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Immunofluorescence analysis was used to show the effect of MT on autophagy-activatingprotein (LC3B) expression in the spinal cord neurons in SCI model rats at day 7. a Immunofluorescence of LC3B (red), NeuN (green) and DAPI (blue). b Statistical analysis of immunofluorescence as a proportion of the LC3B-positive neurons. Data are presented as the mean ± SD. (*P < 0.05, **P < 0.01 vs. the MT group, n = 5, scale bar = 50 μm)
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Spinal cord injury (SCI) leads to neuronal death resulting in central nervous system (CNS) dysfunction; however, the pathogenesis is still poorly understood. Melatonin (MT), a hormone secreted mainly by the pineal gland, is associated with neuroprotective effects against SCI. Enhanced autophagy can promote the recovery of locomotor function and red...
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... Autophagy is significant in the context of SCI, but it also has drawbacks. In SCI, increasing autophagy has been found to support motor recovery [36], but it has also been suggested that inducing autophagy may result in the death of neuronal cells [37]. Despite substantial debate, mounting data seem to point to the fact that autophagy is primarily advantageous in the setting of SCI [38,39]. ...
Spinal cord injury (SCI) can lead to permanent paralysis and various motor, sensory and autonomic nervous system dysfunction. The complex pathophysiological processes limit the effectiveness of many clinical treatments. Mitochondria has been reported to play a key role in the pathogenesis of SCI; while mitophagy is a protective mechanism against mitochondrial dysfunction. However, there is recently little drugs that may targeted activate mitophagy to treat SCI. In this study, we evaluated the role of 20-Deoxyingenol (20-DOI) in SCI and explored its potential mechanisms. We used a SCI rat model and evaluated the functional outcomes after the injury. Western blotting and immunofluorescence techniques were used to analyze the levels of mitophagy, apoptosis, and TFEB-related signaling pathways. Our research results show that 20-DOI significantly improves the apoptosis of neural cells after TBHP stimulation and functional recovery after spinal cord injury. In addition, mitophagy, TFEB levels, and apoptosis are related to the mechanism of 20-DOI treatment for spinal cord injury. Specifically, our research results indicate that 20-DOI restored the autophagic flux after injury, thereby inducing mitophagy, eliminating the accumulation of Cyto C, and inhibiting apoptosis. Further mechanism research suggests that 20-DOI may regulate mitophagy by promoting TFEB nuclear translocation. These results indicate that 20-DOI can significantly promote recovery after spinal cord injury, which may be a promising treatment method for spinal cord injury.
... We observed that PIK3R1, EGFR, HSP90AA1, and TP53 were jointly involved in the PI3K-AKT signaling pathway, which involves controlling the cell viability, inhibits apoptosis, and promotes cell cycle progression. Previous studies suggest that the PI3K/AKT1/ mTOR pathway participates in the apoptosis of spinal cord neurons and glial scar formation after SCI, and inhibiting this pathway can alleviate these negative effects [25,26]. Similarly, EGFR activation is involved in the destruction of the blood-spinal cord barrier (BSCB) and secondary injury after SCI. ...
Spinal cord injury (SCI) is a highly complex neurological disease, but there is no effective repair method. Quercetin is a flavonol drug and has a variety of biological activities, such as scavenging oxygen free radicals in the body to resist oxidation, inhibiting inflammation, and so on. In this study, quercetin was firstly demonstrated to reduce tissue damage, promote neuron survival and repair motor function after SCI in rats through in vivo experiments. Then, 293 potential targets of quercetin repair for SCI were predicted by network pharmacology. GO analysis revealed that the biological processes of potential targets focused mainly on signal transduction, negative regulation of the apoptotic process, protein phosphorylation, drug response, and so on. Similarly, KEGG analysis suggested that these potential targets were involved in cell growth regulation, differentiation, apoptosis, and a few metabolic pathways. PPI network analysis predicted that the key genes were EP300, CREBBP, SRC, HSP90AA1, TP53, PIK3R1, EGFR, ESR1, and CBL. Further, the molecular docking showed that quercetin binds well with these proteins. Finally, RT-qPCR and Western blotting experiments verified that quercetin downregulated the expression levels of PIK3R1 and EGFR. It is suggested that quercetin can repair SCI in rats through PI3K-AKT signaling pathway and EGFR/MAPK pathway, which may provide a new theoretical basis for the repair of spinal cord injury.
... Further studies will focus on better understating its observed effects. For example, it is possible that PI3K/AKT/mTOR pathway plays a crucial role in melatonin activity, which is also advisable to be investigated for a better understanding of the data presented in this report [59]. ...
Melatonin is a hormone secreted mainly by the pineal gland and acts through the Mel1A and Mel1B receptors. Among other actions, melatonin significantly increases osteogenesis during bone regeneration. Human adipose-derived mesenchymal stem cells (ADSCs) are also known to have the potential to differentiate into osteoblast-like cells; however, inefficient culturing due to the loss of properties over time or low cell survival rates on scaffolds is a limitation. Improving the process of ADSC expansion in vitro is crucial for its further successful use in bone regeneration. This study aimed to assess the effect of melatonin on ADSC characteristics, including osteogenicity. We assessed ADSC viability at different melatonin concentrations as well as the effect on its receptor inhibitors (luzindole or 4-P-PDOT). Moreover, we analyzed the ADSC phenotype, apoptosis, cell cycle, and expression of MTNR1A and MTNR1B receptors, and its potential for osteogenic differentiation. We found that ADSCs treated with melatonin at a concentration of 100 µM had a higher viability compared to those treated at higher melatonin concentrations. Melatonin did not change the phenotype of ADSCs or induce apoptosis and it promoted the activity of some osteogenesis-related genes. We concluded that melatonin is safe, non-toxic to normal ADSCs in vitro, and can be used in regenerative medicine at low doses (100 μM) to improve cell viability without negatively affecting the osteogenic potential of these cells.
... Based on the previous studies, PI3Ks signaling pathway plays an important role in regulating autophagy, especially in SCI treatment [1,27,36,55,56]. Several studies explored the therapeutic effects of regulating autophagy on SCI by targeting PI3Ks [12,36,55,56]. ...
... Based on the previous studies, PI3Ks signaling pathway plays an important role in regulating autophagy, especially in SCI treatment [1,27,36,55,56]. Several studies explored the therapeutic effects of regulating autophagy on SCI by targeting PI3Ks [12,36,55,56]. But, it is still confused that whether inducing or inhibiting PI3K-related signaling pathway to regulate autophagy is the better choice. ...
... But, it is still confused that whether inducing or inhibiting PI3K-related signaling pathway to regulate autophagy is the better choice. For example, Zhang et al. activated PI3K signaling pathway with inhibition of autophagy for neurological recovery, while upstream autophagy by activation of PI3Ks was observed by Li et al. [36,56]. PI3Ks phosphorylate to form phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), and phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), which are connected and co-affect autophagy [57][58][59][60] (Fig. 7). ...
There are limited therapeutic options for patient with traumatic spinal cord injury (SCI). Phosphoinositide 3-kinase family (PI3Ks) are the key molecules for regulating cell autophagy, which is a possible way of treating SCI. As we know, PI3K family are composed of eight isoforms, which are distributed into three classes. While the role of PI3Ks in regulating autophagy is controversial and the effects may be in a cell-specific manner. Different isoforms do not distribute in neural cells consistently and it is not clear how the PI3K isoforms regulate and interact with autophagy. Therefore, we explored the distributions and expression of different PI3K isoforms in two key neural cells (PC12 cells and astrocytes). The results showed that the expression of LC3II/I and p62, which are the markers of autophagy, changed in different patterns in PC12 cells and astrocytes after hypoxia/reoxygenation injury (H/R). Furthermore, the mRNA level of eight PI3K isoforms did not change in the same way, and even for the same isoform the mRNA activities are different between PC12 cells and astrocytes. What is more, the results of western blot of PI3K isoforms after H/R were inconsistent with the relevant mRNA. Based on this study, the therapeutic effects of regulating autophagy on SCI are not confirmed definitely, and its molecular mechanisms may be related with different temporal and spatial patterns of activation and distributions of PI3K isoforms.
... [5][6][7] Our previous research shown that the neuronal apoptosis and demyelination caused by inflammation in the SCI tissues disrupt fast SCI healing. [8][9][10] The poor proliferation capacity of mature neurons also remains a great challenge to repair SCI. 11,12 Thus, reducing local inflammatory responses and inducing neural proliferation have great potential to promote SCI healing. ...
Spinal cord injury (SCI) is a serious refractory disease of the central nervous system (CNS), which mostly caused by high-energy trauma. Existing interventions such as hormone shock and surgery are insufficient options, which relate to the secondary inflammation and neuronal dysfunction. Hydrogel with neuron-protective behaviors attracts tremendous attention, and black phosphorus quantum dots (BPQDs) encapsulating with Epigallocatechin-3-gallate (EGCG) hydrogels (E@BP) is designed for inflammatory modulation and SCI treatment in this study. E@BP displays good stability, biocompatibility and safety profiles. E@BP incubation alleviates lipopolysaccharide (LPS)-induced inflammation of primary neurons and enhances neuronal regeneration in vitro. Furthermore, E@BP reconstructs structural versus functional integrity of spinal cord tracts, which promotes recovery of motor neuron function in SCI rats after transplantation. Importantly, E@BP restarts the cell cycle and induces nerve regeneration. Moreover, E@BP diminishes local inflammation of SCI tissues, characterized by reducing accumulation of astrocyte, microglia, macrophages, and oligodendrocytes. Indeed, a common underlying mechanism of E@BP regulating neural regenerative and inflammatory responses is to promote the phosphorylation of key proteins related to AKT signaling pathway. Together, E@BP probably repairs SCI by reducing inflammation and promoting neuronal regeneration via the AKT signaling pathway.
... Neural apoptosis is an important post-SCI pathophysiological event in which its high levels lead to neuronal death, histological insult, and locomotor dysfunction. Evidence has shown that Caspase 3, an interleukin-converting enzyme-like protease, is associated with the activation of apoptosis in neurons after SCI (Xie et al. 2021;Li et al. 2019). Herein, we showed that the rate of TUNEL + cells and mitochondrial apoptotic marker (cleaved-caspase3) increased significantly in different hippocampus areas (CA1, DG), which is mainly greater in injured old rats compared to young ones. ...
Although the disruptive effects of spinal cord injury (SCI) on the hippocampus have been confirmed in some animal studies, no study has investigated its retrograde manifestations in the hippocampus of aged subjects. Herein, we compared the aged rats with young ones 3 weeks after the induction of SCI (Groups: Sham.Young, SCI.Young, Sham.Aged, SCI.Aged). The locomotion, hippocampal apoptosis, hippocampal rhythms (Delta, Theta, Beta, Gamma) max frequency (Max.rf) and power, hippocampal neurogenesis, and hippocampal receptors (NMDA, GABA A, Muscarinic1/M1), which are important in the generation of rhythms and neurogenesis, were compared in aged rats in contrast to young rats. At the end of the third week, the number of apoptotic (Tunel⁺) cells in the hippocampus (CA1, DG) of SCI animals was significantly higher compared to the sham animals, and also, it was significantly higher in the SCI.Aged group compared to SCI.Young group. Moreover, the rate of neurogenesis (DCX⁺, BrdU⁺ cells) and expression of M1 and NMDA receptors were significantly lower in the SCI.Aged group compared to SCI.Young group. The power and Max.fr of all rhythms were significantly lower in SCI groups compared to sham groups. Despite the decrease in the power of rhythms in the SCI.Aged group compared to SCI.Young group, there was no significant difference between them, and in terms of Max.fr index, only the Max.fr of theta and beta rhythms were significantly lower in the SCI.Aged group compared to SCI.Young group. This study showed that SCI could cause more neurodegeneration in the hippocampus of aged animals compared to young animals.
... Melatonin can regulate the immune system, eliminate free radicals, and has neuroprotective properties. Melatonin can act on SIRT1/AMPK or PI3K/AKT/mTOR, two pathways to increase autophagy and reduce apoptosis (Ding et al., 2015;Li et al., 2019;Gao et al., 2020a). Curcumin derived from Curcuma longa exhibits anti-cancer and antioxidant effects in clinical settings. ...
The central nervous system (CNS) is the primary regulator of physiological activity, and when CNS is compromised, its physical functions are affected. Spinal cord injury (SCI) and traumatic brain injury (TBI) are common trauma in CNS that are difficult to recover from, with a higher global disability and mortality rate. Autophagy is familiar to almost all researchers due to its role in regulating the degradation and recycling of cellular defective or incorrect proteins and toxic components, maintaining body balance and regulating cell health and function. Emerging evidence suggests it has a broad and long-lasting impact on pathophysiological process such as oxidative stress, inflammation, apoptosis, and angiogenesis, involving the alteration of autophagy marker expression and function recovery. Changes in autophagy level are considered a potential therapeutic strategy and have shown promising results in preclinical studies for neuroprotection following traumatic brain injury. However, the relationship between upward or downward autophagy and functional recovery following SCI or TBI is debatable. This article reviews the regulation and role of autophagy in repairing CNS trauma and the intervention effects of autophagy-targeted therapeutic agents to find more and better treatment options for SCI and TBI patients.
... This indolamine was found to silence the caspase-1 pathway and reduce the overexpression and activation of caspase-3 [37,38]. Furthermore, melatonin not only suppresses apoptotic responses but also stimulates the Akt pathway, mediating the activation of autophagy and its roles in cell survival [10,39]. Therefore, melatonin has been widely demonstrated to be a potent anti-apoptotic agent mainly due to its regulatory action on proteins involved in mitochondria-mediated apoptosis and on cell survival mechanisms. ...
There are several neurological diseases under which processes related to adult brain neurogenesis, such cell proliferation, neural differentiation and neuronal maturation, are affected. Melatonin can exert a relevant benefit for treating neurological disorders, given its well-known antioxidant and anti-inflammatory properties as well as its pro-survival effects. In addition, melatonin is able to modulate cell proliferation and neural differentiation processes in neural stem/progenitor cells while improving neuronal maturation of neural precursor cells and newly created postmitotic neurons. Thus, melatonin shows relevant pro-neurogenic properties that may have benefits for neurological conditions associated with impairments in adult brain neurogenesis. For instance, the anti-aging properties of melatonin seem to be linked to its neurogenic properties. Modulation of neurogenesis by melatonin is beneficial under conditions of stress, anxiety and depression as well as for the ischemic brain or after a brain stroke. Pro-neurogenic actions of melatonin may also be beneficial for treating dementias, after a traumatic brain injury, and under conditions of epilepsy, schizophrenia and amyotrophic lateral sclerosis. Melatonin may represent a pro-neurogenic treatment effective for retarding the progression of neuropathology associated with Down syndrome. Finally, more studies are necessary to elucidate the benefits of melatonin treatments under brain disorders related to impairments in glucose and insulin homeostasis.
... In vivo (289) 50 mg/kg TNF-α, IL-6, IL-1β Increased anti-inflammatory effect. ...
Neurodegenerative diseases are a serious health issue globally. High morbidity and mortality of these disorders lead to researchers further exploring more effective preventive and therapeutic remedies to combat these devastating diseases. An important strategy is to delay the progression of these debilitating diseases. The prevalence of neurodegenerative disease increases with aging which not only results in neuronal deterioration, but also causes the brain ischemia leading to stroke, and death. Melatonin, a potent endogenous antioxidant mainly secreted by the pineal gland, has often used in the treatment of neuropathologies with great success. Herein, we review the current evidence documenting melatonin’s therapeutic effects on neurodegenerative and brain ischemic diseases; we also summarize the known molecular mechanisms of its protective actions.
... Of these autophagy inducers, mitochondria due to the loss of energy generated in the cell and endoplasmic reticulum through the stress of the reticulum are those that cause more widespread damage. In various cellular systems it has been shown that melatonin is an effective context-dependent regulator of autophagy (Coto-Montes et al. 2012;Park et al. 2012;Jenwitheesuk et al. 2014;Kang et al. 2014;Roohbakhsh et al. 2018;Boga et al. 2019;Li et al. 2019;Xie et al. 2021). Melatonin appears to induce its beneficial effects through autophagy promotion and/or autophagy suppression. ...
