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Long-term stress is a significant risk factor for cardiovascular diseases, including atherosclerosis and endothelial dysfunction. Moreover, prolonged stress has shown to negatively regulate central BDNF expression. The role of central BDNF in CNS disorders is well studied until recently the peripheral BDNF was also found to be involved in endothelial function regulation and atherosclerosis. The peripheral BDNF and its role in chronic stress-induced atherosclerosis and endothelial dysfunction remain unclear. Therefore, we aimed to elucidate the role of BDNF and its modulation by the HDAC inhibitor valproic acid (VA) in chronic unpredictable stress (CUS)-induced atherosclerosis and endothelial dysfunction. We demonstrated that a 10-week CUS mouse model substantially decreases central and peripheral BDNF expression, resulting in enhanced serum lipid indices, plaque deposition, fibrosis, and CD68 expression in thoracic aortas. Further, parameters associated with endothelial dysfunction such as increased levels of endothelin-1 (ET-1), adhesion molecules like VCAM-1, M1 macrophage markers, and decreased M2 macrophage markers, eNOS expression, and nitrite levels in aortas, were also observed. VA (50 mg/kg, 14 days, i. p.) was administered to mice following 8 weeks of CUS exposure until the end of the experimental procedure. VA significantly prevented the decrease in BDNF, eNOS and nitrite levels, reduced lesion formation and fibrosis in thoracic aortas and increased ET-1, and VCAM-1 followed by M2 polarization in VA-treated mice. The study highlights the potential of epigenetic modulation of BDNF as a therapeutic target, in stress-induced cardiovascular pathologies and suggests that VA could be a promising agent for mitigating CUS-induced endothelial dysfunction and atherosclerosis by BDNF modulation.
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Neuroglial cells, also known as glia, are primarily characterized as auxiliary cells within the central nervous system (CNS). The recent findings have shed light on their significance in numerous physiological processes and their involvement in various neurological disorders. Leukodystrophies encompass an array of rare and hereditary neurodegenerative conditions that were initially characterized by the deficiency, aberration, or degradation of myelin sheath within CNS. The primary cellular populations that experience significant alterations are astrocytes, oligodendrocytes and microglia. These glial cells are either structurally or metabolically impaired due to inherent cellular dysfunction. Alternatively, they may fall victim to the accumulation of harmful by-products resulting from metabolic disturbances. In either situation, the possible replacement of glial cells through the utilization of implanted tissue or stem cell-derived human neural or glial progenitor cells hold great promise as a therapeutic strategy for both the restoration of structural integrity through remyelination and the amelioration of metabolic deficiencies. Various emerging treatment strategies like stem cell therapy, ex-vivo gene therapy, infusion of adeno-associated virus vectors, emerging RNA-based therapies as well as long-term therapies have demonstrated success in pre-clinical studies and show promise for rapid clinical translation. Here, we addressed various leukodystrophies in a comprehensive and detailed manner as well as provide prospective therapeutic interventions that are being considered for clinical trials. Further, we aim to emphasize the crucial role of different glial cells in the pathogenesis of leukodystrophies. By doing so, we hope to advance our understanding of the disease, elucidate underlying mechanisms, and facilitate the development of potential treatment interventions.
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Chronically stressed patients often have low vagal tone and increased levels of proinflammatory cytokines, which increase their risk for developing cardiac dysfunction. Transcutaneous vagus nerve stimulation (taVNS) is a way to activate the parasympathetic system, which has the ability to reduce inflammation and antagonize excessive sympathetic responses. However, the effectiveness of taVNS in treating cardiac dysfunction caused by chronic unpredictable stress (CUS) has not been studied. To investigate this, we first validated a rat model of CUS, in which the rats were exposed to random stressors daily for 8 weeks. Post CUS, the rats were treated with taVNS (1.0 ms, 6 V, 6 Hz, for 40 min × 2 weeks, alternatively) and their cardiac function and cholinergic flow were evaluated. Furthermore, serum cardiac troponin I (cTnI), cardiac caspase-3, inducible nitric oxide synthase (iNOS), and transforming growth factor (TGF)-ß1 expression in rats were also assessed. The chronically stressed rats showed depressed behavior with increased levels of serum corticosterone and proinflammatory cytokines. Electrocardiogram (ECG) and heart rate variability (HRV) studies revealed elevated heart rate, diminished vagal tone, and altered sinus rhythm in CUS rats. Furthermore, the CUS rats demonstrated cardiac hypertrophy and fibrosis with increased caspase-3, iNOS, and TGF-ß expression in their myocardium and increased levels of serum cTnI. Interestingly, alternate taVNS therapy for 2 weeks, post CUS, helped alleviate these cardiac abnormalities. These suggest that taVNS could be a useful adjunctive and non-pharmacological approach for managing CUS induced cardiac dysfunction.
Assuntos
Cardiopatias , Estimulação do Nervo Vago , Humanos , Ratos , Animais , Caspase 3 , Nervo Vago/fisiologia , CitocinasRESUMO
The global incidence of autoimmune diseases is on the rise, and many healthcare professionals believe that chronic stress plays a prominent role in both the aggravation and remission of these conditions. It is believed that prolonged exposure to stress is associated with neuroimmune axis malfunction, which eventually dysregulates multiple immunological factors as well as deregulates autoimmune responses that play a central role in various autoimmune diseases, including rheumatoid arthritis and psoriasis. Herein, we performed validation of an 8-week long rat model of chronic unpredictable stress (CUS) which consisted of exposing groups of rats to random stressors daily for 8 weeks. Additionally, we developed a novel rat model combining 8-week long random stressor-induced CUS with CIA-triggered arthritis and IMQ-triggered psoriasis and have successfully used both these models to assess the role of chronic stress in the aggravation of arthritis and psoriasis, respectively. Notably, the 8-week CUS protocol extensively aggravated and prolonged both arthritis and psoriasis condition in the rat model by upregulating the release of different pro-inflammatory cytokines, dysregulation of immune cell responses and oxidative stress system, which were all related to severe inflammation. Further, CUS aggravated macroscopic features and the increase in destruction of joint tissue and epidermal thickness induced by CIA and IMQ, respectively, in rats. In conclusion, this study suggests that exposure to an 8-week long CUS paradigm aggravates the distinctive characteristics of rheumatoid arthritis and psoriasis in rats via amplifying the inflammatory circuits and immune cell responses linked to these autoimmune diseases.
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Artrite Experimental , Artrite Reumatoide , Doenças Autoimunes , Psoríase , Humanos , Ratos , Animais , Inflamação , CitocinasRESUMO
Chronic stress is a major risk factor for various diseases, including cardiovascular diseases (CVDs). Chronic stress enhances the release of pro-inflammatory cytokines like IL-1ß, IL-6, and TNF-α, making individuals susceptible to atherosclerosis which is dominant cause for CVDs. In present study, we validated a mouse model of chronic unpredictable stress (CUS), and assessed the characteristic features of atherosclerosis in thoracic aortas of CUS mice. The CUS procedure consisted of exposing groups of mice to random stressors daily for 10-weeks. The stress response was verified by presence of depressive-like behaviors and increased serum corticosterone in mice which was determined by battery of behavioural tests (SPT, EPMT, NSFT) and ELISA, respectively. Atherosclerosis parameters in CUS mice were evaluated by lipid indices estimation followed by histological assessment of plaque deposition and fibrosis in thoracic aorta. Further, we assessed the efficacy of a polyphenol, i.e. Butein in conferring protection against chronic stress-induced atherosclerosis and the possible mechanism of action. Butein (20 mg/kg x 28 days, alternatively, i.p.) was administered to CUS mice after 6-weeks of CUS exposure till the end of the protocol. Butein treatment decreased peripheral IL-1ß and enhanced peripheral as well as central BDNF levels. Histological assessment revealed decreased macrophage expression and reduced fibrosis in thoracic aorta of Butein treated mice. Further, treatment with Butein lowered lipid indices in CUS mice. Our findings thus, suggest that 10-weeks of CUS induce characteristic features of atherosclerosis in mice and Butein can offer protection in CUS-induced atherosclerosis through multiple mechanisms including anti-inflammatory, antifibrotic and anti-adipogenic actions.
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Aterosclerose , Fator Neurotrófico Derivado do Encéfalo , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Fibrose , Lipídeos , Estresse Psicológico/complicaçõesRESUMO
Motor neuron diseases (MNDs) are rare and frequently fatal neurological disorders in which motor neurons within the brainstem and spinal cord regions slowly die. MNDs are primarily caused by genetic mutations, and > 100 different mutant genes in humans have been discovered thus far. Given the fact that many more MND-related genes have yet to be discovered, the growing body of genetic evidence has offered new insights into the diverse cellular and molecular mechanisms involved in the aetiology and pathogenesis of MNDs. This search may aid in the selection of potential candidate genes for future investigation and, eventually, may open the door to novel interventions to slow down disease progression. In this review paper, we have summarized detailed existing research findings of different MNDs, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal bulbar muscle atrophy (SBMA) and hereditary spastic paraplegia (HSP) in relation to their complex genetic architecture.
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Esclerose Lateral Amiotrófica , Doença dos Neurônios Motores , Atrofia Muscular Espinal , Paraplegia Espástica Hereditária , Esclerose Lateral Amiotrófica/genética , Humanos , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/patologia , Neurônios Motores/patologia , Atrofia Muscular Espinal/genética , Paraplegia Espástica Hereditária/genéticaRESUMO
People with chronic stress have higher levels of pro-inflammatory cytokines, which enhance their susceptibility to cardiovascular diseases. Diacerein has ability to modulate pro-inflammatory cytokines such as IL-1ß and IL-6; however, its efficacy in chronic stress associated cardiovascular diseases is not yet assessed. In this study, we standardized a rat model of chronic unpredictable stress (CUS) demonstrating cardiovascular dysfunctions and further assessed the effect of IL-6 modulator, diacerein, on cardiovascular functions in CUS exposed rats. The CUS procedure consisted of exposing male albino Wistar rats to random stressors, everyday for 8 weeks. The binding affinity of diacerein with IL-6 was ascertained using Docking tools viz AutoDock and SwissDock. Moreover, diacerein was administered (50 mg/kg/day x 20 days P.O) post CUS exposure to rats and the serum IL-6 levels and heart functions of CUS rats were determined by ELISA and ECG-HRV analysis, respectively. 8 weeks of CUS exposure resulted in two-fold increase in serum corticosterone and IL-6 levels in rats. The ECG and HRV analysis of CUS rats showed altered sinus rhythm, elevated heart rate, systolic blood pressure and sympathetic tone. Molecular docking studies revealed diacerein high binding affinity towards IL-6 receptor. The post-treatment of diacerein in CUS rats prevented these cardiovascular dysfunctions. Our findings thus suggests that IL-6 may have a prominent role in chronic stress induced cardiovascular dysfunctions and diacerein, could be used as a preventive measure for such conditions.
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Myocyte enhancer factor 2 (MEF2), a family of transcription factor of MADS (minichromosome maintenance 1, agamous, deficiens and serum response factor)-box family needed in the growth and differentiation of a variety of human cells, such as neural, immune, endothelial, and muscles. As per existing literature, MEF2 transcription factors have also been associated with synaptic plasticity, the developmental mechanisms governing memory and learning, and several neurologic conditions, like autism spectrum disorders (ASDs). Recent genomic findings have ascertained a link between MEF2 defects, particularly in the MEF2C isoform and the ASD. In this review, we summarized a concise overview of the general regulation, structure and functional roles of the MEF2C transcription factor. We further outlined the potential role of MEF2C as a risk factor for various neurodevelopmental disorders, such as ASD, MEF2C Haploinsufficiency Syndrome and Fragile X syndrome.