Myelin histology:a key tool in nervous system research

The myelin sheath is a lipoprotein-rich,multilayered structure capable of increasing conduction velocity in central and peripheral myelinated nerve fibers.Due to the complex structure and composition of myelin,various histological techniques have been developed over the centuries to evaluate myelin under normal,pathological or experimental conditions.Today,methods to assess myelin integrity or content are key tools in both clinical diagnosis and neuroscience research.In this review,we provide an updated summary of the composition and structure of the myelin sheath and discuss some histological procedures,from tissue fixation and processing techniques to the most used and practical myelin histological staining methods.Considering the lipoprotein nature of myelin,the main features and technical details of the different available methods that can be used to evaluate the lipid or protein components of myelin are described,as well as the precise ultrastructural techniques.

Effects of exosomes from mesenchymal stem cells on functional recovery of a patient with total radial nerve injury: A pilot study

BACKGROUND Peripheral nerve injury can result in significant clinical complications that have uncertain prognoses.Currently,there is a lack of effective pharmacological interventions for nerve damage,despite the existence of several small compounds,Despite the objective of achieving full functional restoration by surgical intervention,the persistent challenge of inadequate functional recovery remains a significant concern in the context of peripheral nerve injuries.AIM To examine the impact of exosomes on the process of functional recovery following a complete radial nerve damage.METHODS A male individual,aged 24,who is right-hand dominant and an immigrant,arrived with an injury caused by a knife assault.The cut is located on the left arm,specifically below the elbow.The neurological examination and electrodiagnostic testing reveal evidence of left radial nerve damage.The sural autograft was utilized for repair,followed by the application of 1 mL of mesenchymal stem cell-derived exosome,comprising 5 billion microvesicles.This exosome was split into four equal volumes of 0.25 mL each and delivered microsurgically to both the proximal and distal stumps using the subepineural pathway.The patient was subjected to a period of 180 d during which they had neurological examination and electrodiagnostic testing.RESULTS The duration of the patient’s follow-up period was 180 d.An increasing Tinel’s sign and sensory-motor recovery were detected even at the 10th wk following nerve grafting.Upon the conclusion of the 6-mo post-treatment period,an evaluation was conducted to measure the extent of improvement in motor and sensory functions of the nerve.This assessment was based on the British Medical Research Council scale and the Mackinnon-Dellon scale.The results indicated that the level of improvement in motor function was classified as M5,denoting an excellent outcome.Additionally,the level of improvement in sensory function was classified as S3+,indicating a good outcome.It is noteworthy that these assessments were conducted in the absence of physical therapy.At the 10th wk post-injury,despite the persistence of substantial axonal damage,the nerve exhibited indications of nerve re-innervation as evidenced by control electromyography(EMG).In contrast to the preceding.EMG analysis revealed a significant electrophysiological enhancement in the EMG conducted at the 6th-mo follow-up,indicating ongoing regeneration.CONCLUSION Enhanced comprehension of the neurobiological ramifications associated with peripheral nerve damage,as well as the experimental and therapy approaches delineated in this investigation,holds the potential to catalyze future clinical progress.

Optimal transcorneal electrical stimulation parameters for preserving photoreceptors in a mouse model of retinitis pigmentosa

Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors,leading to progressive photoreceptor loss.Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival.This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation(tcES)in mice affected by inherited retinal degeneration.Additionally,the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans.In this study,we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular,sine,and ramp waveforms.To investigate the functional effects of electrical stimulation on photoreceptors,we used human retinal explant cultures and rhodopsin knockout(Rho^(-/-))mice,demonstrating progressive photoreceptor degeneration with age.Human retinal explants isolated from the donors’eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro.Photoreceptor density was evaluated by rhodopsin immunolabeling.In vivo Rho^(-/-)mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms.Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response(OMR),respectively.Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas.Oscilloscope recordings indicated effective delivery of rectangular,sine,and ramp waveforms to the retina by transcorneal electrical stimulation,of which the ramp waveform required the lowest voltage.Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes.The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro(~0.5-1.5°C).Electrical stimulation increased photoreceptor survival in human retinal explant cultures,particularly at the ramp waveform.Transcorneal electrical stimulation(rectangular+ramp)waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results.Histology and immunolabeling demonstrated increased photoreceptor survival,improved outer nuclear layer thickness,and increased bipolar cell sprouting in Rho^(-/-)mice.These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina,improves photoreceptor survival in both human and mouse retinas,and increases visual function in Rho^(-/-)mice.Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion.

Inhibition of Ehrlich ascites carcinoma growth by melatonin:Studies with micro-CT

Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling pathway.Melatonin has many benefits,such as organizing circadian rhythms and acting as a powerful hormone.We aimed to show the antitumor effects of melatonin in both in vivo and in vitro models through the mammalian target of rapamycin(mTOR)signaling pathway and the Argyrophilic Nucleolar Regulatory Region(AgNOR),using the Microcomputed Tomography(Micro CT).Ehrlich ascites carcinoma(EAC)cells were administered into the mice by subcutaneous injection.Animals with solid tumors were injected intraperitoneally with 50 and 100 mg/kg melatonin for 14 days.Volumetric measurements for the taken tumors were made with micro-CT imaging,immunohistochemistry(IHC),real-time polymerase chain reaction(PCR)and AgNOR.Statistically,the tumor tissue volume in the Tumor+100 mg/kg melatonin group was significantly lower than that in the other groups in the data obtained from micro-CT images.In the IHC analysis,the groups treated with Tumor+100 mg/kg melatonin were compared when the mTOR signaling pathway and factor 8(F8)expression were compared with the control group.It was determined that there was a significant decrease(p<0.05).Significant differences were found in the total AgNOR area/nuclear area(TAA/NA)ratio in the treatment groups(p<0.05).Furthermore,there were significant differences between the amount of mTOR mRNA for the phosphatidylinositol 3-kinase(PI3K),AKT Serine/Threonine Kinase(PKB/AKT)genes(p<0.05).Cell apoptosis was evaluated with Annexin V in an in vitro study with different doses of melatonin;It was observed that 100µg/mL melatonin dose caused an increase in the apoptotic cell death.In this study,we have reported anti-tumor effects of melatonin in cell culture studies as well as in mice models.Comprehensive characterization of the melatonin-mediated cancer inhibitory effects will be valuable in advancing our fundamental molecular understanding and translatability of pre-clinical findings to earlier phases of clinical trials.

Safety and efficiency of Wharton’s Jelly-derived mesenchymal stem cell administration in patients with traumatic brain injury:First results of a phase I study

BACKGROUND Traumatic brain injury(TBI)is characterized by a disruption in the normal function of the brain due to an injury following a trauma,which can potentially cause severe physical,cognitive,and emotional impairment.Stem cell transplantation has evolved as a novel treatment modality in the management of TBI,as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain.Wharton’s Jelly-derived mesenchymal stem cells(WJ-MSCs)have recently shown beneficial effects in the functional recovery of neurological deficits.AIM To evaluate the safety and efficiency of MSC therapy in TBI.METHODS We present 6 patients,4 male and 2 female aged between 21 and 27 years who suffered a TBI.These 6 patients underwent 6 doses of intrathecal,intramuscular(i.m.)and intravenous transplantation of WJ-MSCs at a target dose of 1×106/kg for each application route.Spasticity was assessed using the Modified Ashworth scale(MAS),motor function according to the Medical Research Council Muscle Strength Scale,quality of life was assessed by the Functional Independence Measure(FIM)scale and Karnofsky Performance Status scale.RESULTS Our patients showed only early,transient complications,such as subfebrile fever,mild headache,and muscle pain due to i.m.injection,which resolved within 24 h.During the one year follow-up,no other safety issues or adverse events were reported.These 6 patients showed improvements in their cognitive abilities,muscle spasticity,muscle strength,performance scores and fine motor skills when compared before and after the intervention.MAS values,which we used to assess spasticity,were observed to statistically significantly decrease for both left and right sides(P<0.001).The FIM scale includes both motor scores(P<0.05)and cognitive scores(P<0.001)and showed a significant increase in pretest posttest analyses.The difference observed in the participants’Karnofsky Performance Scale values pre and post the intervention was statistically significant(P<0.001).CONCLUSION This study showed that cell transplantation has a safe,effective and promising future in the management of TBI.

In vivo and in vitro study of resorbable magnesium wires for medical implants:Mg purity,surface quality,Zn alloying and polymer coating

Magnesium is an excellent material in terms of biocompatibility and its corrosion products can serve as an active source for new bone formation.However,localized corrosion and H_(2)generation limit the potential of Mg-based implants.Utilizing low-alloyed Mg-Zn wires can strongly reduce problems with large H_(2)bubbles and improve the mechanical properties considerably while maintaining excellent long-term biocompatibility.Acidic pickling and a polymer coating can be effectively used to lower the rate of in vivo degradation.In this work,microstructural,mechanical,and in vitro characterization of 250μm and 300μm extruded wires made from ultra-pure Mg,commercially pure Mg,Mg-0.15Zn,Mg-0.4Zn and Mg-1Zn was performed.Additionally,Mg-0.4Zn wires together with a variant coated with a copolymer of L-lactide andε-caprolactone were tested in vivo on artificially damaged Wistar rat femurs.Based on the observed Mg-induced osteogenesis,polymer-coated Mg wires with a small addition of Zn are a perspective material for bone-support applications,such as cerclage and fixation wires.

Advances in the treatment of autism spectrum disorder:Wharton jelly mesenchymal stem cell transplantation

BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental disorder with multifaceted origins.In recent studies,neuroinflammation and immune dysregulation have come to the forefront in its pathogenesis.There are studies suggesting that stem cell therapy may be effective in the treatment of ASD.AIM To evolve the landscape of ASD treatment,focusing on the potential benefits and safety of stem cell transplantation.METHODS A detailed case report is presented,displaying the positive outcomes observed in a child who underwent intrathecal and intravenous Wharton’s jelly-derived mesenchymal stem cells(WJ-MSCs)transplantation combined with neurorehabilitation.RESULTS The study demonstrates a significant improvement in the child’s functional outcomes(Childhood Autism Rating Scale,Denver 2 Developmental Screening Test),especially in language and gross motor skills.No serious side effects were encountered during the 2-year follow-up.CONCLUSION The findings support the safety and effectiveness of WJ-MSC transplantation in managing ASD.

Microscopic Structure of the Sigmoido-Jugular Junction in the Third-Trimester Fetus

Context and Justification: The sigmoido-jugular junction connects two structures of different compositions and has a complex organization. The sinusoidal portion of its endothelium contains muscle cells in adults. Is this the same presentation observed in fetuses? Objective: To describe the sigmoido-jugular junction in fetuses. Materials and Methods: Over a period of seven months, a histochemical and immunohistochemical study was conducted on 30 sigmoido-jugular junctions taken from 15 fetuses aged at least 32 weeks of gestation. These fetuses were obtained following expulsion due to intrauterine death, after informed consent from the parents. Results: Three portions can be identified: sigmoid, junctional, and jugular. Histochemical preparations revealed the existence of two constant layers and a third layer present only at the jugular level. From the inside out, the layers are as follows: 1) Inner Layer (Endothelium): This layer is clearer from the junction and reveals the presence of smooth muscle cells at the sigmoid level in immunohistochemistry. 2) Outer Layer: At the sigmoid and junctional levels, this layer consists of collagen fibers and becomes median at the jugular level, where it is composed of elastic and muscular collagen fibers. 3) Third Layer: Present only at the jugular level, this layer corresponds to the adventitia. Conclusion: The architecture of the sigmoido-jugular junction in fetuses, which is identical to that in adults, excludes the metaplastic hypothesis regarding endothelial smooth muscle cells in the sigmoid portion. Instead, it favors their role in regulating encephalic venous drainage.

Hypoxia and inflammatory factor preconditioning enhances the immunosuppressive properties of human umbilical cord mesenchymal stem cells

BACKGROUND Mesenchymal stem cells(MSCs)have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties.However,MSCs exposed to the harsh inflammatory environment of damaged tissue after intravenous transplantation cannot exert their biological effects,and therefore,their therapeutic efficacy is reduced.In this challenging context,an in vitro preconditioning method is necessary for the development of MSC-based therapies with increased immunomodulatory capacity and transplantation efficacy.AIM To determine whether hypoxia and inflammatory factor preconditioning increases the immunosuppressive properties of MSCs without affecting their biological characteristics.METHODS Umbilical cord MSCs(UC-MSCs)were pretreated with hypoxia(2%O_(2))exposure and inflammatory factors(interleukin-1β,tumor necrosis factor-α,interferon-γ)for 24 h.Flow cytometry,polymerase chain reaction,enzyme-linked immunosorbent assay and other experimental methods were used to evaluate the biological characteristics of pretreated UC-MSCs and to determine whether pretreatment affected the immunosuppressive ability of UC-MSCs in coculture with immune cells.RESULTS Pretreatment with hypoxia and inflammatory factors caused UC-MSCs to be elongated but did not affect their viability,proliferation or size.In addition,pretreatment significantly decreased the expression of coagulationrelated tissue factors but did not affect the expression of other surface markers.Similarly,mitochondrial function and integrity were retained.Although pretreatment promoted UC-MSC apoptosis and senescence,it increased the expression of genes and proteins related to immune regulation.Pretreatment increased peripheral blood mononuclear cell and natural killer(NK)cell proliferation rates and inhibited NK cell-induced toxicity to varying degrees.CONCLUSION In summary,hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics.

Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model

Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes,which affect the potency of the functional recovery after spinal cord injury(SCI).Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodeling of the affected neural tissue.In our previous studies for delivering the therapeutic genes at the site of spinal cord injury,we developed a new approach using an autologous leucoconcentrate transduced ex vivo with chimeric adenoviruses(Ad5/35)carrying recombinant cDNA.In the present study,the efficacy of the intravenous infusion of an autologous genetically-enriched leucoconcentrate simultaneously producing recombinant vascular endothelial growth factor(VEGF),glial cell line-derived neurotrophic factor(GDNF),and neural cell adhesion molecule(NCAM)was evaluated with regard to the molecular and cellular changes in remodeling of the spinal cord tissue at the site of damage in a model of mini-pigs with moderate spinal cord injury.Experimental animals were randomly divided into two groups of 4 pigs each:the therapeutic(infused with the leucoconcentrate simultaneously transduced with a combination of the three chimeric adenoviral vectors Ad5/35‐VEGF165,Ad5/35‐GDNF,and Ad5/35‐NCAM1)and control groups(infused with intact leucoconcentrate).The morphometric and immunofluorescence analysis of the spinal cord regeneration in the rostral and caudal segments according to the epicenter of the injury in the treated animals compared to the control mini-pigs showed:(1)higher sparing of the grey matter and increased survivability of the spinal cord cells(lower number of Caspase-3-positive cells and decreased expression of Hsp27);(2)recovery of synaptophysin expression;(3)prevention of astrogliosis(lower area of glial fibrillary acidic protein-positive astrocytes and ionized calcium binding adaptor molecule 1-positive microglial cells);(4)higher growth rates of regeneratingβIII-tubulin-positive axons accompanied by a higher number of oligodendrocyte transcription factor 2-positive oligodendroglial cells in the lateral corticospinal tract region.These results revealed the efficacy of intravenous infusion of the autologous genetically-enriched leucoconcentrate producing recombinant VEGF,GDNF,and NCAM in the acute phase of spinal cord injury on the positive changes in the post-traumatic remodeling nervous tissue at the site of direct injury.Our data provide a solid platform for a new ex vivo gene therapy for spinal cord injury and will facilitate further translation of regenerative therapies in clinical neurology.

Chitosan conduits enriched with fibrin-collagen hydrogel with or without adipose-derived mesenchymal stem cells for the repair of 15-mm-long sciatic nerve defect

Hollow conduits of natural or synthetic origins have shown acceptable regeneration results in short nerve gap repair;however,results are still not comparable with the current gold standard technique“autografts”.Hollow conduits do not provide a successful regeneration outcome when it comes to critical nerve gap repair.Enriching the lumen of conduits with different extracellular materials and cells could provide a better biomimicry of the natural nerve regenerating environment and is expected to ameliorate the conduit performance.In this study,we evaluated nerve regeneration in vivo using hollow chitosan conduits or conduits enriched with fibrin-collagen hydrogels alone or with the further addition of adipose-derived mesenchymal stem cells in a 15 mm rat sciatic nerve transection model.Unexpected changes in the hydrogel consistency and structural stability in vivo led to a failure of nerve regeneration after 15 weeks.Nevertheless,the molecular assessment in the early regeneration phase(7,14,and 28 days)has shown an upregulation of useful regenerative genes in hydrogel enriched conduits compared with the hollow ones.Hydrogels composed of fibrin-collagen were able to upregulate the expression of soluble NRG1,a growth factor that plays an important role in Schwann cell transdifferentiation.The further enrichment with adipose-derived mesenchymal stem cells has led to the upregulation of other important genes such as ErbB2,VEGF-A,BDNF,c-Jun,and ATF3.

Peripheral nerve regeneration through nerve conduits evokes differential expression of growth-associated protein-43 in the spinal cord

Growth-associated protein 43 plays a key role in neurite outgrowth through cytoskeleton remodeling.We have previously demonstrated that structural damage of peripheral nerves induces growth-associated protein 43 upregulation to promote growth cone formation.Conversely,the limited regenerative capacity of the central nervous system due to an inhibitory environment prevents major changes in neurite outgrowth and should be presumably associated with low levels of growth-associated protein 43 expression.However,central alterations due to peripheral nerve damage have never been assessed using the growthassociated protein 43 marker.In this study,we used the tubulization technique to repair 1 cm-long nerve gaps in the rat nerve injury/repair model and detected growth-associated protein 43 expression in the peripheral and central nervous systems.First,histological analysis of the regeneration process confirmed an active regeneration process of the nerve gaps through the conduit from 10 days onwards.The growth-associated protein 43 expression profile varied across regions and follow-up times,from a localized expression to an abundant and consistent expression throughout the regeneration tissue,confirming the presence of an active nerve regeneration process.Second,spinal cord changes were also histologically assessed,and no apparent changes in the structural and cellular organization were observed using routine staining methods.Surprisingly,remarkable differences and local changes appeared in growth-associated protein 43 expression at the spinal cord level,in particular at 20 days post-repair and beyond.Growth-associated protein 43 protein was first localized in the gracile fasciculus and was homogeneously distributed in the left posterior cord.These findings differed from the growth-associated protein 43 pattern observed in the healthy control,which did not express growth-associated protein 43 at these levels.Our results revealed a differential expression in growth-associated protein 43 protein not only in the regenerating nerve tissue but also in the spinal cord after peripheral nerve transection.These findings open the possibility of using this marker to monitor changes in the central nervous system after peripheral nerve injury.

Knockdown of polypyrimidine tract binding protein facilitates motor function recovery after spinal cord injury

After spinal cord injury(SCI),a fibroblast-and microglia-mediated fibrotic scar is formed in the lesion core,and a glial scar is formed around the fibrotic scar as a res ult of the activation and proliferation of astrocytes.Simultaneously,a large number of neuro ns are lost in the injured area.Regulating the dense glial scar and re plenishing neurons in the injured area are essential for SCI repair.Polypyrimidine tra ct binding protein(PTB),known as an RNA-binding protein,plays a key role in neurogenesis.Here,we utilized short hairpin RNAs(shRNAs)and antisense oligonucleotides(ASOs)to knock down PTB expression.We found that reactive spinal astrocytes from mice were directly reprogrammed into motoneuron-like cells by PTB downregulation in vitro.In a mouse model of compressioninduced SCI,adeno-associated viral shRNA-mediated PTB knockdown replenished motoneuron-like cells around the injured area.Basso Mouse Scale scores and forced swim,inclined plate,cold allodynia,and hot plate tests showed that PTB knockdown promoted motor function recovery in mice but did not improve sensory perception after SCI.Furthermore,ASO-mediated PTB knockdown improved motor function resto ration by not only replenishing motoneuron-like cells around the injured area but also by modestly reducing the density of the glial scar without disrupting its overall structure.Together,these findings suggest that PTB knockdown may be a promising therapeutic strategy to promote motor function recovery during spinal cord repair.

Motor neuron-specific RhoA knockout delays degeneration and promotes regeneration of dendrites in spinal ventral horn after brachial plexus injury

Dendrites play irreplaceable roles in the nerve conduction pathway and are vulnerable to various insults.Peripheral axotomy of motor neurons results in the retraction of dendritic arbors,and the dendritic arbor can be re-expanded when reinnervation is allowed.RhoA is a target that regulates the cytoskeleton and promotes neuronal survival and axon regeneration.However,the role of RhoA in dendrite degeneration and regeneration is unknown.In this study,we explored the potential role of RhoA in dendrites.A line of motor neuronal conditional knockout mice was developed by crossbreeding HB9~(Cre+)mice with RhoA~(flox/flox)mice.We established two models for assaying dendrite degeneration and regeneration,in which the brachial plexus was transection or crush injured,respectively.We found that at 28 days after brachial plexus transection,the density,complexity,and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice were slightly decreased compared with that in Cre mice.Dendrites underwent degeneration at 7 and 14 days after brachial plexus transection and recovered at 28–56 days.The density,complexity,and structural integrity of dendrites in the ventral horn of the spinal cord of RhoA conditional knockout mice recovered compared with results in Cre mice.These findings suggest that RhoA knockout in motor neurons attenuates dendrite degeneration and promotes dendrite regeneration after peripheral nerve injury.

Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities

As an important treatment for acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation(allo-HSCT) plays an important role in reducing relapse and improving long-term survival. With rapid advancements in basic research in molecular biology and immunology and with deepening understanding of the biological characteristics of hematopoietic stem cells, allo-HSCT has been widely applied in clinical practice. During allo-HSCT, preconditioning, the donor, and the source of stem cells can be tailored to the patient’s conditions, greatly broadening the indications for HSCT, with clear survival benefits. However, the risks associated with allo-HSCT remain high, i.e. hematopoietic reconstitution failure, delayed immune reconstitution, graft-versus-host disease, and posttransplant relapse, which are bottlenecks for further improvements in allo-HSCT efficacy and have become hot topics in the field of HSCT. Other bottlenecks recognized in the current treatment of individuals diagnosed with acute myeloid leukemia and subjected to allo-HSCT include the selection of the most appropriate conditioning regimen and post-transplantation management. In this paper, we reviewed the progress of relevant research regarding these aspects.

Alginate/gelatin/boron-doped hydroxyapatite-coated Ti implants:in vitro and in vivo evaluation of osseointegration

In this study,boron-doped hydroxyapatite(BHT)-loaded alginate/gelatin-based(A/G)hydrogel coating on Ti was fabricated to support bone integration through triggering osteoinduction,vascularization and immunomodulation.Initially,highly reproducible,cheap and time-effective BHT was produced,which significantly promoted higher osteogenic and angiogenic maturation,while a mild innate immune response was observed.The immense potential of BHT was evidenced by the production of a gap-filling A/G/BHT interphase on Ti implants to mimic the osseous extracellular matrix to achieve functional bridging and exert control over the course of innate immune response.We initially aminosilanized the implant surface using 3-aminopropyl triethoxysilane,and then coated it with 0.25%w/v alginate with 20 mM 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide to allowthe A/G/BHT pre-gel to disperse evenly and covalently attach on the surface.The pre-gel was added with 0.2 M NaCl to homogeneously blend BHT in the structure without inducing ionic crosslinking.Then,the coated implants were freeze-dried and stored.The coated layer demonstrated high cohesive and adhesive strength,and 8-month-long shelf-life at room temperature and normal humidity.The A/G/BHT was able to coat an irregularly shaped Ti implant.Osteoblasts and endothelial cells thrived on the A/G/BHT,and it demonstrated greatly improved osteogenic and angiogenic capacity.Moreover,A/G/BHT maintained macrophage viability and generated an acute increase in immune response that could be resolved rapidly.Finally,A/G/BHT was shown to induce the robust integration of implant in a rabbit femur osteochondral model within 2months.Therefore,we concluded that A/G/BHT coatings could serve as amultifunctional reservoir,promoting the strong and rapid osseointegration of metallic implants.

Role of brahma-related gene 1/brahma-associated factor subunits in neural stem/progenitor cells and related neural developmental disorders

Different fates of neural stem/progenitor cells(NSPCs)and their progeny are determined by the gene regulatory network,where a chromatin-remodeling complex affects synergy with other regulators.Here,we review recent research progress indicating that the BRG1/BRM-associated factor(BAF)complex plays an important role in NSPCs during neural development and neural developmental disorders.Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation,which can also lead to various diseases in humans.We discussed BAF complex subunits and their main characteristics in NSPCs.With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs,we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs.Considering recent progress in these research areas,we suggest that three approaches should be used in investigations in the near future.Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders.More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.

Implantation of hydrogel-liposome nanoplatform inhibits glioblastoma relapse by inducing ferroptosis

Glioblastoma is acknowledged as the most aggressive cerebral tumor in adults.However,the efficacy of current standard therapy is seriously undermined by drug resistance and suppressive immune microenvironment.Ferroptosis is a recently discovered form of iron-dependent cell death that may have excellent prospect as chemosensitizer.The utilization of ferropotosis inducer Erastin could significantly mediate chemotherapy sensitization of Temozolomide and exert anti-tumor effects in glioblastoma.In this study,a combination of hydrogel-liposome nanoplatform encapsulatedwith Temozolomide and ferroptosis inducer Erastin was constructed.Theαvβ3 integrin-binding peptide cyclic RGD was utilized to modify codelivery system to achieve glioblastoma targeting strategy.As biocompatible drug reservoirs,cross-linked GelMA(gelatin methacrylamide)hydrogel and cRGD-coated liposome realized the sustained release of internal contents.In the modified intracranial tumor resection model,GelMA-liposome system achieved slow release of Temozolomide and Erastin in situ for more than 14 d.The results indicated that nanoplatform(T+E@LPs-cRGD+GelMA)improved glioblastoma sensitivity to chemotherapeutic temozolomide and exerted satisfactory anti-tumor effects.It was demonstrated that the induction of ferroptosis could be utilized as a therapeutic strategy to overcome drug resistance.Furthermore,transcriptome sequencing was conducted to reveal the underlying mechanism that the nanoplatform(T+E@LPs-cRGD+GelMA)implicated in.It is suggested that GelMA-liposome system participated in the immune response and immunomodulation of glioblastoma via interferon/PD-L1 pathway.Collectively,this study proposed a potential combinatory therapeutic strategy for glioblastoma treatment.

Protective effect of lycopene on Parkinson's disease cell model based on endoplasmic reticulum stress

Objective:To evaluate the effect of lycopene on Parkinson's disease cell model and its possible mechanism.Methods:The SH-SY5Y cells were treated with 0.5μmol/L rotenone for 24 h to establish Parkinson's disease cell model.The experiments were randomly divided into the control group,the lycopene group,the rotenone group,the pretreatment groups of different concentrations lycopene(low,medium,high concentration).Cell viability was detected by CCK-8 assay,the morphological changes of cells were observed under an inverted microscope,Hoechst staining was used to observe cell apoptosis,the expression and distribution of endoplasmic reticulum stress marker proteins GRP78 and CHOP in each group were detected by Western blot and cell immunofluorescence.Results:The study found that compared with the control group,the cell viability in the rotenone group was significantly decreased with obvious apoptosis;compared with the rotenone group,the cell viability of the lycopene pretreatment group was improved,and the difference was statistically significant(P<0.05);The apoptosis in the lycopene pretreatment group was decreased.The expression of GRP78 and CHOP in the rotenone group was significantly higher than that in the control group(P<0.01),while the expression of both in the high concentration lycopene pretreatment group was lower than that in the rotenone group(P<0.05).Conclusion:Lycopene pretreatment had a significant protective effect on rotenone-induced SH-SY5Y cells,which may be related to the fact that lycopene pretreatment can effectively alleviate endoplasmic reticulum stress in SH-SY5Y cells damaged by rotenone.

Efficacy of Willis covered stent of intracranial pseudoaneurysms in the internal carotid artery: A systematic review and meta-analysis

Objective:To evaluate the efficacy of a novel coated stent in the treatment of intracranial pseudoaneurysm.Methods:MEDLINE,EMBASE,and PubMed databases were searched for literature published between 1990 and April 2022 according to PRISMA guidelines.All studies with≥10 patients reporting successful implantation of Willis covered stent,therapeutic effect,complications,and postoperative follow-up were included.The combined incidence and corresponding 95%confidence intervals were assessed using a generalized linear mixed method and random effects model.Results:Five studies(116 patients with pseudoaneurysms)were included.The experimental groups in the selected studies showed a combined technical success rate of 81.03%(OR=18.31,95%CI=9.39-35.69,I^(2)=79%,P<0.001).Clinical follow-up showed that the complete cure rate was as high as 94.4%after the follow-up(OR=106.81,95%CI=39.08-291.88,I^(2)=0%,P=0.71).Conclusions:Willis covered stent is feasible,safe,and effective in the treatment of intracranial pseudoaneurysm.