Studies have shown that microRNAs(miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is h...Studies have shown that microRNAs(miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is hard to select key miRNAs with essential biological functions among a large number of differentially expressed miRNAs. Previously, we collected injured sciatic nerve stumps at multiple time points after nerve crush injury, examined gene changes at different stages(acute, sub-acute, and post-acute), and obtained mRNA expression profiles. Here, we jointly analyzed mRNAs and miRNAs, and investigated upstream miRNAs of differentially expressed mRNAs using Ingenuity Pathway Analysis bioinformatic software. A total of 31, 42, 30, and 23 upstream miRNAs were identified at 1, 4, 7, and 14 days after rat sciatic nerve injury, respectively. Temporal expression patterns and biological involvement of commonly involved upstream miRNAs(miR-21, let-7, miR-223, miR-10 b, miR-132, miR-15 b, miR-127, miR-29 a, miR-29 b, and miR-9) were then determined at multiple time points. Expression levels of miR-21, miR-132, miR-29 a, and miR-29 b were robustly increased after sciatic nerve injury. Biological processes involving these miRNAs include multicellular organismal response to stress, positive regulation of the epidermal growth factor receptor signaling pathway, negative regulation of epithelial cell differentiation, and regulation of myocardial tissue growth. Moreover, we constructed mechanistic networks of let-7, miR-21, and miR-223, the most significantly involved upstream miRNAs. Our findings reveal that multiple upstream miRNAs(i.e., let-7, miR-21, and miR-223) were associated with gene expression changes in rat sciatic nerve stumps after nerve injury, and these miRNAs play an important role in peripheral nerve regeneration. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China(approval No. 20190303-18) on March 3, 2019.展开更多
Both intracellular sigma peptide(ISP) and phosphatase and tensin homolog agonist protein(PAP4) promote nerve regeneration and motor functional recovery after spinal cord injury. However, the role of these two small pe...Both intracellular sigma peptide(ISP) and phosphatase and tensin homolog agonist protein(PAP4) promote nerve regeneration and motor functional recovery after spinal cord injury. However, the role of these two small peptides in peripheral nerve injury remains unclear. A rat model of brachial plexus injury was established by crush of the C6 ventral root. The rats were then treated with subcutaneous injection of PAP4(497 μg/d, twice per day) or ISP(11 μg/d, once per day) near the injury site for 21 successive days. After ISP and PAP treatment, the survival of motoneurons was increased, the number of regenerated axons and neuromuscular junctions was increased, muscle atrophy was reduced, the electrical response of the motor units was enhanced and the motor function of the injured upper limbs was greatly improved in rats with brachial plexus injury. These findings suggest that ISP and PAP4 promote the recovery of motor function after peripheral nerve injury in rats. The animal care and experimental procedures were approved by the Laboratory Animal Ethics Committee of Jinan University of China(approval No. 20111008001) in 2011.展开更多
Objective:To explore the clinical effect and adverse reactions of Strychnos nux-vomica in bortezomib-induced peripheral neuropathy(BIPN)of patients with multiple myeloma(MM).Methods:A total of 19 MM patients with BIPN...Objective:To explore the clinical effect and adverse reactions of Strychnos nux-vomica in bortezomib-induced peripheral neuropathy(BIPN)of patients with multiple myeloma(MM).Methods:A total of 19 MM patients with BIPN were enrolled and Nux Vomica Capsule(NVC,0.4 g,thrice daily)were orally administrated for 30 days.Comparative analysis on parameters between pre-and post-therapy,including peripheral neuropathy(PN)grade,neurotoxicity score,Chinese medicine(CM)syndrome score,total neuropathy score(TNS),coagulation function,and serum nerve growth factor(NGF)levels were conducted.The adverse events were monitored.Results:In BIPN of MM patients who received NVC,PN grade was lowered,neurotoxicity score was obviously decreased(P 0.01),and both CM syndrome score and TNS were remarkably decreased(P<0.01).After the therapy,activated partial thromboplastin time was prolonged(P<0.01)and fibrinogen was declined(P<0.05),showing improvement in the hypercoagulable state of patients.No significant difference of NGF recovery degrees was detected between pre-and post-therapy(P>0.05).No evident adverse reactions were observed during the course of treatment.Conclusion:Strychnos nux-vomica L.has significantly effect with a good safety in treatment of BIPN in MM patients.展开更多
It was hypothesized that mesenchymal stem cells(MSCs) could provide necessary trophic factors when seeded onto the surfaces of commonly used nerve graft substitutes. We aimed to determine the gene expression of MSCs w...It was hypothesized that mesenchymal stem cells(MSCs) could provide necessary trophic factors when seeded onto the surfaces of commonly used nerve graft substitutes. We aimed to determine the gene expression of MSCs when influenced by Avance~? Nerve Grafts or Neura Gen~? Nerve Guides. Human adipose-derived MSCs were cultured and dynamically seeded onto 30 Avance~? Nerve Grafts and 30 Neura Gen~? Nerve Guides for 12 hours. At six time points after seeding, quantitative polymerase chain reaction analyses were performed for five samples per group. Neurotrophic [nerve growth factor(NGF), glial cell line-derived neurotrophic factor(GDNF), pleiotrophin(PTN), growth associated protein 43(GAP43) and brain-derived neurotrophic factor(BDNF)], myelination [peripheral myelin protein 22(PMP22) and myelin protein zero(MPZ)], angiogenic [platelet endothelial cell adhesion molecule 1(PECAM1/CD31) and vascular endothelial cell growth factor alpha(VEGFA)], extracellular matrix(ECM) [collagen type alpha I(COL1A1), collagen type alpha III(COL3A1), Fibulin 1(FBLN1) and laminin subunit beta 2(LAMB2)] and cell surface marker cluster of differentiation 96(CD96) gene expression was quantified. Unseeded Avance~? Nerve Grafts and Neura Gen~? Nerve Guides were used to evaluate the baseline gene expression, and unseeded MSCs provided the baseline gene expression of MSCs. The interaction of MSCs with the Avance~? Nerve Grafts led to a short-term upregulation of neurotrophic(NGF, GDNF and BDNF), myelination(PMP22 and MPZ) and angiogenic genes(CD31 and VEGFA) and a long-term upregulation of BDNF, VEGFA and COL1A1. The interaction between MSCs and the Neura Gen~? Nerve Guide led to short term upregulation of neurotrophic(NGF, GDNF and BDNF) myelination(PMP22 and MPZ), angiogenic(CD31 and VEGFA), ECM(COL1A1) and cell surface(CD96) genes and long-term upregulation of neurotrophic(GDNF and BDNF), angiogenic(CD31 and VEGFA), ECM genes(COL1A1, COL3A1, and FBLN1) and cell surface(CD96) genes. Analysis demonstrated MSCs seeded onto Neura Gen~? Nerve Gu展开更多
Peripheral nerves have a limited capacity for self-repair and those that are severely damaged or have significant defects are challenging to repair. Investigating the pathophysiology of peripheral nerve repair is impo...Peripheral nerves have a limited capacity for self-repair and those that are severely damaged or have significant defects are challenging to repair. Investigating the pathophysiology of peripheral nerve repair is important for the clinical treatment of peripheral nerve repair and regeneration. In this study, rat models of right sciatic nerve injury were established by a clamping method. Protein chip assay was performed to quantify the levels of neurotrophic, inflammation-related, chemotaxis-related and cell generation-related factors in the sciatic nerve within 7 days after injury. The results revealed that the expression levels of neurotrophic factors(ciliary neurotrophic factor) and inflammationrelated factors(intercellular cell adhesion molecule-1, interferon γ, interleukin-1α, interleukin-2, interleukin-4, interleukin-6, monocyte chemoattractant protein-1, prolactin R, receptor of advanced glycation end products and tumor necrosis factor-α), chemotaxis-related factors(cytokine-induced neutrophil chemoattractant-1, L-selectin and platelet-derived growth factor-AA) and cell generation-related factors(granulocyte-macrophage colony-stimulating factor) followed different trajectories. These findings will help clarify the pathophysiology of sciatic nerve injury repair and develop clinical treatments of peripheral nerve injury. This study was approved by the Ethics Committee of Peking University People's Hospital of China(approval No. 2015-50) on December 9, 2015.展开更多
A new nerve matrix membrane derived from decellularized porcine nerves has been shown to retain the major extracellular matrix components, and to be effective in preventing adhesion between the nerve anastomosis sites...A new nerve matrix membrane derived from decellularized porcine nerves has been shown to retain the major extracellular matrix components, and to be effective in preventing adhesion between the nerve anastomosis sites and the surrounding tissues in a rat sciatic nerve transection model, thereby enhancing regeneration of the nerve. The effectiveness of the membrane may be attributed to its various bioactive components. In this prospective, randomized, single-blind, parallel-controlled multicenter clinical trial, we compared the safety and efficacy of the new nerve matrix membrane with a previously approved bovine tendon-derived type I collagen nerve wrapping. A total of 120 patients with peripheral nerve injury were recruited from Beijing Jishuitan Hospital, The First Bethune Hospital of Jilin University, and Yantai Yuhuangding Hospital, China. The patients were randomly assigned to undergo end-to-end and tension-free neurorrhaphy with nerve matrix membrane(n = 60, 52 male, 8 female, mean age 41.34 years, experimental group) or tendon-derived collagen nerve wrapping(n = 60, 42 male, 18 female, mean age 40.17 years, control group). Patients were followed-up at 14 ± 5, 30 ± 7, 90 ± 10 and 180 ± 20 days after the operation. Safety evaluation included analyses of local and systemic reactions, related laboratory tests, and adverse reactions. Efficacy evaluation included a static 2-point discrimination test, a moving 2-point discrimination test, and a Semmes–Weinstein monofilament examination. Sensory nerve function was evaluated with the British Medical Research Council Scale and Semmes–Weinstein monofilament examination. The ratio(percentage) of patients with excellent to good results in sensory nerve recovery 180 ± 20 days after the treatment was used as the primary effectiveness index. The percentages of patients with excellent to good results in the experimental and control groups were 98.00% and 94.44%, respectively, with no significant difference between the two groups. There were no significant differen展开更多
Due to the limitations in autogenous nerve grafting or Schwann cell transplantation,large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit.Cell based therapies provide a novel treat...Due to the limitations in autogenous nerve grafting or Schwann cell transplantation,large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit.Cell based therapies provide a novel treatment for peripheral nerve injuries.In this study,we first experimented an optimal scaffold material synthesis protocol,from where we selected the 10%GFD formula(10%GelMA hydrogel,recombinant human basic fibroblast growth factor and dental pulp stem cells(DPSCs))to fill a cellulose/soy protein isolate composite membrane(CSM)tube to construct a third generation of nerve regeneration conduit,CSM-GFD.Then this CSM-GFD conduit was applied to repair a 15-mm long defect of sciatic nerve in a rat model.After 12 week post implant surgery,at histologic level,we found CSM-GFD conduit could regenerate nerve tissue like neuron and Schwann like nerve cells and myelinated nerve fibers.At physical level,CSM-GFD achieved functional recovery assessed by a sciatic functional index study.In both levels,CSM-GFD performed like what gold standard,the nerve autograft,could do.Further,we unveiled that almost all newly formed nerve tissue at defect site was originated from the direct differentiation of exogeneous DPSCs in CSM-GFD.In conclusion,we claimed that this third-generation nerve regeneration conduit,CSM-GFD,could be a promising tissue engineering approach to replace the conventional nerve autograft to treat the large gap defect in peripheral nerve injuries.展开更多
Peripheral arterial disease(PAD)is a progressive atherosclerotic disorder characterized by narrowing and occlusion of arteries supplying the lower extremities.Approximately 200 million people worldwide are affected by...Peripheral arterial disease(PAD)is a progressive atherosclerotic disorder characterized by narrowing and occlusion of arteries supplying the lower extremities.Approximately 200 million people worldwide are affected by PAD.The current standard of operative care is open or endovascular revascularization in which blood flow restoration is the goal.However,many patients are not appropriate candidates for these treatments and are subject to continuous ischemia of their lower limbs.Current research in the therapy of PAD involves developing modalities that induce angiogenesis,but the results of simple cell transplantation or growth factor delivery have been found to be relatively poor mainly due to difficulties in stem cell retention and survival and rapid diffusion and enzymolysis of growth factors following injection of these agents in the affected tissues.Biomaterials,including hydrogels,have the capability to protect stem cells during injection and to support cell survival.Hydrogels can also provide a sustained release of growth factors at the injection site.This review will focus on biomaterial systems currently being investigated as carriers for cell and growth factor delivery,and will also discuss biomaterials as a potential stand-alone method for the treatment of PAD.Finally,the challenges of development and use of biomaterials systems for PAD treatment will be reviewed.展开更多
Conventional radiotherapy has a good killing effect on femoral echinococcosis.However,the sciatic nerve around the lesion is irreversibly damaged owing to bystander effects.Although intensity-modulated radiation thera...Conventional radiotherapy has a good killing effect on femoral echinococcosis.However,the sciatic nerve around the lesion is irreversibly damaged owing to bystander effects.Although intensity-modulated radiation therapy shows great advantages for precise dose distribution into lesions,it is unknown whether intensity-modulated radiation therapy can perfectly protect the surrounding sciatic nerve on the basis of good killing of femoral echinococcosis foci.Therefore,this study comparatively analyzed differences between intensity-modulated radiation therapy and conventional radiotherapy on the basis of safety to peripheral nerves.Pure-breed Meriones meridiani with bilateral femoral echinococcosis were selected as the research object.Intensity-modulated radiation therapy was used to treat left femoral echinococcosis of Meriones meridianus,while conventional radiotherapy was used to treat right femoral echinococcosis of the same Meriones meridianus.The total radiation dose was 40 Gy.To understand whether intensity-modulated radiation therapy and conventional radiotherapy can kill femoral echinococcosis,trypan blue staining was used to detect pathological changes of bone Echinococcus granulosus and protoscolex death after radiotherapy.Additionally,enzyme histochemical staining was utilized to measure acid phosphatase activity in the protoscolex after radiotherapy.One week after radiotherapy,the overall structure of echinococcosis in bilateral femurs of Meriones meridiani treated by intensity-modulated radiation therapy disappeared.There was no significant difference in the mortality rate of protoscoleces of Echinococcus granulosus between the bilateral femurs of Meriones meridiani.Moreover,there was no significant difference in acid phosphatase activity in the protoscolex of Echinococcus granulosus between bilateral femurs.To understand the injury of sciatic nerve surrounding the foci of femoral echinococcosis caused by intensity-modulated radiation therapy and conventional radiotherapy,the ultrastructure of sciatic ner展开更多
Encouraging results have been reported for the use of transcranial magnetic stimulationbased nerve stimulation in studies of the mechanisms of neurological regulation,nerve injury repair,and nerve localization.However...Encouraging results have been reported for the use of transcranial magnetic stimulationbased nerve stimulation in studies of the mechanisms of neurological regulation,nerve injury repair,and nerve localization.However,to date,there are only a few reviews on the use of transcranial magnetic stimulation for diabetic neuropathy.Patients with diabetic neuropathy vary in disease progression and show neuropathy in the early stage of the disease with mild symptoms,making it difficult to screen and identify.In the later stage of the disease,irreversible neurological damage occurs,resulting in treatment difficulties.In this review,we summarize the current state of diabetic neuropathy research and the prospects for the application of transcranial magnetic stimulation in diabetic neuropathy.We review significant studies on the beneficial effects of transcranial magnetic stimulation in diabetic neuropathy treatment,based on the outcomes of its use to treat neurodegeneration,pain,blood flow change,autonomic nervous disorders,vascular endothelial injury,and depression.Collectively,the studies suggest that transcranial magnetic stimulation can produce excitatory/inhibitory stimulation of the cerebral cortex or local areas,promote the remodeling of the nervous system,and that it has good application prospects for the localization of the injury,neuroprotection,and the promotion of nerve regeneration.Therefore,transcranial magnetic stimulation is useful for the screening and early treatment of diabetic neuropathy.transcranial magnetic stimulation can also alleviate pain symptoms by changing the cortical threshold and inhibiting the conduction of sensory information in the thalamo-spinal pathway,and therefore it has therapeutic potential for the treatment of pain and pain-related depressive symptoms in patients with diabetic neuropathy.Additionally,based on the effect of transcranial magnetic stimulation on local blood flow and its ability to change heart rate and urine protein content,transcranial magnetic stimulation has potentia展开更多
Microglia and macrophages in the development of maladaptive plastic changes after peripheral nerve injury:Microglia and macrophages encompass the innate immune response to injury in the central and peripheral nervous ...Microglia and macrophages in the development of maladaptive plastic changes after peripheral nerve injury:Microglia and macrophages encompass the innate immune response to injury in the central and peripheral nervous systems,respectively,and are intimately involved in the pathogenesis of maladaptive changes(Tsuda,2019).These dynamic cells can influence neuronal activity in active and quiescent states.Conflicting findings argue that peripheral macrophages facilitate the development of nerve injury-induced neuropathic pain,as opposed to central microglia(Lopes et al.,2017;Yu et al.,2020).展开更多
Veins are easy to obtain,have low immunogenicity,and induce a relatively weak inflammatory response.Therefore,veins have the potential to be used as conduits for nerve regeneration.However,because of the presence of v...Veins are easy to obtain,have low immunogenicity,and induce a relatively weak inflammatory response.Therefore,veins have the potential to be used as conduits for nerve regeneration.However,because of the presence of venous valves and the great elasticity of the venous wall,the vein is not conducive to nerve regeneration.In this study,a novel tissue engineered nerve graft was constructed by combining normal dissected nerve microtissue with an autologous vein graft for repairing 10-mm peripheral nerve defects in rats.Compared with rats given the vein graft alone,rats given the tissue engineered nerve graft had an improved sciatic static index,and a higher amplitude and shorter latency of compound muscle action potentials.Furthermore,rats implanted with the microtissue graft had a higher density and thickness of myelinated nerve fibers and reduced gastrocnemius muscle atrophy compared with rats implanted with the vein alone.However,the tissue engineered nerve graft had a lower ability to repair the defect than autogenous nerve transplantation.In summary,although the tissue engineered nerve graft constructed with autologous vein and nerve microtissue is not as effective as autologous nerve transplantation for repairing long-segment sciatic nerve defects,it may nonetheless have therapeutic potential for the clinical repair of long sciatic nerve defects.This study was approved by the Experimental Animal Ethics Committee of Chinese PLA General Hospital(approval No.2016-x9-07)on September 7,2016.展开更多
A main cause of vision loss in the elderly is age-related macular degeneration(AMD).Among the cellular,biochemical,and molecular changes linked to this disease,inflammation and angiogenesis appear as being crucial in ...A main cause of vision loss in the elderly is age-related macular degeneration(AMD).Among the cellular,biochemical,and molecular changes linked to this disease,inflammation and angiogenesis appear as being crucial in AMD pathogenesis and progression.There are two forms of the disease:dry AMD,accounting for 80–90%of cases,and wet AMD.The disease usually begins as dry AMD associated with retinal pigment epithelium and photoreceptor degeneration,whereas wet AMD is associated with choroidal neovascularization resulting in severe vision impairment.The new vessels are largely malformed,leading to blood and fluid leakage within the disrupted tissue,which provokes inflammation and scar formation and results in retinal damage and detachment.Micro RNAs are dysregulated in AMD and may facilitate the early detection of the disease and monitoring disease progression.Two recent reviews of micro RNAs in AMD had indicated weaknesses or limitations in four earlier investigations.Studies in the last three years have shown considerable progress in overcoming some of these concerns and identifying specific micro RNAs as biomarkers for AMD.Further large-scale studies are warranted using appropriate statistical methods to take into account gender and age disparity in the study populations and confounding factors such as smoking status.展开更多
Acrylamide has been shown to be neurotoxic.Brain-derived neurotrophic factor(BDNF)can alleviate acrylamide-induced synaptic injury;however,the underlying mechanism remains unclear.In this study,dibutyryl-cyclic adenos...Acrylamide has been shown to be neurotoxic.Brain-derived neurotrophic factor(BDNF)can alleviate acrylamide-induced synaptic injury;however,the underlying mechanism remains unclear.In this study,dibutyryl-cyclic adenosine monophosphate-induced mature human neuroblastoma(NB-1)cells were exposed with 0–100μg/mL acrylamide for 24–72 hours.Acrylamide decreased cell viability and destroyed synapses.Exposure of co-cultured NB-1 cells and Schwann cells to 0–100μg/mL acrylamide for 48 hours resulted in upregulated expression of synapsin I and BDNF,suggesting that Schwann cells can activate self-protection of neurons.Under co-culture conditions,activation of the downstream TrkB-MAPK-Erk1/2 pathway strengthened the protective effect.Exogenous BDNF can increase expression of TrkB,Erk1/2,and synapsin I,while exogenous BDNF or the TrkB inhibitor K252a could inhibit these changes.Taken together,Schwann cells may act through the BDNF-TrkB-MAPK-Erk1/2 signaling pathway,indicating that BDNF plays an important role in this process.Therefore,exogenous BDNF may be an effective treatment strategy for acrylamide-induced nerve injury.This study was approved by the Laboratory Animal Welfare and Ethics Committee of the National Institute of Occupational Health and Poison Control,a division of the Chinese Center for Disease Control and Prevention(approval No.EAWE-2017-008)on May 29,2017.展开更多
In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced...In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced and exaggerate during walking,and is relieved by rest.This symptom is termed by intermittent claudication.The limb ischemia also amplifies autonomic responses during exercise.In the process of pain and autonomic responses originating exercising muscle,a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses.This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle.For the sensory nerve receptors,we emphasize the role played by transient receptor potential vanilloid type 1,purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.展开更多
Wallerian degeneration occurs after peripheral nerve injury and provides a beneficial microenvironment for nerve regeneration.Our previous study demonstrated that ascorbic acid promotes peripheral nerve regeneration,p...Wallerian degeneration occurs after peripheral nerve injury and provides a beneficial microenvironment for nerve regeneration.Our previous study demonstrated that ascorbic acid promotes peripheral nerve regeneration,possibly through promoting Schwann cell proliferation and phagocytosis and enhancing macrophage proliferation,migration,and phagocytosis.Because Schwann cells and macrophages are the main cells involved in Wallerian degeneration,we speculated that ascorbic acid may accelerate this degenerative process.To test this hypothesis,400 mg/kg ascorbic acid was administered intragastrically immediately after sciatic nerve transection,and 200 mg/kg ascorbic acid was then administered intragastrically every day.In addition,rat sciatic nerve explants were treated with 200μM ascorbic acid.Ascorbic acid significantly accelerated the degradation of myelin basic protein-positive myelin and neurofilament 200-positive axons in both the transected nerves and nerve explants.Furthermore,ascorbic acid inhibited myelin-associated glycoprotein expression,increased c-Jun expression in Schwann cells,and increased both the number of macrophages and the amount of myelin fragments in the macrophages.These findings suggest that ascorbic acid accelerates Wallerian degeneration by accelerating the degeneration of axons and myelin in the injured nerve,promoting the dedifferentiation of Schwann cells,and enhancing macrophage recruitment and phagocytosis.The study was approved by the Southern Medical University Animal Care and Use Committee(approval No.SMU-L2015081)on October 15,2015.展开更多
Pannexin 1(Panx 1),as a large-pore membrane channel,is highly permeable to ATP and other signaling molecules.Previous studies have demonstrated the expression of Panx 1 in the nervous system,including astrocytes,micro...Pannexin 1(Panx 1),as a large-pore membrane channel,is highly permeable to ATP and other signaling molecules.Previous studies have demonstrated the expression of Panx 1 in the nervous system,including astrocytes,microglia,and neurons.However,the distribution and function of Panx 1 in the peripheral nervous system are not clear.Blocking the function of Panx 1 pharmacologically(carbenoxolone and probenecid)or with small interfering RNA targeting pannexins can greatly reduce hypotonicity-induced ATP release.Treatment of Schwann cells with a Ras homolog family member(Rho)GTPase inhibitor and small interfering RNA targeting Rho or cytoskeleton disrupting agents,such as nocodazole or cytochalasin D,revealed that hypotonicity-induced ATP release depended on intracellular RhoA and the cytoskeleton.These findings suggest that Panx 1 participates in ATP release in Schwann cells by regulating RhoA and the cytoskeleton arrangement.This study was approved by the Animal Ethics Committee of Nantong University,China(No.S20180806-002)on August 5,2018.展开更多
We previously demonstrated that gene-modified umbilical cord blood mononuclear cells overexpressing a combination of recombinant neurotrophic factors are a promising therapeutic approach for cell-mediated gene therapy...We previously demonstrated that gene-modified umbilical cord blood mononuclear cells overexpressing a combination of recombinant neurotrophic factors are a promising therapeutic approach for cell-mediated gene therapy for neurodegenerative diseases,neurotrauma,and stroke.In this study,using a mini pig model of spinal cord injury,we proposed for the first time the use of gene-modified leucoconcentrate prepared from peripheral blood in the plastic blood bag for personalized ex vivo gene therapy.Leucoconcentrate obtained from mini pig peripheral blood was transduced with a chimeric adenoviral vector(Ad5/35 F)that carried an enhanced green fluorescent protein(EGFP)reporter gene in the plastic blood bag.The day after blood donation,the mini pigs were subjected to moderate SCI and four hours post-surgery they were intravenously autoinfused with gene-modified leucoconcentrate.A week after gene-modified leucoconcentrate therapy,fluorescent microscopy revealed EGFP-expressing leucocytes in spinal cord at the site of contusion injury.In the spleen the groups of EGFP-positive cells located in the lymphoid follicles were observed.In vitro flow cytometry and fluorescent microscopy studies of the gene-modified leucoconcentrate samples also confirmed the production of EGFP by leucocytes.Thus,the efficacy of leucocytes transduction in the plastic blood bag and their migratory potential suggest their use for temporary production of recombinant biologically active molecules to correct certain pathological conditions.This paper presents a proof-of-concept of simple,safe and effective approach for personalized ex vivo gene therapy based on gene-modified leucoconcentrate autoinfusion.The animal protocols were approved by the Kazan State Medical University Animal Care and Use Committee(approval No.5)on May 27,2014.展开更多
Vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) are well-known growth factors involved in the regeneration of various tissues and organs, including peripheral nerve system. In the present...Vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) are well-known growth factors involved in the regeneration of various tissues and organs, including peripheral nerve system. In the present study, we elucidated the local and systemic effects of plasmid construct рBud-coVEGF165-coFGF2 injected into the epineurium of intact rat sciatic nerve. Results of histological examination of sciatic nerve and multiplex immunoassays of serum showed the absence of immunogenicity and biosafety of plasmid рBud-coVEGF165-coFGF2. Moreover, local administration of plasmid DNA construct resulted in significantly decreased levels of pro-inflammatory cytokines in the peripheral blood, including tumor necrosis factor α(TNFα) and interleukin-12, and significantly increased levels of cytokines and chemokines including Regulated upon Activation, Normal T Cell Expressed and Presumably Secrete(RANTES), epidermal growth factor, interleukin-2, and monocyte chemoattractant protein 1. These changes in the peripheral blood on day 7 after injection of plasmid construct рBud-coVEGF165-coFGF2 show that the plasmid construct has systemic effects and may modulate immune response. At the same time, reverse transcriptionpolymerase chain reaction revealed transient expression of coFGF2, coVEGF165, ratFGF2 and ratVEGFA with direct transport of transcripts from distal part to proximal part of the sciatic nerve. Immunohistochemical staining revealed prolonged presence of VEGFA in sciatic nerve till 14 days post-injection. These findings suggest that local administration of plasmid construct рBud-coVEGF165-coFGF2 at a concentration of 30 ng/μL results in the formation of pro-angiogenic stimuli and, and the plasmid construct, used as a drug for gene therapy, might potentially facilitate regeneration of the sciatic nerve. The study was approved by the Animal Ethics Committee of Kazan Federal University, procedures were approved by the Local Ethics Committee(approval No. 5) on May 27, 2014.展开更多
Massage therapy is an alternative treatment for chronic pain that is potentially related to brain plasticity.However,the underlying mechanism remains unclear.We established a peripheral nerve injury model in rats by u...Massage therapy is an alternative treatment for chronic pain that is potentially related to brain plasticity.However,the underlying mechanism remains unclear.We established a peripheral nerve injury model in rats by unilateral sciatic nerve transection and direct anastomosis.The experimental rats were treated over the gastrocnemius muscle of the affected hindlimb with a customized massage instrument(0.45 N,120 times/min,10 minutes daily,for 4 successive weeks).Resting-state functional magnetic resonance imaging revealed that compared with control rats,the amplitude of low-frequency fluctuations in the sensorimotor cortex contralateral to the affected limb was significantly lower after sciatic nerve transection.However,amplitudes were significantly higher in the massage group than in a sham-massage group.These findings suggest that massage therapy facilitated adaptive change in the somatosensory cortex that led to the recovery of peripheral nerve injury and repair.This study was approved by the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine of China(approval No.201701001)on January 12,2017.展开更多
基金supported by the National Natural Science Foundation of China,No.31971276(to JHH)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(Major Program),No.19KJA320005(to JHH)。
文摘Studies have shown that microRNAs(miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is hard to select key miRNAs with essential biological functions among a large number of differentially expressed miRNAs. Previously, we collected injured sciatic nerve stumps at multiple time points after nerve crush injury, examined gene changes at different stages(acute, sub-acute, and post-acute), and obtained mRNA expression profiles. Here, we jointly analyzed mRNAs and miRNAs, and investigated upstream miRNAs of differentially expressed mRNAs using Ingenuity Pathway Analysis bioinformatic software. A total of 31, 42, 30, and 23 upstream miRNAs were identified at 1, 4, 7, and 14 days after rat sciatic nerve injury, respectively. Temporal expression patterns and biological involvement of commonly involved upstream miRNAs(miR-21, let-7, miR-223, miR-10 b, miR-132, miR-15 b, miR-127, miR-29 a, miR-29 b, and miR-9) were then determined at multiple time points. Expression levels of miR-21, miR-132, miR-29 a, and miR-29 b were robustly increased after sciatic nerve injury. Biological processes involving these miRNAs include multicellular organismal response to stress, positive regulation of the epidermal growth factor receptor signaling pathway, negative regulation of epithelial cell differentiation, and regulation of myocardial tissue growth. Moreover, we constructed mechanistic networks of let-7, miR-21, and miR-223, the most significantly involved upstream miRNAs. Our findings reveal that multiple upstream miRNAs(i.e., let-7, miR-21, and miR-223) were associated with gene expression changes in rat sciatic nerve stumps after nerve injury, and these miRNAs play an important role in peripheral nerve regeneration. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China(approval No. 20190303-18) on March 3, 2019.
基金supported by the National Natural Science Foundation of China,No. 81971165the National Basic Research Program of China (973 Program),No. 2014CB542205 (both to WW)。
文摘Both intracellular sigma peptide(ISP) and phosphatase and tensin homolog agonist protein(PAP4) promote nerve regeneration and motor functional recovery after spinal cord injury. However, the role of these two small peptides in peripheral nerve injury remains unclear. A rat model of brachial plexus injury was established by crush of the C6 ventral root. The rats were then treated with subcutaneous injection of PAP4(497 μg/d, twice per day) or ISP(11 μg/d, once per day) near the injury site for 21 successive days. After ISP and PAP treatment, the survival of motoneurons was increased, the number of regenerated axons and neuromuscular junctions was increased, muscle atrophy was reduced, the electrical response of the motor units was enhanced and the motor function of the injured upper limbs was greatly improved in rats with brachial plexus injury. These findings suggest that ISP and PAP4 promote the recovery of motor function after peripheral nerve injury in rats. The animal care and experimental procedures were approved by the Laboratory Animal Ethics Committee of Jinan University of China(approval No. 20111008001) in 2011.
基金Supported by Zhejiang Province Traditional Chinese Medicine Scientific Research Fund Project(No.2015ZA094)。
文摘Objective:To explore the clinical effect and adverse reactions of Strychnos nux-vomica in bortezomib-induced peripheral neuropathy(BIPN)of patients with multiple myeloma(MM).Methods:A total of 19 MM patients with BIPN were enrolled and Nux Vomica Capsule(NVC,0.4 g,thrice daily)were orally administrated for 30 days.Comparative analysis on parameters between pre-and post-therapy,including peripheral neuropathy(PN)grade,neurotoxicity score,Chinese medicine(CM)syndrome score,total neuropathy score(TNS),coagulation function,and serum nerve growth factor(NGF)levels were conducted.The adverse events were monitored.Results:In BIPN of MM patients who received NVC,PN grade was lowered,neurotoxicity score was obviously decreased(P 0.01),and both CM syndrome score and TNS were remarkably decreased(P<0.01).After the therapy,activated partial thromboplastin time was prolonged(P<0.01)and fibrinogen was declined(P<0.05),showing improvement in the hypercoagulable state of patients.No significant difference of NGF recovery degrees was detected between pre-and post-therapy(P>0.05).No evident adverse reactions were observed during the course of treatment.Conclusion:Strychnos nux-vomica L.has significantly effect with a good safety in treatment of BIPN in MM patients.
基金supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (No. R01NS102360)。
文摘It was hypothesized that mesenchymal stem cells(MSCs) could provide necessary trophic factors when seeded onto the surfaces of commonly used nerve graft substitutes. We aimed to determine the gene expression of MSCs when influenced by Avance~? Nerve Grafts or Neura Gen~? Nerve Guides. Human adipose-derived MSCs were cultured and dynamically seeded onto 30 Avance~? Nerve Grafts and 30 Neura Gen~? Nerve Guides for 12 hours. At six time points after seeding, quantitative polymerase chain reaction analyses were performed for five samples per group. Neurotrophic [nerve growth factor(NGF), glial cell line-derived neurotrophic factor(GDNF), pleiotrophin(PTN), growth associated protein 43(GAP43) and brain-derived neurotrophic factor(BDNF)], myelination [peripheral myelin protein 22(PMP22) and myelin protein zero(MPZ)], angiogenic [platelet endothelial cell adhesion molecule 1(PECAM1/CD31) and vascular endothelial cell growth factor alpha(VEGFA)], extracellular matrix(ECM) [collagen type alpha I(COL1A1), collagen type alpha III(COL3A1), Fibulin 1(FBLN1) and laminin subunit beta 2(LAMB2)] and cell surface marker cluster of differentiation 96(CD96) gene expression was quantified. Unseeded Avance~? Nerve Grafts and Neura Gen~? Nerve Guides were used to evaluate the baseline gene expression, and unseeded MSCs provided the baseline gene expression of MSCs. The interaction of MSCs with the Avance~? Nerve Grafts led to a short-term upregulation of neurotrophic(NGF, GDNF and BDNF), myelination(PMP22 and MPZ) and angiogenic genes(CD31 and VEGFA) and a long-term upregulation of BDNF, VEGFA and COL1A1. The interaction between MSCs and the Neura Gen~? Nerve Guide led to short term upregulation of neurotrophic(NGF, GDNF and BDNF) myelination(PMP22 and MPZ), angiogenic(CD31 and VEGFA), ECM(COL1A1) and cell surface(CD96) genes and long-term upregulation of neurotrophic(GDNF and BDNF), angiogenic(CD31 and VEGFA), ECM genes(COL1A1, COL3A1, and FBLN1) and cell surface(CD96) genes. Analysis demonstrated MSCs seeded onto Neura Gen~? Nerve Gu
基金supported by the National Key Research and Development Program of China,No. 2016YFC1101604 (to YHK)the Fundamental Research Funds for the Central Universities,Clinical Medicine Plus X-Young Scholars Project of Peking University,No. PKU2020LCXQ020 (to YHK)+2 种基金the Key Laboratory of Trauma and Neural Regeneration (Peking University),Ministry of Education of China,No. BMU2019XY007-01 (to YHK)Guangdong Basic and Applied Basic Research Foundation of China,Nos. 2019A1515110983 (to FY) and 2019A1515011290 (to FY)Shenzhen “San-Ming” Project of Medicine of China,No. SZSM201612092 (to FY)。
文摘Peripheral nerves have a limited capacity for self-repair and those that are severely damaged or have significant defects are challenging to repair. Investigating the pathophysiology of peripheral nerve repair is important for the clinical treatment of peripheral nerve repair and regeneration. In this study, rat models of right sciatic nerve injury were established by a clamping method. Protein chip assay was performed to quantify the levels of neurotrophic, inflammation-related, chemotaxis-related and cell generation-related factors in the sciatic nerve within 7 days after injury. The results revealed that the expression levels of neurotrophic factors(ciliary neurotrophic factor) and inflammationrelated factors(intercellular cell adhesion molecule-1, interferon γ, interleukin-1α, interleukin-2, interleukin-4, interleukin-6, monocyte chemoattractant protein-1, prolactin R, receptor of advanced glycation end products and tumor necrosis factor-α), chemotaxis-related factors(cytokine-induced neutrophil chemoattractant-1, L-selectin and platelet-derived growth factor-AA) and cell generation-related factors(granulocyte-macrophage colony-stimulating factor) followed different trajectories. These findings will help clarify the pathophysiology of sciatic nerve injury repair and develop clinical treatments of peripheral nerve injury. This study was approved by the Ethics Committee of Peking University People's Hospital of China(approval No. 2015-50) on December 9, 2015.
基金supported by the Wu Jieping Medical Foundation of China,No. 320.6750.17273 (to YBG)。
文摘A new nerve matrix membrane derived from decellularized porcine nerves has been shown to retain the major extracellular matrix components, and to be effective in preventing adhesion between the nerve anastomosis sites and the surrounding tissues in a rat sciatic nerve transection model, thereby enhancing regeneration of the nerve. The effectiveness of the membrane may be attributed to its various bioactive components. In this prospective, randomized, single-blind, parallel-controlled multicenter clinical trial, we compared the safety and efficacy of the new nerve matrix membrane with a previously approved bovine tendon-derived type I collagen nerve wrapping. A total of 120 patients with peripheral nerve injury were recruited from Beijing Jishuitan Hospital, The First Bethune Hospital of Jilin University, and Yantai Yuhuangding Hospital, China. The patients were randomly assigned to undergo end-to-end and tension-free neurorrhaphy with nerve matrix membrane(n = 60, 52 male, 8 female, mean age 41.34 years, experimental group) or tendon-derived collagen nerve wrapping(n = 60, 42 male, 18 female, mean age 40.17 years, control group). Patients were followed-up at 14 ± 5, 30 ± 7, 90 ± 10 and 180 ± 20 days after the operation. Safety evaluation included analyses of local and systemic reactions, related laboratory tests, and adverse reactions. Efficacy evaluation included a static 2-point discrimination test, a moving 2-point discrimination test, and a Semmes–Weinstein monofilament examination. Sensory nerve function was evaluated with the British Medical Research Council Scale and Semmes–Weinstein monofilament examination. The ratio(percentage) of patients with excellent to good results in sensory nerve recovery 180 ± 20 days after the treatment was used as the primary effectiveness index. The percentages of patients with excellent to good results in the experimental and control groups were 98.00% and 94.44%, respectively, with no significant difference between the two groups. There were no significant differen
基金supported by the National Natural Science Funding of China(81701032,81871503)the Wenzhou Science and Technology Association Project,the Wenzhou Major Scientific and Technological Innovation Key Medical and Health Project(ZY2019010)+4 种基金the Wenzhou Medical University grant(QTJ16026)Wenzhou Science and Technology Association Project,Wenzhou Basic Research Project(Y20180131)Zhejiang Province Program of the Medical and Health Science and Technology(2018KY537)Zhejiang Natural Science Foundation(LGF18C100002)Zhejiang Xinmiao Talents Program(2018R413186).
文摘Due to the limitations in autogenous nerve grafting or Schwann cell transplantation,large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit.Cell based therapies provide a novel treatment for peripheral nerve injuries.In this study,we first experimented an optimal scaffold material synthesis protocol,from where we selected the 10%GFD formula(10%GelMA hydrogel,recombinant human basic fibroblast growth factor and dental pulp stem cells(DPSCs))to fill a cellulose/soy protein isolate composite membrane(CSM)tube to construct a third generation of nerve regeneration conduit,CSM-GFD.Then this CSM-GFD conduit was applied to repair a 15-mm long defect of sciatic nerve in a rat model.After 12 week post implant surgery,at histologic level,we found CSM-GFD conduit could regenerate nerve tissue like neuron and Schwann like nerve cells and myelinated nerve fibers.At physical level,CSM-GFD achieved functional recovery assessed by a sciatic functional index study.In both levels,CSM-GFD performed like what gold standard,the nerve autograft,could do.Further,we unveiled that almost all newly formed nerve tissue at defect site was originated from the direct differentiation of exogeneous DPSCs in CSM-GFD.In conclusion,we claimed that this third-generation nerve regeneration conduit,CSM-GFD,could be a promising tissue engineering approach to replace the conventional nerve autograft to treat the large gap defect in peripheral nerve injuries.
基金supported by funds from University of Nebraska Medical Center,American Heart Association Career Development Award(18CDA34110314)Nebraska Stem Cell Research Project(NE LB606)and R01AG062198+1 种基金support by a grant from the National Institute of General Medical Sciences,1U54GM115458the UNMC Center for Heart and Vascular Research。
文摘Peripheral arterial disease(PAD)is a progressive atherosclerotic disorder characterized by narrowing and occlusion of arteries supplying the lower extremities.Approximately 200 million people worldwide are affected by PAD.The current standard of operative care is open or endovascular revascularization in which blood flow restoration is the goal.However,many patients are not appropriate candidates for these treatments and are subject to continuous ischemia of their lower limbs.Current research in the therapy of PAD involves developing modalities that induce angiogenesis,but the results of simple cell transplantation or growth factor delivery have been found to be relatively poor mainly due to difficulties in stem cell retention and survival and rapid diffusion and enzymolysis of growth factors following injection of these agents in the affected tissues.Biomaterials,including hydrogels,have the capability to protect stem cells during injection and to support cell survival.Hydrogels can also provide a sustained release of growth factors at the injection site.This review will focus on biomaterial systems currently being investigated as carriers for cell and growth factor delivery,and will also discuss biomaterials as a potential stand-alone method for the treatment of PAD.Finally,the challenges of development and use of biomaterials systems for PAD treatment will be reviewed.
基金supported by the China Postdoctoral Science Foundation,No.2019M652397(to WLX)。
文摘Conventional radiotherapy has a good killing effect on femoral echinococcosis.However,the sciatic nerve around the lesion is irreversibly damaged owing to bystander effects.Although intensity-modulated radiation therapy shows great advantages for precise dose distribution into lesions,it is unknown whether intensity-modulated radiation therapy can perfectly protect the surrounding sciatic nerve on the basis of good killing of femoral echinococcosis foci.Therefore,this study comparatively analyzed differences between intensity-modulated radiation therapy and conventional radiotherapy on the basis of safety to peripheral nerves.Pure-breed Meriones meridiani with bilateral femoral echinococcosis were selected as the research object.Intensity-modulated radiation therapy was used to treat left femoral echinococcosis of Meriones meridianus,while conventional radiotherapy was used to treat right femoral echinococcosis of the same Meriones meridianus.The total radiation dose was 40 Gy.To understand whether intensity-modulated radiation therapy and conventional radiotherapy can kill femoral echinococcosis,trypan blue staining was used to detect pathological changes of bone Echinococcus granulosus and protoscolex death after radiotherapy.Additionally,enzyme histochemical staining was utilized to measure acid phosphatase activity in the protoscolex after radiotherapy.One week after radiotherapy,the overall structure of echinococcosis in bilateral femurs of Meriones meridiani treated by intensity-modulated radiation therapy disappeared.There was no significant difference in the mortality rate of protoscoleces of Echinococcus granulosus between the bilateral femurs of Meriones meridiani.Moreover,there was no significant difference in acid phosphatase activity in the protoscolex of Echinococcus granulosus between bilateral femurs.To understand the injury of sciatic nerve surrounding the foci of femoral echinococcosis caused by intensity-modulated radiation therapy and conventional radiotherapy,the ultrastructure of sciatic ner
基金This work was financially supported by the Science and Technology Project of Nantong City of China,No.JC2018060(to XX).
文摘Encouraging results have been reported for the use of transcranial magnetic stimulationbased nerve stimulation in studies of the mechanisms of neurological regulation,nerve injury repair,and nerve localization.However,to date,there are only a few reviews on the use of transcranial magnetic stimulation for diabetic neuropathy.Patients with diabetic neuropathy vary in disease progression and show neuropathy in the early stage of the disease with mild symptoms,making it difficult to screen and identify.In the later stage of the disease,irreversible neurological damage occurs,resulting in treatment difficulties.In this review,we summarize the current state of diabetic neuropathy research and the prospects for the application of transcranial magnetic stimulation in diabetic neuropathy.We review significant studies on the beneficial effects of transcranial magnetic stimulation in diabetic neuropathy treatment,based on the outcomes of its use to treat neurodegeneration,pain,blood flow change,autonomic nervous disorders,vascular endothelial injury,and depression.Collectively,the studies suggest that transcranial magnetic stimulation can produce excitatory/inhibitory stimulation of the cerebral cortex or local areas,promote the remodeling of the nervous system,and that it has good application prospects for the localization of the injury,neuroprotection,and the promotion of nerve regeneration.Therefore,transcranial magnetic stimulation is useful for the screening and early treatment of diabetic neuropathy.transcranial magnetic stimulation can also alleviate pain symptoms by changing the cortical threshold and inhibiting the conduction of sensory information in the thalamo-spinal pathway,and therefore it has therapeutic potential for the treatment of pain and pain-related depressive symptoms in patients with diabetic neuropathy.Additionally,based on the effect of transcranial magnetic stimulation on local blood flow and its ability to change heart rate and urine protein content,transcranial magnetic stimulation has potentia
基金supported by NIH grant K22NS096030(MDB)American Pain Society Future Leaders Grant(MDB)+1 种基金Rita Allen Foundation Award in Pain(MDB)The University of Texas System STARS program research support grant(MDB).
文摘Microglia and macrophages in the development of maladaptive plastic changes after peripheral nerve injury:Microglia and macrophages encompass the innate immune response to injury in the central and peripheral nervous systems,respectively,and are intimately involved in the pathogenesis of maladaptive changes(Tsuda,2019).These dynamic cells can influence neuronal activity in active and quiescent states.Conflicting findings argue that peripheral macrophages facilitate the development of nerve injury-induced neuropathic pain,as opposed to central microglia(Lopes et al.,2017;Yu et al.,2020).
基金This work was supported by the National Natural Science Foundation of China,Nos.31771052(to YW),81671684(to YXW),81871788(to CZ)National Key Research and Development Program of China,Nos.2017YFA0104702,2017YFA0104703+3 种基金the Natural Science Foundation of Beijing of China,No.7172202(to YW)PLA Youth Training Project for Medical Science of China,No.16QNP144(to YW),the Project for Science and Technology Leader of Anhui Province of China,No.2018H177(to CZ)Funding of“Panfeng”Innovation Team Project for Scientifc Research of Yijishan Hospital,Wannan Medical College,China,No.PF2019007(to HGX)Funding of“Peak”Training Program for Scientifc Research of Yijishan Hospital,Wannan Medical College,China,No.GF2019T02(to HGX).
文摘Veins are easy to obtain,have low immunogenicity,and induce a relatively weak inflammatory response.Therefore,veins have the potential to be used as conduits for nerve regeneration.However,because of the presence of venous valves and the great elasticity of the venous wall,the vein is not conducive to nerve regeneration.In this study,a novel tissue engineered nerve graft was constructed by combining normal dissected nerve microtissue with an autologous vein graft for repairing 10-mm peripheral nerve defects in rats.Compared with rats given the vein graft alone,rats given the tissue engineered nerve graft had an improved sciatic static index,and a higher amplitude and shorter latency of compound muscle action potentials.Furthermore,rats implanted with the microtissue graft had a higher density and thickness of myelinated nerve fibers and reduced gastrocnemius muscle atrophy compared with rats implanted with the vein alone.However,the tissue engineered nerve graft had a lower ability to repair the defect than autogenous nerve transplantation.In summary,although the tissue engineered nerve graft constructed with autologous vein and nerve microtissue is not as effective as autologous nerve transplantation for repairing long-segment sciatic nerve defects,it may nonetheless have therapeutic potential for the clinical repair of long sciatic nerve defects.This study was approved by the Experimental Animal Ethics Committee of Chinese PLA General Hospital(approval No.2016-x9-07)on September 7,2016.
文摘A main cause of vision loss in the elderly is age-related macular degeneration(AMD).Among the cellular,biochemical,and molecular changes linked to this disease,inflammation and angiogenesis appear as being crucial in AMD pathogenesis and progression.There are two forms of the disease:dry AMD,accounting for 80–90%of cases,and wet AMD.The disease usually begins as dry AMD associated with retinal pigment epithelium and photoreceptor degeneration,whereas wet AMD is associated with choroidal neovascularization resulting in severe vision impairment.The new vessels are largely malformed,leading to blood and fluid leakage within the disrupted tissue,which provokes inflammation and scar formation and results in retinal damage and detachment.Micro RNAs are dysregulated in AMD and may facilitate the early detection of the disease and monitoring disease progression.Two recent reviews of micro RNAs in AMD had indicated weaknesses or limitations in four earlier investigations.Studies in the last three years have shown considerable progress in overcoming some of these concerns and identifying specific micro RNAs as biomarkers for AMD.Further large-scale studies are warranted using appropriate statistical methods to take into account gender and age disparity in the study populations and confounding factors such as smoking status.
基金This study was supported by the National Natural Science Foundation of China,Nos.81773474 and 81273110(to BL)the National Key Research and Development Project of China,No.2017YFF0211201(to BL).
文摘Acrylamide has been shown to be neurotoxic.Brain-derived neurotrophic factor(BDNF)can alleviate acrylamide-induced synaptic injury;however,the underlying mechanism remains unclear.In this study,dibutyryl-cyclic adenosine monophosphate-induced mature human neuroblastoma(NB-1)cells were exposed with 0–100μg/mL acrylamide for 24–72 hours.Acrylamide decreased cell viability and destroyed synapses.Exposure of co-cultured NB-1 cells and Schwann cells to 0–100μg/mL acrylamide for 48 hours resulted in upregulated expression of synapsin I and BDNF,suggesting that Schwann cells can activate self-protection of neurons.Under co-culture conditions,activation of the downstream TrkB-MAPK-Erk1/2 pathway strengthened the protective effect.Exogenous BDNF can increase expression of TrkB,Erk1/2,and synapsin I,while exogenous BDNF or the TrkB inhibitor K252a could inhibit these changes.Taken together,Schwann cells may act through the BDNF-TrkB-MAPK-Erk1/2 signaling pathway,indicating that BDNF plays an important role in this process.Therefore,exogenous BDNF may be an effective treatment strategy for acrylamide-induced nerve injury.This study was approved by the Laboratory Animal Welfare and Ethics Committee of the National Institute of Occupational Health and Poison Control,a division of the Chinese Center for Disease Control and Prevention(approval No.EAWE-2017-008)on May 29,2017.
基金This work was supported by the National Institutes of Health,No.NIH P01 HL134609 and R01 HL141198(to JL).
文摘In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced and exaggerate during walking,and is relieved by rest.This symptom is termed by intermittent claudication.The limb ischemia also amplifies autonomic responses during exercise.In the process of pain and autonomic responses originating exercising muscle,a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses.This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle.For the sensory nerve receptors,we emphasize the role played by transient receptor potential vanilloid type 1,purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.
基金supported by the National Natural Science Foundation of China,Nos.81870982&81571182the Program for Changjiang Scholars and Innovative Research Team in Universities of China,No.IRT-16R37+4 种基金the National Key Basic Research Program of China,No.2014CB542202the Science and Technology Project of Guangdong Province of China,No.2015A020212024Key Research&Development Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory of China,No.2018GZR110104008the Natural Science Foundation of Guangdong Province of China,No.2017A030312009Research Grant of Guangdong Province Key Laboratory of Psychiatric Disorders of China,No.N201904(all to JG).
文摘Wallerian degeneration occurs after peripheral nerve injury and provides a beneficial microenvironment for nerve regeneration.Our previous study demonstrated that ascorbic acid promotes peripheral nerve regeneration,possibly through promoting Schwann cell proliferation and phagocytosis and enhancing macrophage proliferation,migration,and phagocytosis.Because Schwann cells and macrophages are the main cells involved in Wallerian degeneration,we speculated that ascorbic acid may accelerate this degenerative process.To test this hypothesis,400 mg/kg ascorbic acid was administered intragastrically immediately after sciatic nerve transection,and 200 mg/kg ascorbic acid was then administered intragastrically every day.In addition,rat sciatic nerve explants were treated with 200μM ascorbic acid.Ascorbic acid significantly accelerated the degradation of myelin basic protein-positive myelin and neurofilament 200-positive axons in both the transected nerves and nerve explants.Furthermore,ascorbic acid inhibited myelin-associated glycoprotein expression,increased c-Jun expression in Schwann cells,and increased both the number of macrophages and the amount of myelin fragments in the macrophages.These findings suggest that ascorbic acid accelerates Wallerian degeneration by accelerating the degeneration of axons and myelin in the injured nerve,promoting the dedifferentiation of Schwann cells,and enhancing macrophage recruitment and phagocytosis.The study was approved by the Southern Medical University Animal Care and Use Committee(approval No.SMU-L2015081)on October 15,2015.
基金This study was supported by the National Natural Science Foundation of China,Nos.31900718(to ZYW),31872773(to GC)the National Key Research and Development Program of China,No.2017YFA0104704(to GC)+2 种基金Basic Research Program of the Education Department of Jiangsu Province of China,Nos.19KJB180024(to ZYW),18KJB180020(to WXS)Postdoctoral Science Foundation of China,No.2019M651925(to ZYW),Jiangsu Students’Platform for Innovation and Entrepreneurship Training Program of China,No.201810304031Z(to YJD)Six Talent Peaks Project in Jiangsu Province of China,No.WSN-007(to WXS).
文摘Pannexin 1(Panx 1),as a large-pore membrane channel,is highly permeable to ATP and other signaling molecules.Previous studies have demonstrated the expression of Panx 1 in the nervous system,including astrocytes,microglia,and neurons.However,the distribution and function of Panx 1 in the peripheral nervous system are not clear.Blocking the function of Panx 1 pharmacologically(carbenoxolone and probenecid)or with small interfering RNA targeting pannexins can greatly reduce hypotonicity-induced ATP release.Treatment of Schwann cells with a Ras homolog family member(Rho)GTPase inhibitor and small interfering RNA targeting Rho or cytoskeleton disrupting agents,such as nocodazole or cytochalasin D,revealed that hypotonicity-induced ATP release depended on intracellular RhoA and the cytoskeleton.These findings suggest that Panx 1 participates in ATP release in Schwann cells by regulating RhoA and the cytoskeleton arrangement.This study was approved by the Animal Ethics Committee of Nantong University,China(No.S20180806-002)on August 5,2018.
基金the Russian Science Foundation(No.16-15-00010to RRI)the Russian Government Program of Competitive Growth of Kazan Federal University。
文摘We previously demonstrated that gene-modified umbilical cord blood mononuclear cells overexpressing a combination of recombinant neurotrophic factors are a promising therapeutic approach for cell-mediated gene therapy for neurodegenerative diseases,neurotrauma,and stroke.In this study,using a mini pig model of spinal cord injury,we proposed for the first time the use of gene-modified leucoconcentrate prepared from peripheral blood in the plastic blood bag for personalized ex vivo gene therapy.Leucoconcentrate obtained from mini pig peripheral blood was transduced with a chimeric adenoviral vector(Ad5/35 F)that carried an enhanced green fluorescent protein(EGFP)reporter gene in the plastic blood bag.The day after blood donation,the mini pigs were subjected to moderate SCI and four hours post-surgery they were intravenously autoinfused with gene-modified leucoconcentrate.A week after gene-modified leucoconcentrate therapy,fluorescent microscopy revealed EGFP-expressing leucocytes in spinal cord at the site of contusion injury.In the spleen the groups of EGFP-positive cells located in the lymphoid follicles were observed.In vitro flow cytometry and fluorescent microscopy studies of the gene-modified leucoconcentrate samples also confirmed the production of EGFP by leucocytes.Thus,the efficacy of leucocytes transduction in the plastic blood bag and their migratory potential suggest their use for temporary production of recombinant biologically active molecules to correct certain pathological conditions.This paper presents a proof-of-concept of simple,safe and effective approach for personalized ex vivo gene therapy based on gene-modified leucoconcentrate autoinfusion.The animal protocols were approved by the Kazan State Medical University Animal Care and Use Committee(approval No.5)on May 27,2014.
基金supported by the Russian Government Program of Competitive Growth of Kazan Federal University,state assignment 20.5175.2017/6.7 of the Ministry of Education and Science of Russian Federation and Grant of the President of the Russian Federation for state support of the leading scientific schools of the Russian Federationsupported by the Russian Government Program of Competitive Growth of the Kazan Federal University(to AR)the Russian Foundation for Basic Research grant 18-54-45023 Ind_a(to IS and GM)。
文摘Vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) are well-known growth factors involved in the regeneration of various tissues and organs, including peripheral nerve system. In the present study, we elucidated the local and systemic effects of plasmid construct рBud-coVEGF165-coFGF2 injected into the epineurium of intact rat sciatic nerve. Results of histological examination of sciatic nerve and multiplex immunoassays of serum showed the absence of immunogenicity and biosafety of plasmid рBud-coVEGF165-coFGF2. Moreover, local administration of plasmid DNA construct resulted in significantly decreased levels of pro-inflammatory cytokines in the peripheral blood, including tumor necrosis factor α(TNFα) and interleukin-12, and significantly increased levels of cytokines and chemokines including Regulated upon Activation, Normal T Cell Expressed and Presumably Secrete(RANTES), epidermal growth factor, interleukin-2, and monocyte chemoattractant protein 1. These changes in the peripheral blood on day 7 after injection of plasmid construct рBud-coVEGF165-coFGF2 show that the plasmid construct has systemic effects and may modulate immune response. At the same time, reverse transcriptionpolymerase chain reaction revealed transient expression of coFGF2, coVEGF165, ratFGF2 and ratVEGFA with direct transport of transcripts from distal part to proximal part of the sciatic nerve. Immunohistochemical staining revealed prolonged presence of VEGFA in sciatic nerve till 14 days post-injection. These findings suggest that local administration of plasmid construct рBud-coVEGF165-coFGF2 at a concentration of 30 ng/μL results in the formation of pro-angiogenic stimuli and, and the plasmid construct, used as a drug for gene therapy, might potentially facilitate regeneration of the sciatic nerve. The study was approved by the Animal Ethics Committee of Kazan Federal University, procedures were approved by the Local Ethics Committee(approval No. 5) on May 27, 2014.
基金National Key R&D Program of China,No.2018YFC2001600(to JGX)Shanghai Science and Technology Committee of China,Nos.18511108300(to JGX),18441903800(to MXZ),18441903900(to XYH)。
文摘Massage therapy is an alternative treatment for chronic pain that is potentially related to brain plasticity.However,the underlying mechanism remains unclear.We established a peripheral nerve injury model in rats by unilateral sciatic nerve transection and direct anastomosis.The experimental rats were treated over the gastrocnemius muscle of the affected hindlimb with a customized massage instrument(0.45 N,120 times/min,10 minutes daily,for 4 successive weeks).Resting-state functional magnetic resonance imaging revealed that compared with control rats,the amplitude of low-frequency fluctuations in the sensorimotor cortex contralateral to the affected limb was significantly lower after sciatic nerve transection.However,amplitudes were significantly higher in the massage group than in a sham-massage group.These findings suggest that massage therapy facilitated adaptive change in the somatosensory cortex that led to the recovery of peripheral nerve injury and repair.This study was approved by the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine of China(approval No.201701001)on January 12,2017.