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.

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.

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.

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.

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.

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.

Valproic Acid: A Potential Therapeutic for Spinal Cord Injury.

The lack of an effective pharmaceutical agent for spinal cord injury (SCI) is a current problematic situation for clinicians, as the rate of motor vehicle accidents among young adults is on the rise. SCI contributes to the high disability rate. Presently, evidences detailing the precise pathological mechanisms in SCI are limited, compounding to the unavailability of an effective treatment method. Surgery, though not a complete curative method, is useful in managing some of the associated symptoms of secondary SCI. Autophagy and inflammation are contributive factors to both exacerbation and improvement of SCI. The mammalian target of rapamycin (mTOR) signaling pathway is a key player in the regulation of inflammatory response and autophagy. Valproic acid (VPA), a clinically used antiepileptic drug, has been suggested to improve neurological conditions, including SCI. This report reviewed the correlation between mTOR and autophagy, as well as autophagy's role and the therapeutic effects of VPA in SCI. VPA regulates autophagy by potentially inhibiting mTORC1, a complex of mTOR, while also hindering inflammatory response. Conclusively, an effective treatment for SCI could lie in the timely regulation of mTOR signaling pathway, and VPA could be the potential drug that improves SCI owing to its propensity to regulate the mTOR signaling pathway.

The Inhibition of Inflammatory Signaling Pathway by Secretory Leukocyte Protease Inhibitor can Improve Spinal Cord Injury.

Spinal cord injury leads to loss of sensory motor functions below the damaged area, and can significantly affects physical and mental health. An effective spinal cord injury treatment is currently unavailable, in part, because of the intricacy of the brain, as well as the complex pathophysiological mechanism of the injury. Inflammation is an important biological process in multitudinous diseases, with no exception for spinal cord injury. Nuclear factor kappa beta (NF-κB) signaling pathway is a key inflammatory element, as it is involved in cell survival, apoptosis, proliferation, differentiation, and immune response. Activation of the NF-κB signaling pathway leads to the release of a large number of inflammatory factors that can affect tissue repair. Hence, the inhibition of inflammatory responses could improve the repair of injured spinal cord tissues. Secretory leukocyte protease inhibitor (SLPI) has anti-inflammatory and anti-bacterial properties, and promotes wound healing. SLPI can bind to the promoter region of tumor necrosis factor-αand interleukin-8 (IL-8) to inhibit the NF-κB signaling pathway. Additionally, SLPI can reduce secondary damages after spinal cord injury, and prevent further complications. In this report, we analyze the pathophysiological mechanism of spinal cord injury, the role of NF-κB signaling pathway following spinal cord injury, and how SLPI regulates the NF-κB signaling pathway to curtail inflammatory reaction.

Application of gene chip technology in the diagnostic and drug resistance detection of Helicobacter pylori in children.

BACKGROUND AND AIMS: Helicobacter pylori (HP) culture for diagnosing HP infection is time-consuming and technologically complex. This study evaluated the clinical significance of gastric mucosal gene chip technology in the rapid diagnosis of HP infection and detection of drug resistance in children. METHODS: Patients (between the age of 2.5 and 16.0 years old) manifesting gastrointestinal symptoms were enrolled in this study. HP culture of gastric mucosa and drug sensitivity test were performed. A gene chip of gastric mucosa was used to detect the presence of HP infection, some single nucleotide polymorphisms in HP drug resistance genes, or associated gene mutation. DNA sequencing was investigated and compared with the gene chip test results. RESULTS: Out of 267 cases, HP culture was positive in 169 cases and negative in 98 cases. HP detection by the gene chip method was positive in 208 cases and negative in 59 cases. The sensitivity, specificity, and accuracy of the gene chip technology for diagnosing HP infection were 96.1, 85.0, and 93.6%, respectively. HP resistance gene locus using the gene chip showed the main mutation locus of clarithromycin to be 2143A/G, levofloxacin at locus GyrA 91 and GyrA 87, and amoxicillin at PBP1 556ser. Concordance rates between gene chip and DNA sequencing for VacA-S/M, 16S rRNA, 23S rRNA, and GyrA were greater than 95%, and that of PBP1 was greater than 82%. CONCLUSION: Gastric mucosal gene chip technology can be used for rapid diagnosis and drug resistance detection of HP infection in children.

Combinational Pretreatment of Colony-Stimulating Factor 1 Receptor Inhibitor and Triptolide Upregulates BDNF-Akt and Autophagic Pathways to Improve Cerebral Ischemia.

Ki20227, a selective inhibitor of colony-stimulating factor 1 receptor (CSF1R), has been suggested to regulate microglia inflammatory function and neuronal synaptic plasticity. Triptolide (TP) pretreatment has neuroprotective effects through its anti-inflammatory and antiapoptotic features in ischemic stroke mice. However, the underlying mechanism and pathway are presently unclear. We thus investigated the association between neuroprotective effects of combined TP and Ki20227 and BDNF-Akt and autophagy pathways. Ki20227 was administrated for 7 days, and TP was administered once 24 hours prior to building the ischemic stroke model in C57BL/6 mice. Behavioral tests, Golgi staining, immunofluorescence, and western blot analyses were employed to examine neuroprotective effects of TP and Ki20227. TP and Ki20227 pretreatments improved the neurobehavioral function in stroke mice. Synaptic protein expressions and density of dendritic spine density were upregulated in Ki20227 and TP pretreated stroke mice. Further, optimized integration of TP and Ki20227 pretreatments upregulated the NeuN expression and downregulated Iba1 expression after stroke. In addition, both TP and Ki20227 pretreatments significantly upregulated BDNF, p-Akt/Akt, and Erk1/2 protein expressions and autophagy related proteins (LC3II/I, Atg5, and p62), indicating the activation of BDNF and autophagic pathways. Optimized integration of TP and Ki20227 can improve cerebral ischemia by inhibiting CSF1R signal and trigger autophagy and BDNF-Akt signaling pathways to increase dendritic spine density and synaptic protein expressions, which in turn enhances neurobehavioral function.

Curcumin Can Improve Spinal Cord Injury by Inhibiting TGF-ß-SOX9 Signaling Pathway.

Spinal cord injury (SCI) is a severe nervous system disease with high morbidity and disability rate. Signaling pathways play a key role in the neuronal restorative mechanism following SCI. SRY-related high mobility group (HMG)-box gene 9 (SOX9) affects glial scar formation via Transforming growth factor beta (TGF-ß) signaling pathway. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is transferred into nucleus to upregulate TGF-ß-SOX9. Curcumin exhibits potent anti-inflammatory and anti-oxidant properties. Curcumin can play an important role in SCI recovery by inhibiting the expression of NF-κB and TGF-ß-SOX9. Herein, we review the potential mechanism of curcumin-inhibiting SOX9 signaling pathway in SCI treatment. The inhibition of NF-κB and SOX9 signaling pathway by curcumin has the potentiality of serving as neuronal regenerative mechanism following SCI.

Progesterone and fluoxetine treatments of postpartum depressive-like behavior in rat model.

Research studies have indicated that alterations in plasma progesterone levels might be associated with the hippocampal synaptic plasticity of postpartum depressive-like behavior. Herein, we assess both progesterone and fluoxetine effects in adult female Sprague-Dawley rats with postpartum depressive-like behavior. Depressive-like behavior of postpartum rats was established using chronic ultra-mild stress (CUMS) method for 1 week from gestation day 15. Postpartum rats that showed depressive-like behavior were treated with either progesterone (subcutaneously, 0.5 mg/kg) from gestation day 17 to gestation day 22 or fluoxetine (by gavage, 10 mg/kg/day) for 4 weeks after birth. Open field and sucrose preference tests were conducted at the start, week 2 and week 4 postpartum. Golgi staining, immunofluorescence and Western blot analyses of rats' hippocampi were conducted on week 4 postpartum. Results showed CUMS increases depressive-like behavior, however, treatment with progesterone and fluoxetine improves this behavior. Both progesterone and fluoxetine treatments increase the numbers of dendritic spines pyramidal neurons in the CA3 region of the hippocampus as well as protein expression levels of microtubule-associated protein 2 (MAP-2) and synaptophysin (SYP). CUMS-induced decrement of MAP-2 and SYP protein expressions can be prevented by treatment with progesterone in advanced pregnant stage and fluoxetine in the postpartum period.

Beneficial Effects of Resveratrol-Mediated Inhibition of the mTOR Pathway in Spinal Cord Injury.

Spinal cord injury (SCI) causes a high rate of morbidity and disability. The clinical features of SCI are divided into acute, subacute, and chronic phases according to its pathophysiological events. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in cell death and inflammation in the acute phase and neuroregeneration in the subacute/chronic phases at different times. Resveratrol has the potential of regulating cell growth, proliferation, metabolism, and angiogenesis through the mTOR signaling pathway. Herein, we explicate the role of resveratrol in the repair of SCI through the inhibition of the mTOR signaling pathway. The inhibition of the mTOR pathway by resveratrol has the potential of serving as a neuronal restorative mechanism following SCI.

Stimulation of Anxiety-Like Behavior via ERK Pathway by Competitive Serotonin Receptors 2A and 1A in Post-Traumatic Stress Disordered Mice.

BACKGROUND/AIMS: Serotonin 5HT2A and 5HT1A receptors (5HT2AR, 5HT1AR) have the closest connection to anxiety-like behavior in post-traumatic stress disorder (PTSD). However, the underlying mechanism remains unclear. In this study, we explored the connection between 5HT2A and 5HT1A receptors and anxiety-like behavior. METHODS: In the PTSD animal model, mice were exposed to conditioned fear stress coupled with single-prolonged stress (CF+SPS). Post stress infliction and behavioral tests, of which include open field, freezing behavior and elevated plus maze tests were carried out to examine establishment of the proposed model. Both Western blot analysis and immunofluorescence labeling were used to evaluate protein expressions of 5HT2AR, 5HT1AR, ERK1, ERK2 and c-Myc in the hippocampi of the mice and RT Q-PCR was employed for evaluation of the relative mRNA expressions. RESULTS: Based on the model established utilizing the CF+SPS procedure, we found 5HT2AR to play a positive role on anxiety-like behavior by inhibiting the expression of 5HT1AR. In addition, the ERK-c-Myc pathway elicited the effect of 5HT2AR and 5HT1AR on anxiety-like behavior in PTSD, 5-HT enhanced the anxiety-like behavior through both 5HT2AR and 5HT1AR. CONCLUSION: These findings suggest competive interaction between 5HT2AR and 5HT1AR actively affects anxiety-like behavior in the hippocampi of PTSD mice via the ERK pathway.

Improved Neural Regeneration with Olfactory Ensheathing Cell Inoculated PLGA Scaffolds in Spinal Cord Injury Adult Rats.

BACKGROUND/AIMS: Every year, around the world, between 250000 and 500000 people suffer from spinal cord injury (SCI). This study investigated the potential for poly (lactic-co-glycolic acid) (PLGA) complex inoculated with olfactory ensheathing cells (OECs) to treat spinal cord injury in a rat model. METHODS: OECs were identified by immunofluorescence based on the nerve growth factor receptor (NGFR) p75. The Basso, Beattie, and Bresnahan (BBB) score, together with an inclined plane (IP) test were used to detect functional recovery. Nissl staining along with the luxol fast blue (LFB) staining were independently employed to illustrate morphological alterations. More so, immunofluorescence labeling of the glial fibrillary acidic protein (GFAP) and the microtubule-associated protein-2 (MAP-2), representing astrocytes and neurons respectively, were investigated at time points of weeks 2 and 8 post-operation. RESULTS: The findings showed enhanced locomotor recovery, axon myelination and better protected neurons post SCI when compared with either PLGA or untreated groups (P < 0.05). CONCLUSION: PLGA complexes inoculated with OECs improve locomotor functional recovery in transected spinal cord injured rat models, which is most likely due to the fact it is conducive to a relatively benevolent microenvironment, has nerve protective effects, as well as the ability to enhance remyelination, via a promotion of cell differentiation and inhibition of astrocyte formation.

The post-therapeutic effect of rapamycin in mild traumatic brain-injured rats ensuing in the upregulation of autophagy and mitophagy.

Mild traumatic brain injury (mTBI), common in juveniles, has been reported to be caused by sports-related concussion. Many young children may suffer from post-concussion syndrome. mTBI, in early stages of life, could play a part in neuron apoptosis and degeneration, cognitive and motor coordination impairment, as well as dementia. Our study was aimed at further investigating the post-therapeutic efficacy of rapamycin in the recuperation of mTBI while at the same time investigating the metamorphosis in both autophagy and mitophagy in mTBI. We created a weight-drop rat mTBI model with the administration of rapamycin at 4 h after every mTBI. Behavioral tests of beam walking and open field task indicated the expected improvement of cognitive and motor coordination functions. Both Western blot and immunofluorescence examinations revealed increased Beclin-1 and PINK1 in the treated rats as well as reduction of caspase-3 and cytochrome C (Cyt C). More so, the TUNEL staining evidenced curtailment of apoptotic cells following treatment with rapamycin. The upregulation of Beclin-1 and PINK1 and the downregulation of caspase-3 and Cyt C extrapolate that rapamycin plays neuroprotective as well as anti-apoptotic role via interposition of both autophagy and mitophagy.

Neuroprotective effect of triptolide on neuronal inflammation in rats with mild brain injury.

Concussions sustained while playing sports are a prominent cause of mild traumatic brain injury (mTBI), which is prevalent among teenagers. The early and intermediate stages of mild traumatic brain injury (mTBI) can be characterized by inflammation, neurodegeneration, and brain tissue edema, which can lead to permanent brain damage. The present study investigated the therapeutic effects of triptolide in mTBI and brain damage recovery. After building mTBI model in male rat, triptolide administrated daily for 1 week in the treated group. On day 3 and day 7 of administration, hippocampus tissues were collected to evaluate inflammation and autophagy in the brain. The expressions of inflammatory factors interleukin (IL)-1ß and tumor necrosis factor-alpha in serum were downregulated, while IL-10 expression was upregulated when compared with the mTBI group on day 3 and day 7. The expression of IL-10 on day 7 was higher than on day 3. Quantitative polymerase chain reaction (qPCR) analysis of inflammatory-related factors (i.e., Il-1ß and nuclear factor-κB (Nf-κb), and western blot as well as immunofluorescence staining of autophagy-related proteins (i.e., LC3B) and aquaporin (AQP 4) showed lower expression on day 3 and day 7 in the triptolide-treated group. Moreover, NeuN immunostaining, and hematoxylin and eosin (HE) staining for hippocampus region revealed that the triptolide-treated group showed a decrease in damaged cells. Our findings emphasize the effectiveness of triptolide therapy after mild traumatic brain injury via modulating autophagy, attenuating inflammation and reduces edema by decreasing AQP 4 expression.

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.

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.

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.