Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide.Despite significant advancements in the field of medicine,effective treatments for traumatic brain injur...Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide.Despite significant advancements in the field of medicine,effective treatments for traumatic brain injury remain limited.Recently,extracellular vesicles released from mesenchymal stem/stromal cells have emerged as a promising novel therapy for traumatic brain injury.Extracellular vesicles are small membrane-bound vesicles that are naturally released by cells,including those in the brain,and can be engineered to contain therapeutic cargo,such as anti-inflammatory molecules,growth factors,and microRNAs.When administered intravenously,extra cellular vesicles can cross the blood-brain barrier and deliver their cargos to the site of injury,where they can be taken up by recipient cells and modulate the inflammatory response,promote neuroregeneration,and improve functional outcomes.In preclinical studies,extracellular vesicle-based therapies have shown promising results in promoting recove ry after traumatic brain injury,including reducing neuronal damage,improving cognitive function,and enhancing motor recovery.While further research is needed to establish the safety and efficacy of extra cellular vesicle-based therapies in humans,extra cellular vesicles represent a promising novel approach for the treatment of traumatic brain injury.In this review,we summarize mesenchymal ste m/stromal cell-de rived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration and brainderived extracellular vesicles as potential biofluid biomarkers in small and large animal models of traumatic brain injury.展开更多
Alternative splicing is the process of producing variably spliced mRNAs by choosing distinct combinations of splice sites within a messenger RNA precursor.This splicing enables mRNA from a single gene to synthesize di...Alternative splicing is the process of producing variably spliced mRNAs by choosing distinct combinations of splice sites within a messenger RNA precursor.This splicing enables mRNA from a single gene to synthesize different proteins,which have different cellular properties and functions and yet arise from the same single gene.A family of splicing factors,Serine-arginine rich proteins,are needed to initiate the assembly and activation of the spliceosome.Serine and arginine rich splicing factor 1,part of the arginine/serine-rich splicing factor protein family,can either activate or inhibit the splicing of mRNAs,depending on the phosphorylation status of the protein and its interaction partners.Considering that serine and arginine rich splicing factor 1 is either an activator or an inhibitor,this protein has been studied widely to identify its various roles in different diseases.Research has found that serine and arginine rich splicing factor 1 is a key target for neuroprotection,showing its promising potential use in therapeutics for neurodegenerative disorders.Furthermore,serine and arginine rich splicing factor 1 might be used to regulate cancer development and autoimmune diseases.In this review,we highlight how serine and arginine rich splicing factor 1 has been studied concerning neuroprotection.In addition,we draw attention to how serine and arginine rich splicing factor 1 is being studied in cancer and immunological disorders,as well as how serine and arginine rich splicing factor 1 acts outside the central or peripheral nervous system.展开更多
Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy.Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammati...Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy.Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth.Multiple pathways are involved in the pathogenesis of perinatal inflammation.However,studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1.In this review,we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury.We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage,and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist,anakinra,as a safe and effective therapeutic intervention.We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment,and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.展开更多
Neurodegenerative diseases are often associated with the accumulation of oxidative stress and neuroinflammation.Edible bird’s nest(EBN)is a glycoprotein(sialylated mucin glycopeptides)found to be beneficial against n...Neurodegenerative diseases are often associated with the accumulation of oxidative stress and neuroinflammation.Edible bird’s nest(EBN)is a glycoprotein(sialylated mucin glycopeptides)found to be beneficial against neurodegenerative diseases.Antioxidative,anti-inflammatory,and anti-apoptotic properties of EBN in preserving neuronal cells were widely researched using in vitro and in vivo models.Functional effects of EBN are often linked to its great number of antioxidants and anti-inflammatory glycopeptides.Bioactive compounds in EBN,especially sialic acid,add value to neurotrophic potential of EBN and contribute to neuronal repair and protection.Various studies reporting the neuroprotective effects of EBN,their molecular mechanisms,and neuroactive composition were gathered in this review to provide better insights on the neuroprotective effects of EBN.展开更多
Acute neurologic injuries represent a common cause of morbidity and mortality in children presenting to the pediatric intensive care unit.After primary neurologic insults,there may be cerebral brain tissue that remain...Acute neurologic injuries represent a common cause of morbidity and mortality in children presenting to the pediatric intensive care unit.After primary neurologic insults,there may be cerebral brain tissue that remains at risk of secondary insults,which can lead to worsening neurologic injury and unfavorable outcomes.A fundamental goal of pediatric neurocritical care is to mitigate the impact of secondary neurologic injury and improve neurologic outcomes for critically ill children.This review describes the physiologic framework by which strategies in pediatric neurocritical care are designed to reduce the impact of secondary brain injury and improve functional outcomes.Here,we present current and emerging strategies for optimizing neuroprotective strategies in critically ill children.展开更多
Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects...Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).展开更多
Spinal cord injury(SCI) is a serious central nervous system trauma that leads to loss of motor and sensory functions in the SCI patients. One of the cell death mechanisms is autophagy, which is ‘self-eating' of t...Spinal cord injury(SCI) is a serious central nervous system trauma that leads to loss of motor and sensory functions in the SCI patients. One of the cell death mechanisms is autophagy, which is ‘self-eating' of the damaged and misfolded proteins and nucleic acids, damaged mitochondria, and other impaired organelles for recycling of cellular building blocks. Autophagy is different from all other cell death mechanisms in one important aspect that it gives the cells an opportunity to survive or demise depending on the circumstances. Autophagy is a therapeutic target for alleviation of pathogenesis in traumatic SCI. However, functions of autophagy in traumatic SCI remain controversial. Spatial and temporal patterns of activation of autophagy after traumatic SCI have been reported to be contradictory. Formation of autophagosomes following therapeutic activation or inhibition of autophagy flux is ambiguous in traumatic SCI studies. Both beneficial and harmful outcomes due to enhancement autophagy have been reported in traumatic SCI studies in preclinical models. Only further studies will make it clear whether therapeutic activation or inhibition of autophagy is beneficial in overall outcomes in preclinical models of traumatic SCI. Therapeutic enhancement of autophagy flux may digest the damaged components of the central nervous system cells for recycling and thereby facilitating functional recovery. Many studies demonstrated activation of autophagy flux and inhibition of apoptosis for neuroprotective effects in traumatic SCI. Therapeutic induction of autophagy in traumatic SCI promotes axonal regeneration, supporting another beneficial role of autophagy in traumatic SCI. In contrast, some other studies demonstrated that disruption of autophagy flux in traumatic SCI strongly correlated with neuronal death at remote location and impaired functional recovery. This article describes our current understanding of roles of autophagy in acute and chronic traumatic SCI, crosstalk between autophagy and apoptosis, therapeutic activation or inhibition of autophagy for promoting functional recovery, and future of autophagy in traumatic SCI.展开更多
TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-po...TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-pore domain potassium channels is the last big family of channels being discovered, therefore it is not surprising that most of the information we know about TREK channels predominantly comes from the study of heterologously expressed channels. Notw让hstanding, in this review we pay special attention to the limited amount of information available on native TREK-like channels and real neurons in relation to neuroprotection. Mainly we focus on the role of free fatty acids, lysophospholipids and other neuroprotective agents like riluzole in the modulation of TREK channels, emphasizing on how important this modulation may be for the development of new therapies against neuropathic pain, depression, schizophrenia, epilepsy, ischemia and cardiac complications.展开更多
Apoptosis is an important factor during the early stage of intracerebral hemorrhage.MiR-181 c plays a key regulatory role in apoptosis.However,whether miR-181 c is involved in apoptosis of prophase cells after intrace...Apoptosis is an important factor during the early stage of intracerebral hemorrhage.MiR-181 c plays a key regulatory role in apoptosis.However,whether miR-181 c is involved in apoptosis of prophase cells after intracerebral hemorrhage remains unclear.Therefore,in vitro and in vivo experiments were conducted to test this hypothesis.In vivo experiments:collagenase type VII was injected into the basal ganglia of adult Sprague-Dawley rats to establish an intracerebral hemorrhage model.MiR-181 c mimic or inhibitor was injected in situ 4 hours after intracerebral hemorrhage.Neurological functional defects(neurological severity scores)were assessed 1,7,and 14 days after model establishment.Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and western blot assay were conducted 14 days after model establishment.In vitro experiments:PC12 cells were cultured under oxygen-glucose deprivation,and hemins were added to simulate intracerebral hemorrhage in vitro.MiR-181 c mimic or inhibitor was added to regulate miR-181 c expression.3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,luciferase reporter system,and western blot assay were performed.Experimental results revealed differences in miR-181 c expression in brain tissues of both patients and rats with cerebral hemorrhage.In addition,in vitro experiments found that miR-181 c overexpression could upregulate the Bcl-2/Bax ratio to inhibit apoptosis,while inhibition of miR-181 c expression could reduce the Bcl-2/Bax ratio and aggravate apoptosis of cells.Regulation of apoptosis occurred through the phosphoinositide 3 kinase(PI3 K)/Akt pathway by targeting of phosphatase and tensin homolog deleted on chromosome ten(PTEN).Higher miR-181 c overexpression correlated with lower neurological severity scores,indicating better recovery of neurological function.In conclusion,miR-181 c affects the prognosis of intracerebral hemorrhage by regulating apoptosis,and these effects might be directly mediated and regulated by targeting of the PTEN\PI3 K/Akt pathway and Bcl-2/Bax ratio.Furthermore,these results indicated that miR-181 c played a neuroprotective role in intracerebral hemorrhage by regulating apoptosis of nerve cells,thus providing a potential target for the prevention and treatment of intracerebral hemorrhage.Testing of human serum was authorized by the Ethics Committee of China Medical University(No.2012-38-1)on February 20,2012.The protocol was registered with the Chinese Clinical Trial Registry(Registration No.ChiCTR-COC-17013559).The animal study was approved by the Institutional Animal Care and Use Committee of China Medical University(approval No.2017008)on March 8,2017.展开更多
Neuronal injuries can lead to various diseases such as neurodegenerative diseases,stroke,trauma,ischemia and,more specifically,glaucoma and optic neuritis.The cellular mechanisms that regulate neuronal death include c...Neuronal injuries can lead to various diseases such as neurodegenerative diseases,stroke,trauma,ischemia and,more specifically,glaucoma and optic neuritis.The cellular mechanisms that regulate neuronal death include calcium influx and calcium overload,excitatory amino acid release,oxidative stress,inflammation and microglial activation.Much attention has been paid to the effective prevention and treatment of neuroprotective drugs by natural products.This review summarizes the neuroprotective aspects of natural products,extracted from Panax ginseng,Camellia sinensis,soy and some other plants,and some of their chemical derivatives.Their antioxidative and anti-inflammatory action and their inhibition of apoptosis and microglial activation are assessed.This will provide new directions for the development of novel drugs and strategies to treat neurodegenerative diseases.展开更多
AIM: To explore the effect of the Notch signaling pathway on retinal ganglion cells(RGCs) and optic nerve in rats with acute ocular hypertension(OH).METHODS: Totally 48 Sprague-Dawley(SD) rats were included, among whi...AIM: To explore the effect of the Notch signaling pathway on retinal ganglion cells(RGCs) and optic nerve in rats with acute ocular hypertension(OH).METHODS: Totally 48 Sprague-Dawley(SD) rats were included, among which 36 rats were selected to establish acute OH models. OH rats received a single intravitreal injection of 2 μL phosphate buffered solution(PBS) and another group of OH rats received a single intravitreal injection of 10 μmol/L γ-secretase inhibitor(DAPT). Quantitative real-time polymerase chain reaction(qPCR) and Western blot assay were adopted to determine the mRNA level of Notch and the protein levels of Notch, Bcl-2, Bax, caspase-3, and growth-associated protein 43(GAP-43). The RGC apoptosis conditions were assessed by TUNEL staining.RESULTS: The OH rats and PBS-injected rats had increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, with severer macular edema and RGCs more loosely aligned, when compared with the normal rats. The DAPT-treated rats displayed increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, in comparison with the OH rats and PBSinjected rats. RGCs were hardly observed and macular edema became severe in the DAPT-treated rat.CONCLUSION: The Notch signaling pathway may suppress the apoptosis of retinal ganglion cells and enhances the regeneration of the damaged optic nerves in rats with acute OH.展开更多
Ischemia as a serious neurodegenerative disorder causes together with reperfusion injury many changes in nervous tissue. Most of the neuronal damage is caused by complex of biochemical reactions and substantial proces...Ischemia as a serious neurodegenerative disorder causes together with reperfusion injury many changes in nervous tissue. Most of the neuronal damage is caused by complex of biochemical reactions and substantial processes, such as protein agregation, reactions of free radicals, insufficient blood supply, glutamate excitotoxicity, and oxidative stress. The result of these processes can be apoptotic or necrotic cell death and it can lead to an irreversible damage. Therefore, neuroprotection and prevention of the neurodegeneration are highly important topics to study. There are several approaches to prevent the ischemic damage. Use of many modern therapeutical methods and the incorporation of several substances into the diet of patients is possible to stimulate the endogenous protective mechanisms and improve the life quality.展开更多
Autophagy has been shown to play an important role in Parkinson’s disease.We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson’s disease through affecting autophagy.In this ...Autophagy has been shown to play an important role in Parkinson’s disease.We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson’s disease through affecting autophagy.In this study,6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells(SKP-SCs).The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine,reduced excessive autophagy,increased tyrosine hydroxylase expression,reducedα-synuclein expression,reduced the autophagosome number,and activated the PI3K/AKT/mTOR pathway.Autophagy activator rapamycin inhibited the effects of SKP-SCs,and autophagy inhibitor 3-methyladenine had the opposite effect.These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy,thereby exhibiting a neuroprotective effect in a cellular model of Parkinson’s disease.This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University(approval No.S20181009-205)on October 9,2018.展开更多
There is mounting evidence that targeting mitochondrial dysfunction following neurotrauma could be key in developing effective therapeutic strategies since mitochondria are known to play a major role in cellular bioen...There is mounting evidence that targeting mitochondrial dysfunction following neurotrauma could be key in developing effective therapeutic strategies since mitochondria are known to play a major role in cellular bioenergetics,function,and survival following traumatic spinal cord injury(SCI)展开更多
Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has dem...Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1(IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sexhormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinasesignaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.展开更多
Neuroglobin(Ngb)is a 17 kDa monomeric hexa-coordinated heme protein belonging to the globin family.Ngb is mainly expressed in neurons of the central and peripheral nervous system,although moderate levels of Ngb have b...Neuroglobin(Ngb)is a 17 kDa monomeric hexa-coordinated heme protein belonging to the globin family.Ngb is mainly expressed in neurons of the central and peripheral nervous system,although moderate levels of Ngb have been detected in non-nervous tissues.In the past decade,Ngb has been studied for its neuroprotective role in a large number of neurological disorders such as Alzheimer’s disease,Huntington’s disease,brain ischemia and hypoxia.This review discusses and summarizes the natural compounds and the small synthetic molecules capable of modulating Ngb expression that exhibits a protective role against various neurodegenerative diseases.展开更多
Photobiomodulation (PBM)- the irradiation of cells or tissues with low-intensity red to near-infrared light - is emerging as an effective means of enhancing cell and tissue resilience and repair. As reviewed elsewhere...Photobiomodulation (PBM)- the irradiation of cells or tissues with low-intensity red to near-infrared light - is emerging as an effective means of enhancing cell and tissue resilience and repair. As reviewed elsewhere (Gordon et al., 2019), the intracellular effects of PBM appear to be primarily mediated by cytochrome C oxidase, a key enzyme in the mitochondrial respiratory chain and a primary photoacceptor of red to near-infrared light. Absorption of light by cytochrome C oxidase alters its redox state, resulting in increased ATP production, the liberation of nitric oxide and a transient burst in reactive oxygen species.展开更多
Both inflammation and anti-inflammation are involved in the protection of retinal cells.Antagonists of the hypothalamic growth hormone-releasing hormone receptor(GHRHR)have been shown to possess potent anti-inflammato...Both inflammation and anti-inflammation are involved in the protection of retinal cells.Antagonists of the hypothalamic growth hormone-releasing hormone receptor(GHRHR)have been shown to possess potent anti-inflammatory properties in experimental disease models of various organs,some with systemic complications.Such effects are also found in ocular inflammatory and neurologic injury studies.In experimental models of mice and rats,both growth hormone-releasing hormone receptor agonists and antagonists may alleviate death of ocular neural cells under certain experimental conditions.This review explores the properties of growth hormone-releasing hormone receptor agonists and antagonists that lead to its protection against inflammatory responses induced by extrinsic agents or neurologic injures in ocular animal models.展开更多
Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism...Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism of antioxidants and overproduction or incorporation of free radicals from environment to living systems leads to serious damage. It also attacks nervous system resulting in neural-degeneration. In order to evaluate the neurotoxic effect on the brain parts of mercury in our study, oxidative stress indices of enzymatic and non enzymatic components were measured in rats intoxicated with mercury (2 mg and 4 mg/kg body weight) for 60 days to adult rats. Along with gravimetry, tissue burden was also recorded. Alterations in these indices were further supported by ultrastructural studies carried out in the brain as indicated by myelin disintegration, cell organelle alterations and neuronal loss by mercury poisoning. Treatment with the antioxidant melatonin (N-acetyl 5-methoxy tryptamine, 5 mg/kg) prevented mercury exerted toxicity due to its antioxidant property. The pathological changes were also ameliorated in the brain region comparatively to support biochemical profile of brain. Thus, melatonin produced neuroprotection against mercury poisoning in rats.展开更多
Red and infrared light(λ=600–1,070 nm)therapy,known also as photobiomodulation,has been reported to offer neuroprotection and to improve locomotor behaviour in animal models of Parkinson’s disease,from rodents to n...Red and infrared light(λ=600–1,070 nm)therapy,known also as photobiomodulation,has been reported to offer neuroprotection and to improve locomotor behaviour in animal models of Parkinson’s disease,from rodents to non-human primates(Rojas and Gonzalez-Lima,2011;Hamblin,2016;Johnstone et al.,2016).The neuroprotective aspect of this therapy is particularly relevant;the saving of neurons展开更多
基金supported by Notional Institutes of Health Grant,No.1R01NS100710-01A1(to YX)。
文摘Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide.Despite significant advancements in the field of medicine,effective treatments for traumatic brain injury remain limited.Recently,extracellular vesicles released from mesenchymal stem/stromal cells have emerged as a promising novel therapy for traumatic brain injury.Extracellular vesicles are small membrane-bound vesicles that are naturally released by cells,including those in the brain,and can be engineered to contain therapeutic cargo,such as anti-inflammatory molecules,growth factors,and microRNAs.When administered intravenously,extra cellular vesicles can cross the blood-brain barrier and deliver their cargos to the site of injury,where they can be taken up by recipient cells and modulate the inflammatory response,promote neuroregeneration,and improve functional outcomes.In preclinical studies,extracellular vesicle-based therapies have shown promising results in promoting recove ry after traumatic brain injury,including reducing neuronal damage,improving cognitive function,and enhancing motor recovery.While further research is needed to establish the safety and efficacy of extra cellular vesicle-based therapies in humans,extra cellular vesicles represent a promising novel approach for the treatment of traumatic brain injury.In this review,we summarize mesenchymal ste m/stromal cell-de rived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration and brainderived extracellular vesicles as potential biofluid biomarkers in small and large animal models of traumatic brain injury.
文摘Alternative splicing is the process of producing variably spliced mRNAs by choosing distinct combinations of splice sites within a messenger RNA precursor.This splicing enables mRNA from a single gene to synthesize different proteins,which have different cellular properties and functions and yet arise from the same single gene.A family of splicing factors,Serine-arginine rich proteins,are needed to initiate the assembly and activation of the spliceosome.Serine and arginine rich splicing factor 1,part of the arginine/serine-rich splicing factor protein family,can either activate or inhibit the splicing of mRNAs,depending on the phosphorylation status of the protein and its interaction partners.Considering that serine and arginine rich splicing factor 1 is either an activator or an inhibitor,this protein has been studied widely to identify its various roles in different diseases.Research has found that serine and arginine rich splicing factor 1 is a key target for neuroprotection,showing its promising potential use in therapeutics for neurodegenerative disorders.Furthermore,serine and arginine rich splicing factor 1 might be used to regulate cancer development and autoimmune diseases.In this review,we highlight how serine and arginine rich splicing factor 1 has been studied concerning neuroprotection.In addition,we draw attention to how serine and arginine rich splicing factor 1 is being studied in cancer and immunological disorders,as well as how serine and arginine rich splicing factor 1 acts outside the central or peripheral nervous system.
基金supported by the CJ Martin Postdoctoral Fellowshipgrants from the National Health and Medical Research Council of Australia (1090890 and 1164954)+1 种基金the Cerebral Palsy Alliance, Harold and Cora Brennen Benevolent Trust, Health Research Council of New Zealand (17/601)the Victorian Government’s Operational Infrastructure Support Program (to RG)
文摘Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy.Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth.Multiple pathways are involved in the pathogenesis of perinatal inflammation.However,studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinatal encephalopathy and excessive production of the pro-inflammatory effector cytokine interleukin-1.In this review,we summarize clinical and preclinical evidence that underpins interleukin-1 as a critical factor in initiating and perpatuating systemic and central nervous system inflammation and subsequent perinatal brain injury.We also highlight the important role of endogenous interleukin-1 receptor antagonist in mitigating interleukin-1-driven neuroinflammation and tissue damage,and summarize outcomes from clinical and mechanistic animal studies that establish the commercially available interleukin-1 receptor antagonist,anakinra,as a safe and effective therapeutic intervention.We reflect on the evidence supporting clinical translation of interleukin-1 receptor antagonist for infants at the greatest risk of perinatal inflammation and impaired neurodevelopment,and suggest a path to advance interleukin-1 receptor antagonist along the translational path for perinatal neuroprotection.
基金supported by the Research Excellence Consortium(KKP/2020/UKM-UKM/5/1)provided by Ministry of Higher Education,Malaysiasupported by the Fundamental Research Grant Scheme(FRGS),Project No.FP016-2019A,Reference Code:FRGS/1/2019/SKK09/UM/02/2.
文摘Neurodegenerative diseases are often associated with the accumulation of oxidative stress and neuroinflammation.Edible bird’s nest(EBN)is a glycoprotein(sialylated mucin glycopeptides)found to be beneficial against neurodegenerative diseases.Antioxidative,anti-inflammatory,and anti-apoptotic properties of EBN in preserving neuronal cells were widely researched using in vitro and in vivo models.Functional effects of EBN are often linked to its great number of antioxidants and anti-inflammatory glycopeptides.Bioactive compounds in EBN,especially sialic acid,add value to neurotrophic potential of EBN and contribute to neuronal repair and protection.Various studies reporting the neuroprotective effects of EBN,their molecular mechanisms,and neuroactive composition were gathered in this review to provide better insights on the neuroprotective effects of EBN.
文摘Acute neurologic injuries represent a common cause of morbidity and mortality in children presenting to the pediatric intensive care unit.After primary neurologic insults,there may be cerebral brain tissue that remains at risk of secondary insults,which can lead to worsening neurologic injury and unfavorable outcomes.A fundamental goal of pediatric neurocritical care is to mitigate the impact of secondary neurologic injury and improve neurologic outcomes for critically ill children.This review describes the physiologic framework by which strategies in pediatric neurocritical care are designed to reduce the impact of secondary brain injury and improve functional outcomes.Here,we present current and emerging strategies for optimizing neuroprotective strategies in critically ill children.
基金supported by the Natural Science Foundation of Shandong Province of China,No.ZR2015HM023(to MSW)the Science and Technology Plan Project of Qingdao City of China,No.19-6-1-50-nsh(to MSW)
文摘Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).
基金supported in part by the Investigator Initiated Research grant(SCIRF-2015-I-0)from the South Carolina Spinal Cord Injury Research Fund(SCIRF,Columbia,SC,US)an incentive award from the Soy Health Research Program(SHRP,United Soybean Board,Chesterfield,MO,US)the R01 grants(CA91460 and NS057811)from the National Institutes of Health(Bethesda,MD,US)
文摘Spinal cord injury(SCI) is a serious central nervous system trauma that leads to loss of motor and sensory functions in the SCI patients. One of the cell death mechanisms is autophagy, which is ‘self-eating' of the damaged and misfolded proteins and nucleic acids, damaged mitochondria, and other impaired organelles for recycling of cellular building blocks. Autophagy is different from all other cell death mechanisms in one important aspect that it gives the cells an opportunity to survive or demise depending on the circumstances. Autophagy is a therapeutic target for alleviation of pathogenesis in traumatic SCI. However, functions of autophagy in traumatic SCI remain controversial. Spatial and temporal patterns of activation of autophagy after traumatic SCI have been reported to be contradictory. Formation of autophagosomes following therapeutic activation or inhibition of autophagy flux is ambiguous in traumatic SCI studies. Both beneficial and harmful outcomes due to enhancement autophagy have been reported in traumatic SCI studies in preclinical models. Only further studies will make it clear whether therapeutic activation or inhibition of autophagy is beneficial in overall outcomes in preclinical models of traumatic SCI. Therapeutic enhancement of autophagy flux may digest the damaged components of the central nervous system cells for recycling and thereby facilitating functional recovery. Many studies demonstrated activation of autophagy flux and inhibition of apoptosis for neuroprotective effects in traumatic SCI. Therapeutic induction of autophagy in traumatic SCI promotes axonal regeneration, supporting another beneficial role of autophagy in traumatic SCI. In contrast, some other studies demonstrated that disruption of autophagy flux in traumatic SCI strongly correlated with neuronal death at remote location and impaired functional recovery. This article describes our current understanding of roles of autophagy in acute and chronic traumatic SCI, crosstalk between autophagy and apoptosis, therapeutic activation or inhibition of autophagy for promoting functional recovery, and future of autophagy in traumatic SCI.
基金supported by grants to JAL from the Spanish Government:Secretaría de Estado de Investigación,Desarrollo e Innovación(MINECO,BFU2014-58999-P),Galician Government:Consellería de Cultura,Educación e Ordenación Universitaria,Xunta de Galicia(GPC2015/022)European Regional Development Fund(FP7-316265-BIOCAPS)supported with Fondo Europeo de Desarrollo Regional Funds
文摘TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-pore domain potassium channels is the last big family of channels being discovered, therefore it is not surprising that most of the information we know about TREK channels predominantly comes from the study of heterologously expressed channels. Notw让hstanding, in this review we pay special attention to the limited amount of information available on native TREK-like channels and real neurons in relation to neuroprotection. Mainly we focus on the role of free fatty acids, lysophospholipids and other neuroprotective agents like riluzole in the modulation of TREK channels, emphasizing on how important this modulation may be for the development of new therapies against neuropathic pain, depression, schizophrenia, epilepsy, ischemia and cardiac complications.
基金supported by the National Natural Science Foundation of China,No.81571120(to ZYH)
文摘Apoptosis is an important factor during the early stage of intracerebral hemorrhage.MiR-181 c plays a key regulatory role in apoptosis.However,whether miR-181 c is involved in apoptosis of prophase cells after intracerebral hemorrhage remains unclear.Therefore,in vitro and in vivo experiments were conducted to test this hypothesis.In vivo experiments:collagenase type VII was injected into the basal ganglia of adult Sprague-Dawley rats to establish an intracerebral hemorrhage model.MiR-181 c mimic or inhibitor was injected in situ 4 hours after intracerebral hemorrhage.Neurological functional defects(neurological severity scores)were assessed 1,7,and 14 days after model establishment.Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and western blot assay were conducted 14 days after model establishment.In vitro experiments:PC12 cells were cultured under oxygen-glucose deprivation,and hemins were added to simulate intracerebral hemorrhage in vitro.MiR-181 c mimic or inhibitor was added to regulate miR-181 c expression.3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,luciferase reporter system,and western blot assay were performed.Experimental results revealed differences in miR-181 c expression in brain tissues of both patients and rats with cerebral hemorrhage.In addition,in vitro experiments found that miR-181 c overexpression could upregulate the Bcl-2/Bax ratio to inhibit apoptosis,while inhibition of miR-181 c expression could reduce the Bcl-2/Bax ratio and aggravate apoptosis of cells.Regulation of apoptosis occurred through the phosphoinositide 3 kinase(PI3 K)/Akt pathway by targeting of phosphatase and tensin homolog deleted on chromosome ten(PTEN).Higher miR-181 c overexpression correlated with lower neurological severity scores,indicating better recovery of neurological function.In conclusion,miR-181 c affects the prognosis of intracerebral hemorrhage by regulating apoptosis,and these effects might be directly mediated and regulated by targeting of the PTEN\PI3 K/Akt pathway and Bcl-2/Bax ratio.Furthermore,these results indicated that miR-181 c played a neuroprotective role in intracerebral hemorrhage by regulating apoptosis of nerve cells,thus providing a potential target for the prevention and treatment of intracerebral hemorrhage.Testing of human serum was authorized by the Ethics Committee of China Medical University(No.2012-38-1)on February 20,2012.The protocol was registered with the Chinese Clinical Trial Registry(Registration No.ChiCTR-COC-17013559).The animal study was approved by the Institutional Animal Care and Use Committee of China Medical University(approval No.2017008)on March 8,2017.
基金supported by the National Natural Science Foundation of China,Nos.81600738(to FF),81771239(to ZF),81430043(to ZF),81801300(to NS)。
文摘Neuronal injuries can lead to various diseases such as neurodegenerative diseases,stroke,trauma,ischemia and,more specifically,glaucoma and optic neuritis.The cellular mechanisms that regulate neuronal death include calcium influx and calcium overload,excitatory amino acid release,oxidative stress,inflammation and microglial activation.Much attention has been paid to the effective prevention and treatment of neuroprotective drugs by natural products.This review summarizes the neuroprotective aspects of natural products,extracted from Panax ginseng,Camellia sinensis,soy and some other plants,and some of their chemical derivatives.Their antioxidative and anti-inflammatory action and their inhibition of apoptosis and microglial activation are assessed.This will provide new directions for the development of novel drugs and strategies to treat neurodegenerative diseases.
基金Supported by Fund of Hainan Provincial Health Department(No.1601032037A2001)
文摘AIM: To explore the effect of the Notch signaling pathway on retinal ganglion cells(RGCs) and optic nerve in rats with acute ocular hypertension(OH).METHODS: Totally 48 Sprague-Dawley(SD) rats were included, among which 36 rats were selected to establish acute OH models. OH rats received a single intravitreal injection of 2 μL phosphate buffered solution(PBS) and another group of OH rats received a single intravitreal injection of 10 μmol/L γ-secretase inhibitor(DAPT). Quantitative real-time polymerase chain reaction(qPCR) and Western blot assay were adopted to determine the mRNA level of Notch and the protein levels of Notch, Bcl-2, Bax, caspase-3, and growth-associated protein 43(GAP-43). The RGC apoptosis conditions were assessed by TUNEL staining.RESULTS: The OH rats and PBS-injected rats had increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, with severer macular edema and RGCs more loosely aligned, when compared with the normal rats. The DAPT-treated rats displayed increased expression levels of Notch1, Bax, caspase-3, and GAP-43, decreased expression levels of Bcl-2, and increased RGC apoptosis, in comparison with the OH rats and PBSinjected rats. RGCs were hardly observed and macular edema became severe in the DAPT-treated rat.CONCLUSION: The Notch signaling pathway may suppress the apoptosis of retinal ganglion cells and enhances the regeneration of the damaged optic nerves in rats with acute OH.
文摘Ischemia as a serious neurodegenerative disorder causes together with reperfusion injury many changes in nervous tissue. Most of the neuronal damage is caused by complex of biochemical reactions and substantial processes, such as protein agregation, reactions of free radicals, insufficient blood supply, glutamate excitotoxicity, and oxidative stress. The result of these processes can be apoptotic or necrotic cell death and it can lead to an irreversible damage. Therefore, neuroprotection and prevention of the neurodegeneration are highly important topics to study. There are several approaches to prevent the ischemic damage. Use of many modern therapeutical methods and the incorporation of several substances into the diet of patients is possible to stimulate the endogenous protective mechanisms and improve the life quality.
基金Technology Project of Nantong of China,Nos.JC2020052(to XSG),JCZ19087(to XSG)the National Natural Science Foundation of China,Nos.81873742(to KFK),81901195(to JBS),81502867(to TX),82073627(to TX).
文摘Autophagy has been shown to play an important role in Parkinson’s disease.We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson’s disease through affecting autophagy.In this study,6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells(SKP-SCs).The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine,reduced excessive autophagy,increased tyrosine hydroxylase expression,reducedα-synuclein expression,reduced the autophagosome number,and activated the PI3K/AKT/mTOR pathway.Autophagy activator rapamycin inhibited the effects of SKP-SCs,and autophagy inhibitor 3-methyladenine had the opposite effect.These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy,thereby exhibiting a neuroprotective effect in a cellular model of Parkinson’s disease.This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University(approval No.S20181009-205)on October 9,2018.
基金funded by NIH R21NS096670(AGR)Craig H.Neilsen Foundation 476719(AGR)+3 种基金Kentucky Spinal Cord and Head Injury Research Trust#15-14A(PGS)Veterans Affairs Merit Review Award#I01BX003405(PGS)University of Kentucky Spinal Cord and Brain Injury Center Chair Endowments(AGR&PGS)NIH/NINDS 2P30NS051220
文摘There is mounting evidence that targeting mitochondrial dysfunction following neurotrauma could be key in developing effective therapeutic strategies since mitochondria are known to play a major role in cellular bioenergetics,function,and survival following traumatic spinal cord injury(SCI)
文摘Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1(IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sexhormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinasesignaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.
基金This work was supported by the Italian Ministero dell’Istruzione,dell’Universitáe della Ricerca PRIN 2017SNRXH3(to EO and SN)PRA_2018_20 University of Pisa(to EO).
文摘Neuroglobin(Ngb)is a 17 kDa monomeric hexa-coordinated heme protein belonging to the globin family.Ngb is mainly expressed in neurons of the central and peripheral nervous system,although moderate levels of Ngb have been detected in non-nervous tissues.In the past decade,Ngb has been studied for its neuroprotective role in a large number of neurological disorders such as Alzheimer’s disease,Huntington’s disease,brain ischemia and hypoxia.This review discusses and summarizes the natural compounds and the small synthetic molecules capable of modulating Ngb expression that exhibits a protective role against various neurodegenerative diseases.
文摘Photobiomodulation (PBM)- the irradiation of cells or tissues with low-intensity red to near-infrared light - is emerging as an effective means of enhancing cell and tissue resilience and repair. As reviewed elsewhere (Gordon et al., 2019), the intracellular effects of PBM appear to be primarily mediated by cytochrome C oxidase, a key enzyme in the mitochondrial respiratory chain and a primary photoacceptor of red to near-infrared light. Absorption of light by cytochrome C oxidase alters its redox state, resulting in increased ATP production, the liberation of nitric oxide and a transient burst in reactive oxygen species.
基金supported by the National Natural Science Foundation of China(81570849 to LPC)Joint Regional Basic Science and Applied Basic Science Research Fund of Guangdong Province(2019 A1515110685 to TKN)+4 种基金Special Fund for Chinese Medicine Development of Guangdong Province(20202089 to TKN)the Natural Science Foundation of Guangdong Province(2020 A1515010415 to LPC)an internal grant from Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong KongGrant for Key Disciplinary Project of Clinical Medicine under the Guangdong High-level University Development Program, ChinaThe Chinese University of Hong Kong Direct Grant(2020.067 to WKC)
文摘Both inflammation and anti-inflammation are involved in the protection of retinal cells.Antagonists of the hypothalamic growth hormone-releasing hormone receptor(GHRHR)have been shown to possess potent anti-inflammatory properties in experimental disease models of various organs,some with systemic complications.Such effects are also found in ocular inflammatory and neurologic injury studies.In experimental models of mice and rats,both growth hormone-releasing hormone receptor agonists and antagonists may alleviate death of ocular neural cells under certain experimental conditions.This review explores the properties of growth hormone-releasing hormone receptor agonists and antagonists that lead to its protection against inflammatory responses induced by extrinsic agents or neurologic injures in ocular animal models.
文摘Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism of antioxidants and overproduction or incorporation of free radicals from environment to living systems leads to serious damage. It also attacks nervous system resulting in neural-degeneration. In order to evaluate the neurotoxic effect on the brain parts of mercury in our study, oxidative stress indices of enzymatic and non enzymatic components were measured in rats intoxicated with mercury (2 mg and 4 mg/kg body weight) for 60 days to adult rats. Along with gravimetry, tissue burden was also recorded. Alterations in these indices were further supported by ultrastructural studies carried out in the brain as indicated by myelin disintegration, cell organelle alterations and neuronal loss by mercury poisoning. Treatment with the antioxidant melatonin (N-acetyl 5-methoxy tryptamine, 5 mg/kg) prevented mercury exerted toxicity due to its antioxidant property. The pathological changes were also ameliorated in the brain region comparatively to support biochemical profile of brain. Thus, melatonin produced neuroprotection against mercury poisoning in rats.
基金Tenix corp and Salteri family for funding my laboratory work
文摘Red and infrared light(λ=600–1,070 nm)therapy,known also as photobiomodulation,has been reported to offer neuroprotection and to improve locomotor behaviour in animal models of Parkinson’s disease,from rodents to non-human primates(Rojas and Gonzalez-Lima,2011;Hamblin,2016;Johnstone et al.,2016).The neuroprotective aspect of this therapy is particularly relevant;the saving of neurons
