The choline pathway as a strategy to promote central nervous system(CNS) remyelination

Multiple sclerosis is a chronic companied by demyelination inflammatory disease that is ac- and axonal damage resulting in neurological deficits. Remyelination is the natural endogenous repair mechanism of demyelinated axons and it is supposed to protect axons/neurons from degeneration and thus the patient from progressive disability （Franklin and Ffrench-Constant, 2008）. Current therapeutics for patients with multiple sclerosis are to some extent very effective in inhibiting neuroinflamma- tion and demyelination. However, to date there are no substanc- es available that can enhance remyelination. Remyelination is the result of recruitment/proliferation of new oligodendrocyte precursor cells （OPC） and differentiation into mature myelin producing oligodendrocytes （Franklin and Ffrench-Constant, 2008）. These processes are supported by many factors and signals and failure at any stage might lead to repair failure. Strategies to enhance myelin repair are either the promotion of endogenous repair mechanisms via modulation of OPC prolif- eration and oligodendrocyte differentiation or the transplantion of myelinating cells into lesions. Due to the multiloculated pro- cess in multiple sclerosis and the ethical problems with the cell source, the latter is less favoured. The endogenous promotion of remvelination could be achieved by several approaches such as：

The role of axon guidance molecules in the pathogenesis of epilepsy

Current treatments for epilepsy can only manage the symptoms of the condition but cannot alter the initial onset or halt the progression of the disease. Consequently, it is crucial to identify drugs that can target novel cellular and molecular mechanisms and mechanisms of action. Increasing evidence suggests that axon guidance molecules play a role in the structural and functional modifications of neural networks and that the dysregulation of these molecules is associated with epilepsy susceptibility. In this review, we discuss the essential role of axon guidance molecules in neuronal activity in patients with epilepsy as well as the impact of these molecules on synaptic plasticity and brain tissue remodeling. Furthermore, we examine the relationship between axon guidance molecules and neuroinflammation, as well as the structural changes in specific brain regions that contribute to the development of epilepsy. Ample evidence indicates that axon guidance molecules, including semaphorins and ephrins, play a fundamental role in guiding axon growth and the establishment of synaptic connections. Deviations in their expression or function can disrupt neuronal connections, ultimately leading to epileptic seizures. The remodeling of neural networks is a significant characteristic of epilepsy, with axon guidance molecules playing a role in the dynamic reorganization of neural circuits. This, in turn, affects synapse formation and elimination. Dysregulation of these molecules can upset the delicate balance between excitation and inhibition within a neural network, thereby increasing the risk of overexcitation and the development of epilepsy. Inflammatory signals can regulate the expression and function of axon guidance molecules, thus influencing axonal growth, axon orientation, and synaptic plasticity. The dysregulation of neuroinflammation can intensify neuronal dysfunction and contribute to the occurrence of epilepsy. This review delves into the mechanisms associated with the pathogenicity of axon guidance molecules in epilepsy, offering a valuable reference for the exploration of therapeutic targets and presenting a fresh perspective on treatment strategies for this condition.

Electroacupuncture improves learning and memory functions in a rat cerebral ischemia/reperfusion injury model through PI3K/Akt signaling pathway activation

Electroacupuncture has been widely used to treat cognitive impairment after cerebral ischemia,but the underlying mechanism has not yet been fully elucidated.Studies have shown that autophagy plays an important role in the formation and development of cognitive impairment,and the phosphoinositide 3-kinase(PI3K)/Akt signaling pathway plays an important role in autophagy regulation.To investigate the role played by the PI3K/Akt signaling pathway in the electroacupuncture treatment of cerebral ischemia/reperfusion rat models,we first established a rat model of cerebral ischemia/reperfusion through the occlusion of the middle cerebral artery using the suture method.Starting at 2 hours after modeling,electroacupuncture was delivered at the Shenting(GV24)and Baihui(GV20)acupoints,with a dilatational wave(1-20 Hz frequency,2 mA intensity,6 V peak voltage),for 30 minutes/day over 8 consecutive days.Our results showed that electroacupuncture reduced the infarct volume in a rat model of cerebral ischemia/reperfusion injury,increased the mRNA expression levels of the PI3K/Akt signaling pathwayrelated factors Beclin-1,mammalian target of rapamycin(mTOR),and PI3K,increased the protein expression levels of phosphorylated Akt,Beclin-1,PI3K,and mTOR in the ischemic cerebral cortex,and simultaneously reduced p53 mRNA and protein expression levels.In the Morris water maze test,the latency to find the hidden platform was significantly shortened among rats subjected to electroacupuncture stimulation compared with rats without electroacupuncture stimulation.In the spatial probe test,the number of times that a rat crossed the target quadrant was increased in rats subjected to electroacupuncture stimulation compared with rats without electroacupuncture stimulation.Electroacupuncture stimulation applied to the Shenting(GV24)and Baihui(GV20)acupoints activated the PI3K/Akt signaling pathway and improved rat learning and memory impairment.This study was approved by the Animal Ethics Committee of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine,China(approval No.8150150901)on March 10,2016.

Connexin:a potential novel target for protecting the central nervous system?

Connexin subunits are proteins that form gap junction channels, and play an important role in communication between adjacent cells. This review article discusses the function of connexins/hemichannels/gap junctions under physiological conditions, and summarizes the findings re-garding the role of connexins/hemichannels/gap junctions in the physiological and pathological mechanisms underlying central nervous system diseases such as brain ischemia, traumatic brain and spinal cord injury, epilepsy, brain and spinal cord tumor, migraine, neuroautoimmune disease, Alzheimer’s disease, Parkinson’s disease, X-linked Charcot-Marie-Tooth disease, Peli-zaeus-Merzbacher-like disease, spastic paraplegia and maxillofacial dysplasia. Connexins are considered to be a potential novel target for protecting the central nervous system.

Batroxobin inhibits astrocyte activation following nigrostriatal pathway injury

Batroxobin is a thrombin-like serine protease from the venom of the Bothrops atrox and Bothrops moojeni snake species.Sirtuin 1(Sirt1)has been shown to play an important role in neuroprotection after traumatic brain injury.However,its underlying mechanism of action remains poorly understood.The purpose of this study was to investigate whether the mechanism by which batroxobin participates in the activation of astrocytes is associated with Sirt1.Mouse models of nigrostriatal pathway injury were established.Immediately after modeling,mice were intraperitoneally administered 39 U/kg batroxobin.Batroxobin significantly reduced the expression of cleaved caspase-3 in both the substantia nigra and striatum,inhibited neuronal apoptosis,and promoted the recovery of rat locomotor function.These changes coincided with a remarkable reduction in astrocyte activation.Batroxobin also reduced Sirt1 expression and extracellular signal-regulated kinase activation in brain tissue.Intraperitoneal administration of the Sirt1-specific inhibitor EX527(5 mg/kg)30 minutes prior to injury could inhibit the abovementioned effects.In mouse astrocyte cultures,1 ng/mL batroxobin attenuated interleukin-1β-induced activation of astrocytes and extracellular signal-regulated kinase.EX527 could also inhibit the effects of batroxobin.These findings suggest that batroxobin inhibits astrocyte activation after nigrostriatal pathway injury through the Sirt1 pathway.This study was approved by the Animal Ethics Committee of China Medical University,China(approval No.CMU2020037)on July 19,2015.

Mechanism underlying treatment of ischemic stroke using acupuncture:transmission and regulation

The inflammatory response after cerebral ischemia/reperfusion is an important cause of neurological damage and repair.After cerebral ischemia/reperfusion,microglia are activated,and a large number of circulating inflammatory cells infiltrate the affected area.This leads to the secretion of inflammatory mediators and an inflammatory cascade that eventually causes secondary brain damage,including neuron necrosis,blood-brain barrier destruction,cerebral edema,and an oxidative stress response.Activation of inflammatory signaling pathways plays a key role in the pathological process of ischemic stroke.Increasing evidence suggests that acupuncture can reduce the inflammatory response after cerebral ischemia/reperfusion and promote repair of the injured nervous system.Acupuncture can not only inhibit the activation and infiltration of inflammatory cells,but can also regulate the expression of inflammation-related cytokines,balance the effects of pro-inflammatory and anti-inflammatory factors,and interfere with inflammatory signaling pathways.Therefore,it is important to study the transmission and regulatory mechanism of inflammatory signaling pathways after acupuncture treatment for cerebral ischemia/reperfusion injury to provide a theoretical basis for clinical treatment of this type of injury using acupuncture.Our review summarizes the overall conditions of inflammatory cells,mediators,and pathways after cerebral ischemia/reperfusion,and discusses the possible synergistic intervention of acupuncture in the inflammatory signaling pathway network to provide a foundation to explore the multiple molecular mechanisms by which acupuncture promotes nerve function restoration.

Apelin-13 inhibits apoptosis and excessive autophagy in cerebral ischemia/reperfusion injury

Apelin-13 is a novel endogenous ligand for an angiotensin-like orphan G-protein coupled receptor,and it may be neuroprotective against cerebral ischemia injury.However,the precise mechanisms of the effects of apelin-13 remain to be elucidated.To investigate the effects of apelin-13 on apoptosis and autophagy in models of cerebral ischemia/reperfusion injury,a rat model was established by middle cerebral artery occlusion.Apelin-13(50μg/kg)was injected into the right ventricle as a treatment.In addition,an SH-SY5Y cell model was established by oxygen-glucose deprivation/reperfusion,with cells first cultured in sugar-free medium with 95%N2 and 5%CO2 for 4 hours and then cultured in a normal environment with sugar-containing medium for 5 hours.This SH-SY5Y cell model was treated with 10-7 M apelin-13 for 5 hours.Results showed that apelin-13 protected against cerebral ischemia/reperfusion injury.Apelin-13 treatment alleviated neuronal apoptosis by increasing the ratio of Bcl-2/Bax and significantly decreasing cleaved caspase-3 expression.In addition,apelin-13 significantly inhibited excessive autophagy by regulating the expression of LC3B,p62,and Beclin1.Furthermore,the expression of Bcl-2 and the phosphatidylinositol-3-kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR)pathway was markedly increased.Both LY294002(20μM)and rapamycin(500 nM),which are inhibitors of the PI3K/Akt/mTOR pathway,significantly attenuated the inhibition of autophagy and apoptosis caused by apelin-13.In conclusion,the findings of the present study suggest that Bcl-2 upregulation and mTOR signaling pathway activation lead to the inhibition of apoptosis and excessive autophagy.These effects are involved in apelin-13-induced neuroprotection against cerebral ischemia/reperfusion injury,both in vivo and in vitro.The study was approved by the Animal Ethical and Welfare Committee of Jining Medical University,China(approval No.2018-JS-001)in February 2018.

Mechanism of delayed encephalopathy after acute carbon monoxide poisoning

Many hypotheses exist regarding the mechanism underlying delayed encephalopathy after acute carbon monoxide poisoning(DEACMP),including the inflammation and immune-mediated damage hypothesis and the cellular apoptosis and direct neuronal toxicity hypothesis;however,no existing hypothesis provides a satisfactory explanation for the complex clinical processes observed in DEACMP.Leucine-rich repeat and immunoglobulin-like domain-containing protein-1(LINGO-1)activates the Ras homolog gene family member A(Rho A)/Rho-associated coiled-coil containing protein kinase 2(ROCK2)signaling pathway,which negatively regulates oligodendrocyte myelination,axonal growth,and neuronal survival,causing myelin damage and participating in the pathophysiological processes associated with many central nervous system diseases.However,whether LINGO-1 is involved in DEACMP remains unclear.A DEACMP model was established in rats by allowing them to inhale 1000 ppm carbon monoxide gas for 40 minutes,followed by 3000 ppm carbon monoxide gas for an additional 20 minutes.The results showed that compared with control rats,DEACMP rats showed significantly increased water maze latency and increased protein and m RNA expression levels of LINGO-1,Rho A,and ROCK2 in the brain.Compared with normal rats,significant increases in injured neurons in the hippocampus and myelin sheath damage in the lateral geniculate body were observed in DEACMP rats.From days 1 to 21 after DEACMP,the intraperitoneal injection of retinoic acid(10 mg/kg),which can inhibit LINGO-1 expression,was able to improve the above changes observed in the DEACMP model.Therefore,the overexpression of LINGO-1 appeared to increase following carbon monoxide poisoning,activating the Rho A/ROCK2 signaling pathway,which may be an important pathophysiological mechanism underlying DEACMP.This study was reviewed and approved by the Medical Ethics Committee of Xiangya Hospital of Central South Hospital(approval No.201612684)on December 26,2016.

Enriched environment boosts the post-stroke recovery of neurological function by promoting autophagy

Autophagy is crucial for maintaining cellular homeostasis,and can be activated after ischemic stroke.It also participates in nerve injury and repair.The purpose of this study was to investigate whether an enriched environment has neuroprotective effects through affecting autophagy.A Sprague-Dawley rat model of transient ischemic stroke was prepared by occlusion of the middle cerebral artery followed by reperfusion.One week after surgery,these rats were raised in either a standard environment or an enriched environment for 4 successive weeks.The enriched environment increased Beclin-1 expression and the LC3-II/LC3-I ratio in the autophagy/lysosomal pathway in the penumbra of middle cerebral artery-occluded rats.Enriched environment-induced elevations in autophagic activity were mainly observed in neurons.Enriched environment treatment also promoted the fusion of autophagosomes with lysosomes,enhanced the lysosomal activities of lysosomal-associated membrane protein 1,cathepsin B,and cathepsin D,and reduced the expression of ubiquitin and p62.After 4 weeks of enriched environment treatment,neurological deficits and neuronal death caused by middle cerebral artery occlusion/reperfusion were significantly alleviated,and infarct volume was significantly reduced.These findings suggest that neuronal autophagy is likely the neuroprotective mechanism by which an enriched environment promotes recovery from ischemic stroke.This study was approved by the Animal Ethics Committee of the Kunming University of Science and Technology,China(approval No.5301002013855)on March 1,2019.

Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4

Our previous studies showed that ferroptosis plays an important role in the acute and subacute stages of spinal cord injury.High intracellular iron levels and low glutathione levels make oligodendrocytes vulnerable to cell death after central nervous system trauma.In this study,we established an oligodendrocyte(OLN-93 cell line)model of ferroptosis induced by RSL-3,an inhibitor of glutathione peroxidase 4(GPX4).RSL-3 significantly increased intracellular concentrations of reactive oxygen species and malondialdehyde.RSL-3 also inhibited the main antiferroptosis pathway,i.e.,SLC7A11/glutathione/glutathione peroxidase 4(xCT/GSH/GPX4),and downregulated acyl-coenzyme A synthetase long chain family member 4.Furthermore,we evaluated the ability of several compounds to rescue oligodendrocytes from ferroptosis.Liproxstatin-1 was more potent than edaravone or deferoxamine.Liproxstatin-1 not only inhibited mitochondrial lipid peroxidation,but also restored the expression of GSH,GPX4 and ferroptosis suppressor protein 1.These findings suggest that GPX4 inhibition induces ferroptosis in oligodendrocytes,and that liproxstatin-1 is a potent inhibitor of ferroptosis.Therefore,liproxstatin-1 may be a promising drug for the treatment of central nervous system diseases.

P2X7 receptor activation aggravates NADPH oxidase 2-induced oxidative stress after intracerebral hemorrhage

Oxidative stress is a crucial pathological process that contributes to secondary injury following intracerebral hemorrhage. P2X7 receptor(P2X7R), which is activated by the abnormal accumulation of extracellular ATP, plays an important role in the regulation of oxidative stress in the central nervous system, although the effects of activated P2X7R-associated oxidative stress after intracerebral hemorrhage remain unclear. Mouse models of intracerebral hemorrhage were established through the stereotactic injection of 0.075 U VII collagenase into the right basal ganglia. The results revealed that P2X7R expression peaked 24 hours after intracerebral hemorrhage, and P2X7R expressed primarily in neurons. The inhibition of P2X7R, using A438079(100 mg/kg, intraperitoneal), reduced nicotinamide adenine dinucleotide phosphate oxidase 2(NOX2) expression and malondialdehyde generation, increased superoxide dismutase and glutathione/oxidized glutathione levels, and alleviated neurological damage, brain edema, and apoptosis after intracellular hemorrhage. The P2X7R inhibitor A438079(100 mg/kg, intraperitoneal injection) inhibited the activation of extracellular signal-regulated kinase 1/2(ERK1/2) and nuclear factor kappa-B(NF-κB) after intracerebral hemorrhage. Blocking ERK1/2 activation, using the ERK1/2 inhibitor U0126(2 μg, intraventricular injection), reduced the level of NOX2-mediated oxidative stress induced by P2X7R activation after intracellular hemorrhage. Similarly, the inhibition of NF-κB, using the NF-κB inhibitor JSH-23(3.5 μg, intraventricular), reduced the level of NOX2-mediated oxidative stress induced by P2X7R activation. Finally, GSK2795039(100 mg/kg, intraperitoneal), a NOX2 antagonist, attenuated P2X7R-mediated oxidative stress, neurological damage, and brain edema after intracerebral hemorrhage. The results indicated that P2X7R activation aggravated NOX2-induced oxidative stress through the activation of the ERK1/2 and NF-κB pathways following intracerebral hemorrhage in mice. The present study was approved by the Ethics Committee of Huazhong University of Science and Technology, China(approval No. TJ-A20160805) on August 26, 2016.

MAP4K4 induces early blood-brain barrier damage in a murine subarachnoid hemorrhage model

Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4(MAP4 K4)is expressed in endothelial cells and activates inflammatory vascular damage.Endothelial cells are important components of the blood-brain barrier.To investigate whether MAP4 K4 plays a role in the pathophysiology of subarachnoid hemorrhage,we evaluated the time-course expression of MAP4 K4 after subarachnoid hemorrhage.A subarachnoid hemorrhage model was established using the intravascular perforation method.The model mice were assigned to four groups:MAP4 K4 recombinant protein,scramble small interfering RNA,and MAP4 K4 small interfering RNA were delivered by intracerebroventricular injection,while PF-06260933,a small-molecule inhibitor of MAP4 K4,was administrated orally.Neurological score assessments,brain water assessments,Evans blue extravasation,immunofluorescence,western blot assay,and gelatin zymography were performed to analyze neurological outcomes and mechanisms of vascular damage.MAP4 K4 expression was elevated in the cortex at 24 hours after subarachnoid hemorrhage,and colocalized with endothelial markers.MAP4 K4 recombinant protein aggravated neurological impairment,brain edema,and blood-brain barrier damage;upregulated the expression of phosphorylated nuclear factor kappa B(p-p65)and matrix metalloproteinase 9(MMP9);and degraded tight junction proteins(ZO-1 and claudin 5).Injection with MAP4 K4 small interfering RNA reversed these effects.Furthermore,administration of the MAP4 K4 inhibitor PF-06260933 reduced blood-brain barrier damage in mice,promoted the recovery of neurological function,and reduced p-p65 and MMP9 protein expression.Taken together,the results further illustrate that MAP4 K4 causes early blood-brain barrier damage after subarachnoid hemorrhage.The mechanism can be confirmed by inhibiting the MAP4 K4/NF-κB/MMP9 pathway.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of General Hospital of Northern Theater Command(No.2018002)on January 15,2018.

Melatonin ameliorates microvessel abnormalities in the cerebral cortex and hippocampus in a rat model of Alzheimer’s disease

Melatonin can attenuate cardiac microvascular ischemia/reperfusion injury,but it remains unclear whether melatonin can also ameliorate cerebral microvascular abnormalities.Rat models of Alzheimer’s disease were established by six intracerebroventricular injections of amyloidbeta 1–42,administered once every other day.Melatonin(30 mg/kg)was intraperitoneally administered for 13 successive days,with the first dose given 24 hours prior to the first administration of amyloid-beta 1–42.Melatonin ameliorated learning and memory impairments in the Morris water maze test,improved the morphology of microvessels in the cerebral cortex and hippocampus,increased microvessel density,alleviated pathological injuries of cerebral neurons,and decreased the expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2.These findings suggest that melatonin can improve microvessel abnormalities in the cerebral cortex and hippocampus by lowering the expression of vascular endothelial growth factor and its receptors,thereby improving the cognitive function of patients with Alzheimer’s disease.This study was approved by the Animal Care and Use Committee of Jinzhou Medical University,China(approval No.2019015)on December 6,2018.

Preventive electroacupuncture reduces cognitive deficits in a rat model of D-galactose-induced aging

Acupuncture can reduce cognitive deficits in Alzheimer’s disease.However,whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood.Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline.Therefore,we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications.A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks.Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration.Preventive electroacupuncture alleviated memory impairment,decreased tau hyperphosphorylation,and reduced glycogen synthase kinase-3βprotein and mRNA expression levels in the brainstem dorsal raphe nucleus,where intracellular neurofibrillary tangle lesions first occur.In addition,the DNA methylation level in the promoter region of the glycogen synthase kinase-3βgene was increased.The effects of preventive electroacupuncture were stronger than those of preventive acupuncture.Intraperitoneal injection of 0.4 mg/kg 5-aza-2ʹ-deoxycytidine,an inhibitor of DNA methyltransferase that blocks epigenetic modifications,antagonized the effects of preventive electroacupuncture.Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3βgene in the dorsal raphe nucleus.This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine,China(approval No.HUCMS201712001)on November 28,2017.

Muse cells decrease the neuroinflammatory response by modulating the proportion of M1 and M2 microglia in vitro

Neuroinflammation hinders repair of the central nervous system(CNS).Stem cell transplantation is a very promising approach for treatment of CNS injuries.However,it is difficult to select seed cells that can both facilitate nerve regeneration and improve the microenvironment in the CNS.In this study,we isolated multilineage-differentiating stress-enduring(Muse)cells from bone marrow mesenchymal stem cells.We explored the anti-inflammatory effect and mechanism of Muse cells in vitro by coculture of Muse cells with lipopolysaccharide-stimulated microglia.Our results showed that Muse cells effectively reduced the transcription and secretion of tumor necrosis factorαand interleukin-1βand increased the expression of transforming growth factor-βand interleukin-10 in microglia.In addition,Muse cells decreased the number of M1 microglia and increased the proportion of M2 microglia in an inflammatory environment more effectively than bone marrow mesenchymal stem cells.We also show that Muse cells inhibited the protein expression of toll-like receptor 4(TLR4)and myeloid differentiation primary response protein(MyD88)and inhibited the expression of the phosphorylated forms of transcription factor p65,nuclear factor(NF)-κB inhibitor alpha,and p38 mitogen-activated protein kinase(MAPK)in microglia.Therefore,we suggest Muse cells cause antineuroinflammatory effects by inhibition of the TLR4/MyD88/NF-κB and p38 MAPK signaling pathways in microglia.Our results shed light on the function of Muse cells in relation to CNS diseases and provide insight into the selection of seed cells.

Analyzing the Prebiotic Potential of Glucosamine for Targeting the Gut Microbiome Health

Recognizing the composition and modulation of the microbiome, a viable therapeutic tool for multi-targeted therapy is a new strategy that has recently been explored. Glucosamine (GS) is being studied for its prebiotic potential in addition to being the most abundant and naturally occurring amino monosaccharide. The current study focuses on glucosamine’s prebiotic potential by assessing the stability of various GS concentrations (1% - 5%) in the gastrointestinal tract (GIT) and its ability to be fermented by the gut microbiota. The results showed that GS stimulated the most growth in L. acidophilus even after a longer incubation time than B. bifidum and L. acidophilus growth was concentration-dependent, with maximum growth at 3% with a simultaneous decrease in pH (5.6 - 1.7). The decrease in GS concentration with time also represented the growth of bacterial species, demonstrating the species’ utilization of GS. Furthermore, at 3%, GS also represented the prebiotic index of 1.9. In addition, the concentration of GS in various simulated GIT fluids was estimated in both fast and fed conditions to examine GS stability at various levels in the gut. The results showed that GS remained unaffected and non-digestible in all of the simulated GIT fluids (salivary, gastric, intestinal, and colonic), but there was a slight decrease in GS concentration (2.8%) in the fasted state of gastric fluid due to low pH levels (1.6). As a result, the findings are conclusive and suggest that GS possesses prebiotic properties.

Research development of the pathogenesis pathways for neuroschistosomiasis

The infection of the central nervous system （CNS） by schistosome may or may not have clinical manifestations. When symptomatic, neuroschistosomiasis （NS） is one of the most severe presentations of schistosome infection. Among the NS symptoms, cerebral invasion is mostly caused by Schistosoma japonicum （S. japonicum）, and the spinal cord symptoms are mainly caused by S. mansoni or S. haematobium. There are 2 main pathways by which schistosomes cause NS： egg embolism and worm migration, via either artery or vein system, especially the valveless perivertebral Batson＇s plexus. The adult worm migrates anomalously through the above pathways to the CNS where they lay eggs. Due to the differences in species of schistosomes and stages of infection, mechanisms vary greatly. The portal hypertension with hepatosplenic schistosomiasis also plays an important role in the pathogenesis. Here the pathways through which NS occurs in the CNS were reviewed.

A neuromorphic device mimicking synaptic plasticity under different body fluid K^(+) homeostasis for artificial reflex path construction and pattern recognition

The ionic environment of body fluids influences nervous functions for maintaining homeostasis in organisms and ensures normal perceptual abilities and reflex activities.Neural reflex activities,such as limb movements,are closely associated with potassium ions(K+).In this study,we developed artificial synaptic devices based on ion concentration-adjustable gels for emulating various synaptic plasticities under different K+concentrations in body fluids.In addition to performing essential synaptic functions,potential applications in information processing and associative learning using short-and long-term plasticity realized using ion concentration-adjustable gels are presented.Artificial synaptic devices can be used for constructing an artificial neural pathway that controls artificial muscle reflex activities and can be used for image pattern recognition.All tests show a strong relationship with ion homeostasis.These devices could be applied to neuromorphic robots and human-machine interfaces.

Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

Interaction and regulatory functions of μ- and δ-opioid receptors in nociceptive afferent neurons

μ-opioid receptor （MOR） agonists such as morphine are powerful analgesics used for pain therapy. However, the use of these drugs is limited by their side-effects, which include antinociceptive tolerance and dependence. Earlier studies reported that MOR analgesic tolerance is reduced by blockade of 5-opioid receptors （DORs） that interact with MORs. Recent studies show that the MOR/DOR interaction in nociceptive afferent neurons in the dorsal root ganglion may contribute to morphine analgesic tolerance. Further analysis of the mechanisms for regulating the trafficking of receptors, ion channels and signaling molecules in nociceptive afferent neurons would help to understand the nociceptive mechanisms and improve pain therapy.