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Treating Multiple sclerosis (MS), a well-known immune-mediated disease characterized by axonal demyelination, is challenging due to its complex causes. Naphthalenedione, present in numerous plants, is being explored as a potential medicine for MS due to its immunomodulatory properties. However, its effects on lymphocytes can vary depending on factors such as the specific compound, concentration, and experimental conditions. In this study, we aim to explore the therapeutic potential of 2-bromo-1,4-naphthalenedione (BrQ), a derivative of naphthalenedione, in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and to elucidate its underlying mechanisms. We observed that mice treated with BrQ exhibited reduced severity of EAE symptoms, including lower clinical scores, decreased leukocyte infiltration, and less extensive demyelination in central nervous system. Furthermore, it was noted that BrQ does not directly affect the remyelination process. Through cell-chat analysis based on bulk RNA-seq data, coupled with validation of flow analysis, we discovered that BrQ significantly promotes the expansion of CD8+ T cells and their interactions with other immune cells in peripheral immune system in EAE mice. Subsequent CD8+ T cell depletion experiments confirmed that BrQ alleviates EAE in a CD8+ T cell-dependent manner. Mechanistically, expanded CD8+ cells were found to selectively reduce antigen-specific CD4+ cells and subsequently inhibit Th1 and Th17 cell development in vivo, ultimately leading to relief from EAE. In summary, our findings highlight the crucial role of BrQ in modulating the pathogenesis of MS, suggesting its potential as a novel drug candidate for treating MS and other autoimmune diseases.
Assuntos
Linfócitos T CD8-Positivos , Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Células Th1 , Células Th17 , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Camundongos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Feminino , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Proliferação de Células/efeitos dos fármacosRESUMO
BACKGROUND: Obesity caused by the overconsumption of energy-dense foods high in fat and sugar has contributed to the growing prevalence of type 2 diabetes. Betaine, found in food or supplements, has been found to lower blood glucose concentrations, but its exact mechanism of action is not well understood. OBJECTIVES: A comprehensive evaluation of the potential mechanisms by which betaine supplementation improves glucose metabolism. METHODS: Hyperglycemic mice were fed betaine to measure the indexes of glucose metabolism in the liver and muscle. To explore the mechanism behind the regulation of betaine on glucose metabolism, Ribonucleic Acid-Seq was used to analyze the livers of the mice. In vitro, HepG2 and C2C12 cells were treated with betaine to more comprehensively evaluate the effect of betaine on glucose metabolism. RESULTS: Betaine was added to the drinking water of high-fat diet-induced mice, and it was found to reduce blood glucose concentrations and liver triglyceride concentrations without affecting body weight, confirming its hypoglycemic effect. To investigate the specific mechanism underlying its hypoglycemic effect, protein-protein interaction enrichment analysis of the liver revealed key nodes associated with glucose metabolism, including cytochrome P450 family activity, insulin sensitivity, glucose homeostasis, and triglyceride concentrations. The Kyoto Encyclopedia of Genes and Genomes and gene ontogeny enrichment analyses showed significant enrichment of the Notch signaling pathway. These results provided bioinformatic evidence for specific pathways through which betaine regulates glucose metabolism. Key enzyme activities involved in glucose uptake, glycogen synthesis, and glycogenolysis pathways of the liver and muscle were measured, and improvements were observed in these pathways. CONCLUSIONS: This study provides new insight into the mechanisms by which betaine improves glucose metabolism in the liver and muscle and supports its potential as a drug for the treatment of metabolic disorders related to glucose.
Assuntos
Betaína , Diabetes Mellitus Tipo 2 , Camundongos , Animais , Betaína/metabolismo , Camundongos Obesos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Fígado/metabolismo , Triglicerídeos , Dieta Hiperlipídica/efeitos adversos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Camundongos Endogâmicos C57BL , Glucose/metabolismo , Metabolismo dos LipídeosRESUMO
Aims: Although there is evidence that patients with stroke who exercise regularly before stroke have a better prognosis than those who do not exercise, the detailed mechanism remains unclear. Moreover, neuronal death plays a central role in neurological dysfunction caused by ischemic stroke. Thus, we investigated whether exercise could reduce stroke-induced neuronal death and its associated mediators in the current study. Results: Ferroptosis was the most dominant form of programmed cell death in neurons. Preconditioning exercise before stroke improved the neurological function and decreased the infarct area in rats with ischemic stroke. Preconditioning exercise attenuated stroke-induced ferroptosis by reducing lipid peroxidation (LPO) production, upregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and downregulating acyl-CoA synthetase long-chain family member 4 (ACSL4). High-throughput sequencing and dual luciferase reporter assays revealed that exercise-induced exosomal miR-484 inhibits Acsl4 expression. Moreover, we showed that exercise-induced exosomal miR-484 is mainly derived from skeletal muscle, and the neuroprotective effect of preconditioning exercise is suppressed by inhibiting miR-484 production in skeletal muscle. Innovation: This study suggested that neuronal ferroptosis is the most dominant form of programmed cell death in a hypoxic environment. Moreover, we showed that the ferroptosis pathway is a potential therapeutic target in ischemic stroke and that preconditioning exercise could be an effective antioxidant intervention for cerebral ischemia. Conclusion: Our work revealed that preconditioning exercise before stroke exerts neuroprotective effects against brain ischemia by skeletal muscle-derived exosomal miR-484 via inhibiting ferroptosis.
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OBJECTIVE: Poststroke spasticity (PSS) reduces arm function and leads to low levels of independence. This study suggested applying machine learning (ML) from routinely available data to support the clinical management of PSS. DESIGN: 172 patients with acute first-ever stroke were included in this prospective cohort study. Twenty clinical information and rehabilitation assessments were obtained to train various ML algorithms for predicting 6-month PSS defined by a modified Ashworth scale (MAS) score ≥ 1. Factors significantly relevant were also defined. RESULTS: The study results indicated that multivariate adaptive regression spline (area under the curve (AUC) value: 0.916; 95% confidence interval (CI): 0.906-0.923), adaptive boosting (AUC: 0.962; 95% CI: 0.952-0.973), random forest (RF) (AUC: 0.975; 95% CI: 0.968-0.981), support vector machine (SVM) (AUC: 0.980; 95% CI: 0.970-0.989) outperformed the traditional logistic model (AUC: 0.897; 95% CI: 0.884-0.910) (P < 0.05). Among all of the algorithms, the RF and SVM models outperformed the others (P < 0.05). FMA score, days in hospital, age, stroke location, and paretic side were the most important features. CONCLUSION: These findings suggest that ML algorithms can help augment clinical decision-making processes for the assessment of PSS occurrence, which may enhance the efficacy of management for patients with PSS in the future.
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Background: Human olfactory mesenchymal stem cells (OMSC) have become a novel therapeutic option for immune disorder or demyelinating disease due to their immunomodulatory and regenerative potentials. However, the immunomodulatory effects of OMSC still need to be elucidated, and comparisons of the effects of different MSCs are also required in order to select an optimal cell source for further applications. Results: In animal experiments, we found neural functional recovery and delayed EAE attack in the OMSC treatment group. Compared with umbilical cord-derived mesenchymal stem cells (UMSC) treatment group and the control group, the OMSC treatment group had a better neurological improvement, lower serum levels of IFN-γ, and a lower proportion of CD4+IFN-γ+ T splenic lymphocyte. We also observed OMSC effectively suppressed CD4+IFN-γ+ T cell proportion in vitro when co-cultured with human peripheral blood-derived lymphocytes. The OMSC-mediated immunosuppressive effect on human CD4+IFN-γ+ T cells was attenuated by blocking cyclooxygenase activity. Conclusion: Our results suggest that OMSC treatment delayed the onset and promoted the neural functional recovery in the EAE mouse model possibly by suppressing CD4+IFN-γ+ T cells. OMSC transplantation might become an alternative therapeutic option for neurological autoimmune disease.
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OBJECTIVE: To test whether the presence of N30 somatosensory evoked potentials, generated from the supplementary motor area and premotor cortex, correlate with post-stroke spasticity, motor deficits, or motor recovery stage. DESIGN: A cross-sectional study. PATIENTS: A total of 43 patients with stroke hospitalized at Maoming People's Hospital, Maoming, China. METHODS: Forty-three stroke patients underwent neurofunctional tests, including Modified Ashworth Scale (MAS), Brunnstrom stage, manual muscle test and neurophysiological tests, including N30 somatosensory evoked potentials, N20 somatosensory evoked potentials, motor evoked potentials, H-reflex. The results were compared between groups. Correlation and regression analyses were performed as well. RESULTS: Patients with absence of N30 somatosensory evoked potential exhibited stronger flexor carpi radialis muscle spasticity (r = -0.50, p < 0.05) and worse motor function (r = 0.57, p < 0.05) than patients with presence of N30 somatosensory evoked potential. The generalized linear model (GLM) including both N30 somatosensory evoked potentials and motor evoked potentials (Akaike Information Criterion (AIC) = 121.99) better reflected the recovery stage of the affected proximal upper limb than the models including N30 somatosensory evoked potentials (AIC = 125.06) or motor evoked potentials alone (AIC = 127.45). CONCLUSION: N30 somatosensory evoked potential status correlates with the degrees of spasticity and motor function of stroke patients. The results showed that N30 somatosensory evoked potentials hold promise as a biomarker for the development of spasticity and the recovery of proximal limbs.
Assuntos
Espasticidade Muscular , Acidente Vascular Cerebral , Estudos Transversais , Potencial Evocado Motor , Potenciais Somatossensoriais Evocados , Humanos , Espasticidade Muscular/etiologia , Acidente Vascular Cerebral/complicaçõesRESUMO
Background: Exosomes, especially stem cell-derived exosomes, have been widely studied in pre-clinical research of ischemic stroke. However, their pooled effects remain inconclusive. Methods: Relevant literature concerning the effects of exosomes on neurological performance in a rodent model of ischemic stroke was identified via searching electronic databases, including PubMed, Embase, and Web of Science. The primary outcomes included neurological function scores (NFS) and infarct volume (IV), and the secondary outcomes were several pro-inflammatory factors and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells. Subgroup analyses regarding several factors potentially influencing the effects of exosomes on NFS and IV were also conducted. Results: We identified 21 experiments from 18 studies in the meta-analysis. Pooled analyses showed the positive and significant effects of exosomes on NFS (standardized mean difference -2.79; 95% confidence interval -3.81 to -1.76) and IV (standardized mean difference -3.16; 95% confidence interval -4.18 to -2.15). Our data revealed that the effects of exosomes on neurological outcomes in rodent stroke models might be related to routes of administration and exosomes sources. In addition, there was significant attenuation in pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and interleukin-1ß, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells when undergoing exosomes treatment. Conclusion: Cell-derived exosomes treatment demonstrated statistically significant improvements in structural and neurological function recovery in animal models of ischemic stroke. Our results also provide relatively robust evidence supporting cell-derived exosomes as a promising therapy to promote neurological recovery in stroke individuals.