OTULIN Can Improve Spinal Cord Injury by the NF-κB and Wnt/ß-Catenin Signaling Pathways.

Spinal cord injury (SCI) is a significant health concern, as it presently has no effective treatment in the clinical setting. Inflammation is a key player in the pathophysiological process of SCI, with a number of studies evidencing that the inhibition of the NF-κB signaling pathway may impede the inflammatory response and improve SCI. OTULIN, as a de-ubiquitination enzyme, the most notable is its anti-inflammatory effect. OTULIN can inhibit the NF-κB signaling pathway to suppress the inflammatory reaction via de-ubiquitination. In addition, OTULIN may promote vascular regeneration through the Wnt/ß-catenin pathway in the wake of SCI. In this review, we analyze the structure and physiological function of OTULIN, along with both NF-κB and Wnt/ß-catenin signaling pathways. Furthermore, we examine the significant role of OTULIN in SCI through its impairment of the NF-κB signaling pathway, which could open the possibility of it being a novel interventional target for the condition.

Curcumin can improve spinal cord injury by inhibiting DNA methylation.

Spinal cord injury (SCI) is a serious central nervous system disease. Traumatic SCI often causes persistent neurological deficits below the injury level. Epigenetic changes occur after SCI. Studies have shown DNA methylation to be a key player in nerve regeneration and remodeling, and in regulating some pathophysiological characteristics of SCI. Curcumin is a natural polyphenol from turmeric. It has anti-inflammatory, antioxidant, and neuroprotective effects, and can mitigate the cell and tissue damage caused by SCI. This report analyzed the specific functions of DNA methylation in central nervous system diseases, especially traumatic brain injury and SCI. DNA methylation can regulate the level of gene expressions in the central nervous system. Therefore, pharmacological interventions regulating DNA methylation may be promising for SCI.

Triptolide activates the Nrf2 signaling pathway and inhibits the NF-κB signaling pathway to improve Alzheimer disease.

Alzheimer disease (AD) is a common neurodegenerative disease with pathological features of accumulated amyloid plaques, neurofibrillary tangles, and the significant inflammatory environment. These features modify the living microenvironment for nerve cells, causing the damage, dysfunction, and death. Progressive neuronal loss directly leads to cognitive decline in AD patients and is closely related to brain inflammation. Therefore, impairing inflammation via signaling pathways may facilitate either the prevention or delay of the degenerative process. Triptolide has been evidenced to possess potent anti-inflammatory effect. In this review, we elaborate on two signaling pathways (the NF-κB and Nrf2 signaling pathways) that are involved in the anti-inflammatory effect of triptolide.

Sestrin2 can alleviate endoplasmic reticulum stress to improve traumatic brain injury by activating AMPK/mTORC1 signaling pathway.

Traumatic brain injury (TBI), as a serious central nervous system disease, can result in severe neurological dysfunction or even disability and death of patients. The early and effective intervention of secondary brain injury can improve the prognosis of TBI. Endoplasmic reticulum (ER) stress is one of the main reasons to recover TBI. ER stress inhibition may be beneficial in treating TBI. Sestrin2 is a crucial regulator of ER stress, and its activation can significantly improve TBI. In this paper, we analyze the biological function of sestrin2, the latest findings on ER stress, and the relationship between ER stress and TBI. We elucidate the relationship of sestrin2 inhibiting ER stress via activating the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (MTORC1) signaling. Finally, we elaborate on the possible role of sestrin2 in TBI and explain how its activation potentially improves TBI.

Pharmacological intervention of curcumin via the NLRP3 inflammasome in ischemic stroke.

Ischemic-induced neuronal injury arises due to low oxygen/nutrient levels and an inflammatory response that exacerbates neuronal loss. NOD-like receptor family pyrin domain-containing 3 (NLRP3) is an important regulator of inflammation after ischemic stroke, with its inhibition being involved in nerve regeneration. Curcumin, a main active ingredient in Chinese herbs, plays a positive role in neuronal repair and neuroprotection by regulating the NLRP3 signaling pathway. Nevertheless, the signaling mechanisms relating to how curcumin regulates NLRP3 inflammasome in inflammation and neural restoration following ischemic stroke are unknown. In this report, we summarize the main biological functions of the NLRP3 inflammasome along with the neuroprotective effects and underlying mechanisms of curcumin via impairment of the NLRP3 pathway in ischemic brain injury. We also discuss the role of medicinal interventions that target the NLRP3 and potential pathways, as well as possible directions for curcumin therapy to penetrate the blood-brain barrier (BBB) and hinder inflammation in ischemic stroke. This report conclusively demonstrates that curcumin has neuroprotective properties that inhibit inflammation and prevent nerve cell loss, thereby delaying the progression of ischemic brain damage.

The role of long noncoding ribonucleic acids in the central nervous system injury.

Central nervous system (CNS) injury involves complex pathophysiological molecular mechanisms. Long noncoding ribonucleic acids (lncRNAs) are an important form of RNA that do not encode proteins but take part in the regulation of gene expression and various biological processes. Multitudinous studies have evidenced lncRNAs to have a significant role in the process of progression and recovery of various CNS injuries. Herein, we review the latest findings pertaining to the role of lncRNAs in CNS, both normal and diseased state. We aim to present a comprehensive clinical application prospect of lncRNAs in CNS, and thus, discuss potential strategies of lncRNAs in treating CNS injury.

Syntaphilin Inactivation Can Enhance Axonal Mitochondrial Transport to Improve Spinal Cord Injury.

Mitochondria are important organelle of eukaryotic cells. They consists of a large number of different proteins that provide most of the ATP and supply power for the growth, function, and regeneration of neurons. Therefore, smitochondrial transport ensures that adequate ATP is supplied for metabolic activities. Spinal cord injury (SCI), a detrimental condition, has high morbidity and mortality rates. Currently, the available treatments only provide symptomatic relief for long-term disabilities. Studies have implicated mitochondrial transport as a critical factor in axonal regeneration. Hence, enhancing mitochondrial transports could be beneficial for ameliorating SCI. Syntaphilin (Snph) is a mitochondrial docking protein that acts as a "static anchor," and its inhibition enhances mitochondrial transports. Therefore, Snph as a key mediator of mitochondrial transports, may contribute to improving axonal regeneration following SCI. Herein, we examine Snph's biological effects and its relation to mitochondrial pathway. Then, we elaborate on mitochondrial transports after SCI, the possible role of Snph in SCI, and some possible therapeutic approaches by Snph.

Ginsenosides can target brain-derived neurotrophic factor to improve Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease (ND). It is the progressive loss of neurons and abnormal accumulation of α-synuclein due to multiple etiologies. Currently, supportive treatment is the only intervention for PD. However, supportive treatment has serious side effects. Ginsenosides, a group of sterol compounds, are the main active ingredients of ginseng. They have a potential role in NDs and psychosis. The brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway is closely related to the growth, survival and differentiation of neurons. Ginsenosides exert a neuroprotective role in NDs and psychosis by upregulating BDNF and activating the BDNF/TrkB signaling pathway. Herein, we analyzed the relationship between ginsenosides, BDNF, the BDNF/TrkB signaling pathway, NDs, and psychosis. We hypothesize that ginsenosides may protect neurons to improve PD by activating the BDNF/TrkB pathway.

Biometals in Alzheimer disease: emerging therapeutic and diagnostic potential of molybdenum and iodine.

The current ageing trend of the world population has, in part, accounted for Alzheimer disease (AD) being a public health issue in recent times. Although some progress has been made in clarifying AD-related pathophysiological mechanisms, effective intervention is still elusive. Biometals are indispensable to normal physiological functions of the human body-for example, neurogenesis and metabolism. However, their association with AD remains highly controversial. Copper (Cu) and zinc (Zn) are biometals that have been investigated at great length in relation to neurodegeneration, whereas less attention has been afforded to other trace biometals, such as molybdenum (Mo), and iodine. Given the above context, we reviewed the limited number of studies that have evidenced various effects following the usage of these two biometals in different investigative models of AD. Revisiting these biometals via thorough investigations, along with their biological mechanisms may present a solid foundation for not only the development of effective interventions, but also as diagnostic agents for AD.

Maresin1 can be a potential therapeutic target for nerve injury.

Nerve injury significantly affects human motor and sensory function due to destruction of the integrity of nerve structure. In the wake of nerve injury, glial cells are activated, and synaptic integrity is destroyed, causing inflammation and pain hypersensitivity. Maresin1, an omega-3 fatty acid, is a derivative of docosahexaenoic acid. It has showed beneficial effects in several animal models of central and peripheral nerve injuries. In this review, we summarize the anti-inflammatory, neuroprotective and pain hypersensitivity effects of maresin1 in nerve injury and provide a theoretical basis for the clinical treatment of nerve injury using maresin1.

Quercetin activates the Sestrin2/AMPK/SIRT1 axis to improve amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease with poor prognosis. The intricacies surrounding its pathophysiology could partly account for the lack of effective treatment for ALS. Sestrin2 has been reported to improve metabolic, cardiovascular and neurodegenerative diseases, and is involved in the direct and indirect activation of the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) axis. Quercetin, as a phytochemical, has considerable biological activities, such as anti-oxidation, anti-inflammation, anti-tumorigenicity, and neuroprotection. Interestingly, quercetin can activate the AMPK/SIRT1 signaling pathway to reduce endoplasmic reticulum stress, and alleviate apoptosis and inflammation. This report examines the molecular relationship between Sestrin2 and AMPK/SIRT1 axis, as well as the main biological functions and research progress of quercetin, together with the correlation between quercetin and Sestrin2/AMPK/SIRT1 axis in neurodegenerative diseases.

Ellagic acid activates the Keap1-Nrf2-ARE signaling pathway in improving Parkinson's disease: A review.

Parkinson's disease (PD) is a familiar neurodegenerative disease, accompanied by motor retardation, static tremor, memory decline and dementia. Heredity, environment, age and oxidative stress have been suggested as key factors in the instigation of PD. The Keap1-Nrf2-ARE signaling is one of the most significant anti- oxidative stress (OS) pathways. The Keap1 is a negative regulator of the Nrf2. The Keap1-Nrf2-ARE pathway can induce cell oxidation resistance and reduce nerve injury to treat neurodegenerative diseases. Ellagic acid (EA) can inhibit the Keap1 to accumulate the Nrf2 in the nucleus, and act on the ARE to produce target proteins, which in turn may alleviate the impact of OS on neuronal cells of PD. This review analyzes the structure and physiological role of EA, along with the structure, composition and functions of the Keap1-Nrf2-ARE signaling pathway. We further expound on the mechanism of ellagic acid in its activation of the Keap1-Nrf2-ARE signaling pathway, as well as the relationship between EA in impairing the TLR4/Myd88/NF-κB and Nrf2 pathways. Ellagic acid has the potentiality of improving PD by activating the Keap1-Nrf2-ARE signaling pathway and scavenging free radicals.

Protective role of ethyl pyruvate in spinal cord injury by inhibiting the high mobility group box-1/toll-like receptor4/nuclear factor-kappa B signaling pathway.

Spinal cord injury (SCI) is a high incident rate of central nervous system disease that usually causes paralysis below the injured level. The occurrence of chronic inflammation with the axonal regeneration difficulties are the underlying barriers for the recovery of SCI patients. Current studies have paid attention to controlling the instigative and developmental process of neuro-inflammation. Ethyl pyruvate, as a derivative of pyruvate, has strong anti-inflammatory and neuroprotective functions. Herein, we reviewed the recent studies of ethyl pyruvate and high mobility group box-1 (HMGB1). We think HMGB1 that is one of the main nuclear protein mediators to cause an inflammatory response. This protein induces astrocytic activation, and promotes glial scar formation. Interestingly, ethyl pyruvate has potent inhibitory effects on HMGB1 protein, as it inhibits chronic inflammatory response by modulating the HMGB1/TLR4/NF-κB signaling pathway. This paper discusses the potential mechanism of ethyl pyruvate in inhibiting chronic inflammation after SCI. Ethyl pyruvate can be a prospective therapeutic agent for SCI.

Enhanced Glial Reaction and Altered Neuronal Nitric Oxide Synthase are Implicated in Attention Deficit Hyperactivity Disorder.

Attention deficit hyperactivity disorder (ADHD) has a complex etiology, and its specific causal factors remain to be elucidated. Aberration of nitric oxide synthase (nNOS) and inflammation, together with astrocytic and microglial cells have been continually associated with several neurological disorders, including ADHD. Using spontaneously hypertensive rat (SHR), we investigated the changes in nNOS, inflammatory, microglial and astrocytic markers in the frontal cortex and hippocampus at three different ages: onset of hypertension stage (i.e., 6 weeks after birth of SHR), established hypertension stage (i.e., 12 weeks after birth of SHR) and senescent stage (i.e., 12 months after birth of SHR), and compared with its age-matched normotensive control, Wistar-Kyoto (WKY) rats. A significant upregulation of Iba-1 expression in the senescent stage of SHR was observed. Further, we observed an upregulated nNOS expression in both onset and established stages of SHR, and a downregulated nNOS in the senescent stage. Our study showed an age-related increment of astrogliosis in the cortex and hippocampi of aged SHR. On the basis of our results, alterations in the nNOS and Iba-1 expressions, as well as age-related astrogliosis, may contribute to ADHD pathogenesis.

Muscone Can Improve Spinal Cord Injury by Activating the Angiogenin/Plexin-B2 Axis.

Spinal cord injury (SCI) is a devastating neurological disorder that usually damages sensorimotor and autonomic functions. Signaling pathways can play a key role in the repair process of SCI. The plexin-B2 acts as a receptor for angiogenin and mediates ribosomal RNA transcription, influencing cell survival and proliferation. Protein kinase B serine/threonine kinase interacts with angiogenin to form a positive feedback effect. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor can induce angiogenin nuclear translocation. Moreover, the BDNF can promote the secretion of angiogenin. Interestingly, all of them can activate the angiogenin/plexin-B2 axis. Muscone has anti-inflammatory and proliferative features as it can inhibit nuclear transcription factor kappa-B (NF-κB) and activate the angiogenin/plexin-B2 axis, thus being significant agent in the SCI repair process. Herein, we review the potential mechanism of angiogenin/plexin-B2 axis activation and the role of muscone in SCI treatment. Muscone may attenuate inflammatory responses and promote neuronal regeneration after SCI.

Adipose-Derived Mesenchymal Stem Cells Combined With Extracellular Vesicles May Improve Amyotrophic Lateral Sclerosis.

The complexity of central nervous system diseases together with their intricate pathogenesis complicate the establishment of effective treatment strategies. Presently, the superiority of adipose-derived mesenchymal stem cells (ADSCs) on neuronal injuries has attracted significant attention. Similarly, extracellular vesicles (EVs) are potential interventional agents that could identify and treat nerve injuries. Herein, we reviewed the potential effects of ADSCs and EVs on amyotrophic lateral sclerosis (ALS) injured nerves, and expound on their practical application in the clinic setting. This article predominantly focused on the therapeutic role of ADSCs concerning the pathogenesis of ALS, the protective and reparative effects of EVs on nerve injury, as well as the impact following the combined usage of ADSCs and EVs in ALS.

Quercetin Can Improve Spinal Cord Injury by Regulating the mTOR Signaling Pathway.

The pathogenesis of spinal cord injury (SCI) is complex. At present, there is no effective treatment for SCI, with most current interventions focused on improving the symptoms. Inflammation, apoptosis, autophagy, and oxidative stress caused by secondary SCI may instigate serious consequences in the event of SCI. The mammalian target of rapamycin (mTOR), as a key signaling molecule, participates in the regulation of inflammation, apoptosis, and autophagy in several processes associated with SCI. Quercetin can reduce the loss of myelin sheath, enhance the ability of antioxidant stress, and promote axonal regeneration. Moreover, quercetin is also a significant player in regulating the mTOR signaling pathway that improves pathological alterations following neuronal injury. Herein, we review the therapeutic effects of quercetin in SCI through its modulation of the mTOR signaling pathway and elaborate on how it can be a potential interventional agent for SCI.

Curcumin can improve Parkinson's disease via activating BDNF/PI3k/Akt signaling pathways.

Parkinson's disease is a common progressive neurodegenerative disease, and presently has no curative agent. Curcumin, as one of the natural polyphenols, has great potential in neurodegenerative diseases and other different pathological settings. The brain-derived neurotrophic factor (BDNF) and phosphatidylinositol 3 kinase (PI3k)/protein kinase B (Akt) signaling pathways are significantly involved nerve regeneration and anti-apoptotic activities. Currently, relevant studies have confirmed that curcumin has an optimistic impact on neuroprotection via regulating BDNF and PI3k/Akt signaling pathways in neurodegenerative disease. Here, we summarized the relationship between BDNF and PI3k/Akt signaling pathway, the main biological functions and neuroprotective effects of curcumin via activating BDNF and PI3k/Akt signaling pathways in Parkinson's disease. This paper illustrates that curcumin, as a neuroprotective agent, can delay the progression of Parkinson's disease by protecting nerve cells.

The combination of autologous mesenchymal stem cell-derived exosomes and neurotrophic factors as an intervention for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a chronic progressive degeneration of motor neurons and has a high mortality. Riluzole and edaravone are the only approved medications currently being used for amyotrophic lateral sclerosis in clinical settings. However, they can lead to serious complications, such as injuries to the liver and kidney. To date, there is no effective treatment for amyotrophic lateral sclerosis. In this regard, investigations concerning the employment of exosomes, mesenchymal stem cells, and neurotrophic factors to ameliorate amyotrophic lateral sclerosis are attracting considerable attention in the scientific community. Herein, we systematically analyze the relationship relevant to autologous mesenchymal stem cell derived-exosomes, neurotrophic factors and amyotrophic lateral sclerosis. Mesenchymal stem cells modulate immune response, mitigate oxidative stress, promote neuronal regeneration, and differentiate into neuronal and glial cells. Furthermore, exosomes from mesenchymal stem cells exert beneficial effects on their mother cells by preventing abnormal differentiation of mesenchymal stem cells. Similarly, neurotrophic factors regulate inflammatory response, stimulate the neuron repair, and the recovery of neuronal functioning. Therefore, autologous mesenchymal stem cells-derived exosomes combined with neurotrophic factors could potentially be an effective interventional medium for amyotrophic lateral sclerosis.

SARM1 can be a potential therapeutic target for spinal cord injury.

Injury to the spinal cord is devastating. Studies have implicated Wallerian degeneration as the main cause of axonal destruction in the wake of spinal cord injury. Therefore, the suppression of Wallerian degeneration could be beneficial for spinal cord injury treatment. Sterile alpha and armadillo motif-containing protein 1 (SARM1) is a key modulator of Wallerian degeneration, and its impediment can improve spinal cord injury to a significant degree. In this report, we analyze the various signaling domains of SARM1, the recent findings on Wallerian degeneration and its relation to axonal insults, as well as its connection to SARM1, the mitogen-activated protein kinase (MAPK) signaling, and the survival factor, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). We then elaborate on the possible role of SARM1 in spinal cord injury and explicate how its obstruction could potentially alleviate the injury.