothesis for the mechanism of action of AST in neuropathic pain following spinal cord injury.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Humanos , Xantofilas/farmacologia , Xantofilas/uso terapêuticoRESUMO
Central neuropathic pain (CNP) is a complicated medical problem that involves both the spinal and supraspinal regions of the central nervous system. Estrogen, a neuroprotective agent, has been considered a possible candidate for CNP treatment. In this study, we examined the effects of a single dose of 17ß-estradiol on glutamate levels in the ventral posterolateral (VPL) nucleus of the rat thalamus. Furthermore, we determined whether there was a correlation between glutamate levels and neuropathic pain induced by unilateral electrolytic spinothalamic tract (STT) lesion. STT lesioning was performed in male Wistar rats at the T8-T9 vertebrae; rats were then administered 17ß-estradiol (4 mg/kg, i.p.) 30 min after injury. Glutamate samples were collected using a microdialysis probe and quantified by high performance liquid chromatography. Mechanical allodynia (MA) and thermal hyperalgesia (TH) thresholds were measured pre-injury and 7, 14, and 28 days post-injury. We found that STT lesion significantly increased glutamate levels in the ipsilateral VPL nucleus 14 and 28 days post-injury; this was accompanied by allodynia and hyperalgesia in the hind paws of the rats. Administering 17ß-estradiol to the rats decreased glutamate levels in the ipsilateral VPL nucleus and significantly increased MA and TH thresholds. These results suggest that glutamate in the VPL nucleus of the thalamus is involved in the pathology of neuropathic pain after STT injury; furthermore, 17ß-estradiol may attenuate this neuropathic pain by decreasing glutamate levels.
Assuntos
Analgésicos/uso terapêutico , Estradiol/uso terapêutico , Ácido Glutâmico/metabolismo , Neuralgia/tratamento farmacológico , Traumatismos da Medula Espinal/complicações , Núcleos Ventrais do Tálamo/efeitos dos fármacos , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Estradiol/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Masculino , Neuralgia/etiologia , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismos da Medula Espinal/metabolismo , Núcleos Ventrais do Tálamo/metabolismoRESUMO
Spinal cord injury (SCI) is a common neurological disease worldwide, often resulting in a substantial decrease in quality of life, disability, and in severe cases, even death. Unfortunately, there is currently no effective treatment for this disease. Nevertheless, current basic and clinical evidence suggests that vitamins, with their antioxidant properties and biological functions, may play a valuable role in improving the quality of life for individuals with SCI. They can promote overall health and facilitate the healing process. In this review, we discuss the mechanisms and therapeutic potential of vitamins in the treatment of SCI.
Assuntos
Traumatismos da Medula Espinal , Vitaminas , Traumatismos da Medula Espinal/tratamento farmacológico , Humanos , Vitaminas/uso terapêutico , Vitaminas/farmacologia , Animais , Antioxidantes/uso terapêutico , Antioxidantes/farmacologiaRESUMO
The abrupt hyperglycemic reperfusion following thrombectomy has been shown to harm the efficacy of the intervention in stroke patients with large vessel occlusion. Studies of ours and others have shown thioredoxin-interacting protein (TXNIP) is critically involved in hyperglycemic stroke injury. We recently found verapamil ameliorates cerebrovascular toxicity of tissue plasminogen activators in hyperglycemic stroke. The present study aims to answer if verapamil exerts direct neuroprotective effects and alleviates glucose toxicity following thrombectomy in a preclinical model of hyperglycemic stroke. Primary cortical neural (PCN) cultures were exposed to hyperglycemic reperfusion following oxygen-glucose deprivation (OGD), with or without verapamil treatment. In a mouse model of intraluminal stroke, animals were subjected to 4 h middle cerebral artery occlusion (MCAO) and intravenous glucose infusion. Glucose infusion lasted one more hour at reperfusion, along with intra-arterial (i.a.) verapamil infusion. Animals were subjected to sensorimotor function tests and histological analysis of microglial phenotype at 72 h post-stroke. According to our findings, glucose concentrations (2.5-20 mM) directly correlated with TXNIP expression in OGD-exposed PCN cultures. Verapamil (100 nM) effectively improved PCN cell neurite growth and reduced TXNIP expression as well as interaction with NOD-like receptor pyrin domain-containing-3 (NLRP3) inflammasome, as determined by immunoblotting and immunoprecipitation. In our mouse model of extended hyperglycemic MCAO, i.a. verapamil (0.5 mg/kg) could attenuate neurological deficits induced by hyperglycemic stroke. This was associated with reduced microglial pro-inflammatory transition. This finding encourages pertinent studies in hyperglycemic patients undergoing thrombectomy where the robust reperfusion may exacerbate glucose toxicity.
RESUMO
Spinal cord edema is a quick-onset phenomenon with long-term effects. This complication is associated with inflammatory responses, as well as poor motor function. No effective treatment has been developed against spinal edema, which urges the need to provide novel therapies. Astaxanthin (AST) is a fat-soluble carotenoid with anti-inflammatory effects and a promising candidate for treating neurological disorders. This study aimed to investigate the underlying mechanism of AST on the inhibition of spinal cord edema, astrocyte activation, and reduction of inflammatory responsesin a rat compression spinal cord injury (SCI) model. Male rats underwent laminectomy at thoracic 8-9, and the SCI model was induced using an aneurysm clip. After SCI, rats received dimethyl sulfoxide or AST via intrathecal injection. The effects of AST were examined on the motor function, spinal cord edema, integrity of blood-spinal cord barrier (BSCB), and expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), glial fibrillary acidic protein (GFAP), and aquaporin-4 (AQP4), and matrix metallopeptidase- 9 (MMP-9) post-SCI. We showed that AST potentially improved the recovery of motor function and inhibited the spinal cord edema via maintaining the integrity of BSCB, reducing the expression of HMGB1, TLR4, and NF-κB, MMP-9 as well as downregulation of astrocyte activation (GFAP) and AQP4 expression. AST improves motor function and reduces edema and inflammatory responses in the spinal tissue. These effects are mediated by suppression of the HMGB1/TLR4/NF-κB signaling pathway, suppressing post-SCI astrocyte activation, and decreasing AQP4 and MMP-9 expression.
Assuntos
Antioxidantes , Astrócitos , Proteína HMGB1 , Traumatismos da Medula Espinal , Animais , Masculino , Ratos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Proteína HMGB1/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Receptor 4 Toll-Like/metabolismo , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Injeções EspinhaisRESUMO
Over the last two decades, it has become evident that estrogens preserve the integrity of energy homeostasis at central and peripheral levels. Estrogen deficiency, such as that caused by menopause or ovariectomy, has been linked to obesity and metabolic disorders that can be resolved or reversed by estrogen therapy. 17ß-estradiol (E2), as the major estrogen in the body, primarily regulates energy balance via estrogen receptor alpha (ERα). At the central level, E2 plays its catabolic role predominantly by interacting with hypothalamic arcuate neurons and sending signals via ventromedial hypothalamic neurons to control brown adipose tissue-mediated thermogenesis. In peripheral tissues, several organs, particularly the liver, brown and white adipose tissues, and pancreatic ß cells, have attracted considerable attention. In this review, we focused on the current state of knowledge of "central and peripheral" estrogen signaling in regulating energy balance via "nuclear and extranuclear pathways" in both "females and males". In this context, according to an exploratory approach, we tried to determine the principal estrogen receptor subtype/isoform in each section, the importance of extranuclear-initiated estrogen signaling on metabolic functions, and how sex differences related to ER signaling affect the prevalence of some of the metabolic disorders. Moreover, we discussed the data from a third viewpoint, understanding the clinical significance of estrogen signaling in abnormal metabolic conditions such as obesity or being on a high-fat diet. Collectively, this review exposes novel and important research gaps in our current understanding of dysmetabolic diseases and can facilitate finding more effective treatment options for these disorders.
Assuntos
Receptor alfa de Estrogênio , Estrogênios , Humanos , Feminino , Masculino , Estrogênios/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estradiol/metabolismo , Homeostase , Receptores de Estrogênio , Obesidade/metabolismoRESUMO
Spinal cord injury (SCI) is globally considered as one of the most debilitating disorders, which interferes with daily activities and life of the affected patients. Despite many developments in related recognizing and treating procedures, post-SCI neuropathic pain (NP) is still a clinical challenge for clinicians with no distinct treatments. Accordingly, a comprehensive search was conducted in PubMed, Medline, Scopus, Web of Science, and national database (SID and Irandoc). The relevant articles regarding signaling pathways, therapeutic targets and pharmacotherapy of post-SCI pain were also reviewed. Data were collected with no time limitation until November 2020. The present study provides the findings on molecular mechanisms and therapeutic targets, as well as developing the critical signaling pathways to introduce novel neuroprotective treatments of post-SCI pain. From the pathophysiological mechanistic point of view, post-SCI inflammation activates the innate immune system, in which the immune cells elicit secondary injuries. So, targeting the critical signaling pathways for pain management in the SCI population has significant importance in providing new treatments. Indeed, several receptors, ion channels, excitatory neurotransmitters, enzymes, and key signaling pathways could be used as therapeutic targets, with a pivotal role of n-methyl-D-aspartate, gamma-aminobutyric acid, and inflammatory mediators. The current review focuses on conventional therapies, as well as crucial signaling pathways and promising therapeutic targets for post-SCI pain to provide new insights into the clinical treatment of post-SCI pain. The need to develop innovative delivery systems to treat SCI is also considered.
Assuntos
Manejo da Dor/métodos , Dor/tratamento farmacológico , Dor/etiologia , Traumatismos da Medula Espinal/complicações , Animais , Humanos , Neuralgia/tratamento farmacológico , Neuralgia/etiologiaRESUMO
Spinal cord injury (SCI) is a severely debilitating problem leading to substantial decrease in the quality of life. After spinal cord injury, inflammation and oxidative stress plays a key role in initiating the secondary injury cascades leading to progressive tissue degradation and extreme functional deficits. Given that the primary mechanical injuries to spinal cord are rarely repaired, the pharmacological interventions may improve the neurological outcomes caused by secondary injury. Astaxanthin (AST) is considered as a xanthophyll carotenoid with potent antioxidant and anti-inflammatory properties, which has various pharmacological activities. In the present study, we aimed to firstly assess the protective effect of AST, and then to define the AST mechanism of action on a rat model of SCI. Based on the results of von Frey test, AST treatment significantly alleviated the SCI-induced neuropathic pain compared with the control groups (P < 0.05). The expression analysis by western blot shows reduced expression levels of COX-2, TNF-α, IL-1ß, and IL-6 following AST treatment (P < 0.05). The activity of antioxidant enzymes was evaluated using ELISA. Therefore, ELISA experiments showed a significant reduction in the level of oxidative stress in SCI rat following AST treatment (P < 0.05). Furthermore, histopathological evaluations revealed that myelinated white matter and motor neuron number were significantly preserved after treatment with AST (P < 0.05). In conclusion, our study shows that AST could improve SCI through anti-inflammatory and antioxidant effects which leads to decreased tissue damage and mechanical pain after SCI.
Assuntos
Antioxidantes , Traumatismos da Medula Espinal , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Qualidade de Vida , Ratos , Medula Espinal/metabolismo , Xantofilas/metabolismo , Xantofilas/farmacologiaRESUMO
Despite reduction in environmental lead, chronic lead exposure still possess a public health hazard, particularly in children, with devastating effects on developing CNS. To investigate the mechanism of this neurotoxicity, young and adult rats were used to study whether exposure to 500 ppm concentrations of lead could induce apoptosis in hippocampus. 2-4 and 12-14-week-old rats received lead acetate in concentration of 500 ppm for 40 days. Control animals received deionized distilled water. In lead-treated groups, the blood lead levels were increased by 3-4 folds. Light and electron microscopical study of hippocampus revealed increased apoptotic cells. Western blot analysis of Bax and Bcl-2 (pro- and anti-apoptotic gene products, respectively) indicated higher expression of Bax protein and no significant change in bcl-2 expression and accordingly increased the Bax/Bcl-2 ratio compared to control group, confirming the histological study. In conclusion, these data suggest that neurotoxicity of chronic lead exposure in hippocampus in vivo may partly be due to facilitation of apoptosis.
Assuntos
Hipocampo/metabolismo , Intoxicação por Chumbo/metabolismo , Chumbo/administração & dosagem , Proteína X Associada a bcl-2/metabolismo , Animais , Apoptose , Western Blotting , Doença Crônica , Hipocampo/patologia , Hipocampo/ultraestrutura , Chumbo/sangue , Intoxicação por Chumbo/sangue , Masculino , Ratos , Ratos Wistar , Coloração e Rotulagem , Extratos de TecidosRESUMO
The differentiation of neural cells from embryonic stem cells is influenced by several growth factors. Amniotic epithelial cells (AECs) share many of the same characteristics as embryonic stem cells, and therefore those factors may similarly affect the derivation of neural cells from AECs. In this study, we examined the differentiation of neural cells in vitro from AECs following AECs treatment with retinoic acid (RA), basic fibroblast growth factor (bFGF) as well as investigation of bFGF withdrawal on neuronal differentiation. We also studied whether blocking bone morphogenetic protein (BMP) signaling using its antagonist, noggin, affects the derivation of neuronal cells from AECs. The effects of serum on the rate of neural markers expression were also examined. Analysis of AECs derived neurons was performed at some neural markers expression level by immunocytochemistry. All cultures treated with noggin showed the higher levels of neural markers expression than noggin free cultures. Combined treatment with bFGF and RA showed the highest level of neural markers in all treatment groups with or without noggin. bFGF withdrawal did not promote expression of neural markers, while its maintenance increased the expression of these markers. Serum-free condition decreased the viability of cells but increased the rate of neural markers expression. These results show the capability of AECs to express neural cell markers and this ability is affected by some factors including serum, noggin, bFGF and RA.
Assuntos
Âmnio/citologia , Diferenciação Celular , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Biomarcadores/metabolismo , Proteínas de Transporte/farmacologia , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Separação Celular , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Mamíferos/citologia , Fator de Crescimento Epidérmico/farmacologia , Células Epiteliais/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Imunofluorescência , Humanos , Neurônios/efeitos dos fármacos , Soro , Tretinoína/farmacologia , Tubulina (Proteína)/metabolismoRESUMO
Spinal cord injury (SCI), a multifactorial disease, can lead to irreversible motor and sensory disabilities. Cell therapy in combination with pharmacological agents can be a promising approach to attenuate SCI damages. Epidermal neural crest stem cells (EPI-NCSCs) extracted from bulge hair follicle in adults are attractive candidates due to the possibility of autologous transplantation. This study evaluated the effect of EPI-NCSCs combined with astaxanthin (Ast), a potent antioxidant, on damages induced by SCI. Male rats were treated with Ast (0.2 mM) and EPI-NCSCs (106/10 µl PBS) alone and combined together after SCI contusion. Motor function was assessed by Basso, Beattie and Bresnahan (BBB) test on days 1, 3, 7, 14, 21, 28, 35 and 42 post-injury. Motor neurons number and myelin level were evaluated on days 14 and 42 using Nissl and Luxol Fast Blue staining. The gene expression of mitochondrial biogenesis involved factors (PGC1α, NRF1 and TFAM) was measured by qPCR. All treatments improved motor function, with the highest BBB score in Ast + Cell compared to Ast and Cell. Decreased motor neurons number and myelin level following SCI, were increased by Ast, Cell and Ast + Cell, but combination therapy significantly had a better effect. We observed reduction in PGC1α, NRF1, and TFAM expression in spinal tissue after SCI, and treatment with Cell and Ast + Cell significantly restored NRF1 and TFAM mRNA levels. These results suggested that Ast in combination with EPI-NCSCs has better effects on behavioral dysfunction, motor neuron loss and demyelination after SCI. These protective effects may be attributed to mitochondrial biogenesis activation.
Assuntos
Mitocôndrias/metabolismo , Crista Neural/citologia , Células-Tronco Neurais/transplante , Traumatismos da Medula Espinal/terapia , Animais , Células Cultivadas , Terapia Combinada , Modelos Animais de Doenças , Masculino , Mitocôndrias/genética , Transtornos Motores/metabolismo , Bainha de Mielina/metabolismo , Células-Tronco Neurais/citologia , Fator 1 Nuclear Respiratório/genética , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Ratos , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Fatores de Transcrição/genética , Transplante Autólogo , Regulação para Cima , Xantofilas/administração & dosagem , Xantofilas/farmacologiaRESUMO
Epidermal neural crest stem cells (EPI-NCSCs) are propitious candidates for cell replacement therapy and supplying neurotrophic factors in the neurological disorders. Considering the potential remyelinating and regenerative effects of fingolimod, in this study, we evaluated its effects on EPI-NCSCs viability and the expression of neurotrophic and oligodendrocyte differentiation factors. EPI-NCSCs, extracted from the bulge of rat hair follicles, were characterized and treated with fingolimod (0, 50, 100, 200, 400, 600, 1000, and 5000 nM). The cell viability was evaluated by MTT assay at 6, 24 and 72 h. The expression of neurotrophic and differentiation factors in the cells treated with 100 and 400 nM fingolimod were measured at 24 and 120 h. Fingolimod at 50-600 nM increased the cells viability after 6 h, with no change at the higher concentrations. The highest concentration (5000nM) induced toxicity at 24 and 72 h. NGF and GDNF genes expression were decreased at 120 h, but on the contrary, brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) were increased by both concentrations at both time points. Oligodendrocyte markers including platelet-derived growth factor receptor A (PDGFRα), neuron-glial antigen 2 (NG2) and growth associated protein 43 (GAP43) were elevated at 120 h, which was accompanied with reduce in stemness markers (Nestin and early growth response 1 (EGR1)). Fingolimod increased the expression of neurotrophic factors in EPI-NCSCs, and guided them to oligodendrocyte fate. Therefore, fingolimod in combination with EPI-NCSCs, can be considered as a promising approach for demyelinating neurological disorders.
Assuntos
Epiderme/metabolismo , Cloridrato de Fingolimode/farmacologia , Crista Neural/metabolismo , Células-Tronco Neurais/metabolismo , Oligodendroglia/efeitos dos fármacos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Animais , Biomarcadores , Sobrevivência Celular/efeitos dos fármacos , Doenças Desmielinizantes/tratamento farmacológico , Relação Dose-Resposta a Droga , Epiderme/efeitos dos fármacos , Folículo Piloso/efeitos dos fármacos , Masculino , Fatores de Crescimento Neural/metabolismo , Crista Neural/citologia , Crista Neural/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Oligodendroglia/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: Spinal cord injury (SCI) causes continuous neurological deficits and major sensory-motor impairments. There is no effective treatment to enhance sensory-motor function following SCI. Thus, it is crucial to develop novel therapeutics for this particular patient population. Astaxanthin (AST) is a strong antioxidant, anti-inflammatory and anti-apoptotic agent. In the present study, it was tested in a severe compression SCI model with emphasis on sensory-motor outcomes, signalling pathway, along with other complications. METHODS: A severe SCI was induced by compression of the rat thoracic spinal cord with an aneurysm clip and treatment with AST or the vehicle was carried out, 30 min after injury. Behavioural tests including open field, von Frey, hot plate and BBB were performed weekly to 28 days post-injury. Rats were assigned to measure blood glucose, weight and auricle temperature. Western blot and histological analysis also were performed at the same time points. RESULTS: AST decreased mechanical and thermal pain and also improved motor function performance, reduced blood glucose and auricle temperature increases and attenuated weight loss in SCI rats. Western blot analysis showed decreased activation of ERK1/2 and increased activation of AKT following AST treatment. The histology results revealed that AST considerably preserved myelinated white matter and the number of motor neurons following SCI. CONCLUSION: Taken together, the beneficial effects of AST to improve sensory-motor outcomes, attenuate pathological tissue damage and modulate ERK and AKT signalling pathways following SCI, suggest it as a strong therapeutic agent towards clinical applications. SIGNIFICANCE: Spinal cord injury (SCI) impairs sensory-motor function and causes complications, which astaxanthin (AST) has the potential to be used as a treatment for. The present study investigates the effects of AST in a compression model of SCI with emphasis on sensory-motor outcomes alongside other complications, histopathological damage and also related signalling pathways.