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Increasing evidence suggested that inhibiting the apoptosis of Schwann cells (SCs) and promoting nerve growth factor (NGF) expression in sciatic nerves play key roles in preventing the onset of diabetic peripheral neuropathy (DPN). Curcumin, a primary bioactive substance in turmeric with multiple characteristics, has been shown to have many therapeutic effects in a variety of diseases. However, curcumin is poorly studied in the DPN models. We aimed to explore the therapeutic benefits and underlying mechanism of curcumin in high fat/sugar diets joint streptozotocin (STZ)-induced DPN rat models. Sprague-Dawley (SD) rats were divided into five groups (6 rats per group), control group, DPN group, Curcumin groups (50, 100, and 150 mg/kg). Curcumin was administered intragastrically once per day for 4 continuous weeks. Body weight (BW) and fasting blood glucose (FBG) were monitored in all groups. The mechanical withdraw threshold (MWT) was measured. We also assessed neuropathic change by testing nerve conductance velocity (NCV) in sciatic nerves. TEM was applied to observe the sciatic nerves ultrastructure. The SCs apoptosis in sciatic nerves was stained using TUNEL kit. NGF contents in sciatic nerves and serum were detected using western blotting and ELISA analysis. The results showed curcumin had no obvious effect on the BW and FBG change. Curcumin (100 and 150â mg/kg) attenuated the MWT, NCV, and sciatic nerves ultrastructure in DPN rats. Curcumin (50, 100 and 150â mg/kg) reduced SCs apoptosis in sciatic nerves. In addition, curcumin at 150â mg/kg had the best efficacy in increasing protein expression of NGF in sciatic nerves and serum NGF level. Our work demonstrated that curcumin has neuroprotective effects for the treatment of DPN.
Assuntos
Curcumina , Diabetes Mellitus , Neuropatias Diabéticas , Animais , Ratos , Curcumina/farmacologia , Curcumina/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Fator de Crescimento Neural/metabolismo , Ratos Sprague-DawleyRESUMO
Hyperglycemia is considered a risk factor for the enhancement of local anesthetic-induced neurotoxicity. Transient receptor potential melastatin 7 (TRPM7), a kinase-coupled cation channel, has been implicated in a variety of neuropathological processes, including intracellular calcium disturbance and high glucose-induced neuropathy. In this study, we investigated whether TRPM7-related pathophysiology is involved in bupivacaine-induced neurotoxicity in SH-SY5Y cells and how hyperglycemia acts as a risk factor. For initial neurotoxicity evaluation, it was confirmed that cell damage and apoptosis induced by acute exposure to bupivacaine were dependent on its concentration and glucose preconditioning. High glucose preconditioning facilitated the bupivacaine-induced fast and temporary rise in intracellular free calcium concentration ([Ca2+ ]i ), which was attributed to both calcium influx through TRPM7 and calcium store release. Additionally, bupivacaine was shown to increase TRPM7-like currents, particularly in cells preconditioned with high glucose. Bupivacaine-induced neurotoxicity in hyperglycemia was correlated with extracellular signal-regulated kinase (ERK), but not protein kinase B (AKT) activation. Inhibition of TRPM7 and ERK activity alleviates bupivacaine neurotoxicity. These results suggest that therapeutically targeting TRPM7-related pathophysiological changes could be a potential strategy for treating local anesthetic-induced neurotoxicity exacerbated by hyperglycemia.
Assuntos
Bupivacaína/efeitos adversos , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Glucose/farmacologia , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Bupivacaína/farmacologia , Linhagem Celular Tumoral , HumanosRESUMO
Diabetic peripheral neuropathy (DPN) is a common nerve-damaging complication of diabetes mellitus. Effective treatments are needed to alleviate and reverse diabetes-associated damage to the peripheral nerves. Curcumin is an effective neuroprotectant that plays a protective role in DPN promoted by Schwann cells (SCs) lesions. However, the potential molecular mechanism of curcumin remains unclear. Therefore, our aim is to study the detailed molecular mechanism of curcumin-mediated SCs repair in order to improve the efficacy of curcumin in the clinical treatment of DPN. First, candidate target genes of curcumin in rat SC line RSC96 cells stimulated by high glucose were identified by RNA sequencing and bioinformatic analyses. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was carried out by Metascape, followed by 8 algorithms on Cytoscape to determine 4 hub genes, namly Hmox1, Pten, Vegfa and Myc. Next, gene set enrichment analysis (GSEA) and Pearson function showed that Hmox1 was significantly correlated with apoptosis. Subsequently, qRT-PCR, MTT assay, flow cytometry, caspase-3 activity detection and westernblot showed that curcumin treatment increased RSC96 cell viability, reduced cell apoptosis, increased Hmox1, Pten, Vegfa and Myc expression, and up-regulated Akt phosphorylation level under high glucose environment. Finally, molecular docking predicted the binding site of curcumin to Hmox1. These results suggest that curcumin can reduce the apoptosis of SCs induced by high glucose, and Hmox1 is a potential target for curcumin. Our findings provide new insights about the mechanism of action of curcumin on SC as a potential treatment in DPN.
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Postoperative ileus (POI) is the cessation or reduction of gastrointestinal (GI) motility after surgery. Reactive enteric glial cells (EGCs) are critical for maintaining bowel function. However, the triggering mechanisms and downstream effects of reactive EGCs in POI were poorly understood. The goal of this current study was to investigate whether the inducible nitric oxide synthase (iNOS)-driven reactive EGCs participated in GI motility disorders and mechanisms underlying altered GI motility in POI. Intestinal manipulation (IM)-induced POI mice and iNOS-/- mice were used in the study. Longitudinal muscle and myenteric plexuses (LMMPs) from the distal small intestine were stained by immunofluorescence. Our results found that the GI motility disorders occurred in the IM-induced POI mice, and reactive EGCs were observed in LMMPs. Glial metabolic inhibitor gliotoxin fluorocitrate (FC) treatment or iNOS gene knockout attenuated GI motility dysfunction. In addition, we also found that FC treatment or iNOS gene knockout significantly inhibited the fluorescence intensity macrophage colony-stimulating factor (M-CSF), which reduced M2 phenotype macrophages activation in LMMPs of IM-induced POI mice. Our findings demonstrated that iNOS-driven reactive EGCs played a key role and were tightly linked to the MMs homeostasis in the POI mice. EGCs are emerging as a new frontier in neurogastroenterology and a potential therapeutic target.
Assuntos
Íleus , Camundongos , Animais , Óxido Nítrico Sintase Tipo II/metabolismo , Íleus/metabolismo , Motilidade Gastrointestinal/fisiologia , Neuroglia/metabolismo , Intestino Delgado/metabolismoRESUMO
Introduction: Owing to advancements in non-invasive magnetic resonance imaging, many studies have repeatedly showed that diabetes affects the central nervous system in the presence of peripheral neuropathy, suggesting a common or interacting pathological mechanism for both complications. Methods: We aimed to investigate the role of abnormal gut microbiota in rats with diabetic peripheral neuropathy (DPN) combined with cognitive dysfunction. Glucose-compliant rats with nerve conduction deficits were screened as a successful group of DPN rats. The DPN group was then divided into rats with combined cognitive impairment (CD) and rats with normal cognitive function (NCD) based on the results of the Novel object recognition test. Rat feces were then collected for 16S rRNA gene sequencing of the intestinal flora. Results and Discussion: The results revealed that abnormalities in Firmicutes, Ruminococcaceae, Bacteroidia, and Actinobacteria-like microorganisms may induce DPN complicated by cognitive dysfunction.
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To investigate autonomic substrates of brainstem-gut circuitry identified using trans-synaptic tracing with pseudorabies virus (PRV)-152, a strain that expresses enhanced green fluorescent protein, and PRV-614, a strain that expresses enhanced red fluorescent protein, injecting into the rat rectum wall. 3-7 days after PRV-152 injection, spinal cord and brainstem were removed and sectioned, and processed for PRV-152 visualization using immunofluorescence labeling against PRV-152. 6 days after PRV-614 injection, brainstem was sectioned and the neurochemical phenotype of PRV-614-positive neurons was identified using double immunocytochemical labeling against PRV-614 and TPH. We observed that the largest number of PRV-152- or PRV-614-positive neurons was located in the gigantocellular reticular nucleus (Gi), lateral paragigantocellular (LPGi), rostral ventrolateral reticular nucleus (RVL), solitary tract nucleus (Sol), locus coeruleus (LC), raphe magnus nucleus (RMg), subcoeruleus nucleus (SubCD). Double-labeled PRV-614/tryptophan hydroxylase (TPH) neurons were concentrated in the RMg, LPGi and Sol. These brainstem neurons are candidates for relaying autonomic command signals to the gut. The autonomic substrate of brainstem-gut circuitry likely plays an important role in mediating different aspects of stress behaviors.
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Some reports have demonstrated that deep brain stimulation (DBS) is a promising treatment for patients who suffer from intractable anorexia nervosa. However, the nature of DBS may not be viewed as a standard clinical treatment option for anorexia nervosa because of the unpredictable outcome before DBS. Just like DBS in the brain, electroacupuncture at acupoints is also efficient in treating refractory anorexia nervosa. Some neuroimaging studies using functional magnetic resonance imaging, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) had revealed that both DBS and electroacupuncture at acupoints with electrical stimulation are related to the changes in cerebral glucose metabolism. Therefore, we hypothesize that the changes in cerebral glucose metabolism after electroacupuncture might be useful to predict the therapeutic effect of deep brain stimulation for refractory anorexia nervosa.