Objective:To study the influence of mouse nerve growth factor (mNGF) combined with hyperbaric oxygen on serum cytokines and cognitive function in patients with delayed encephalopathy after carbon monoxide poisoning (D...Objective:To study the influence of mouse nerve growth factor (mNGF) combined with hyperbaric oxygen on serum cytokines and cognitive function in patients with delayed encephalopathy after carbon monoxide poisoning (DEACMP).Methods: 218 patients with DEACMP who were treated in our hospital between June 2012 and September 2016 were chosen as research subjects and retrospectively divided into the control group (n=100) who underwent hyperbaric oxygen treatment and the observation group (n=118) who underwent mouse nerve growth factor combined with hyperbaric oxygen treatment. Serum contents of nerve injury indexes and inflammatory mediators were compared between two groups of patients and cognitive function was assessed.Results:Before treatment, differences in serum levels of nerve injury indexes and inflammatory mediators, total MMSE score and each dimension score were not statistically significant between two groups of patients. After treatment, serum contents of nerve injury indexes creatine kinase-BB (CK-BB), neuron-specific enolase (NSE), S-100β protein (S-100β) and lactate (Lac) in observation group were lower than those in control group;serum contents of inflammatory mediators interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-18 (IL-18), hypersensitive C-reactive protein (hs-CRP) and tumor necrosis factor (TNF-α) were lower than those in control group;total MMSE score and each dimension score were higher than those of control group.Conclusion:mNGF combined with hyperbaric oxygen treatment of DEACMP is helpful to reduce the nerve injury and systemic inflammatory response, and improve the cognitive function.展开更多
Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic ker...Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.展开更多
The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting vision.The major clinical treatments for diabetic mac...The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting vision.The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation.However,although the macular thickness can be normalized with each of these two therapies used alone,the vision does not improve in many patients.This might result from the incomplete recovery of retinal ganglion cell injury.Therefore,a prospective,non-randomized,controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery.In this trial,150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods,followed by treatment with anti-vascular endothelial growth factor drugs,laser photocoagulation therapy,and their combination.All patients will be followed up for 12 months.The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment.The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1,3,6,and 9 months after treatment,retinal nerve fiber layer thickness,best-corrected visual acuity,macular area thickness,and choroidal thickness before and 1,3,6,9,and 12 months after treatment.Safety measure is the incidence of adverse events at 1,3,6,9,and 12 months after treatment.The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period.The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity.The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No.(2023)(26)on April 25,2023,and was registered with the Chinese Clinical Trial Registry(registration number:ChiCTR2300072478,June 14,2023,protocol version:2.0).展开更多
We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique.Multiple growth factors play a synergistic role...We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique.Multiple growth factors play a synergistic role in promoting the repair of peripheral nerve injury;as a result,in this study,we added basic fibroblast growth factors to the microspheres to further promote nerve regeneration.First,in an in vitro biomimetic microenvironment,we developed and used a drug screening biomimetic microfluidic chip to screen the optimal combination of nerve growth factor/basic fibroblast growth factor to promote the regeneration of Schwann cells.We found that 22.56 ng/mL nerve growth factor combined with 4.29 ng/mL basic fibroblast growth factor exhibited optimal effects on the proliferation of primary rat Schwann cells.The successfully prepared nerve growth factor-basic fibroblast growth factor-poly-lactide-co-glycolid sustained-release microspheres were used to treat rat sciatic nerve transection injury using the small gap sleeve bridge technique.Compared with epithelium sutures and small gap sleeve bridging alone,the small gap sleeve bridging technique combined with drug-free sustained-release microspheres has a stronger effect on rat sciatic nerve transfection injury repair at the structural and functional level.展开更多
Traumatic brain injury is one of the main causes of mortality and disability worldwide.Traumatic brain injury is characterized by a primary injury directly induced by the impact,which progresses into a secondary injur...Traumatic brain injury is one of the main causes of mortality and disability worldwide.Traumatic brain injury is characterized by a primary injury directly induced by the impact,which progresses into a secondary injury that leads to cellular and metabolic damages,starting in the first few hours and days after primary mechanical injury.To date,traumatic brain injury is not targetable by therapies aimed at preventing and/or limiting the outcomes of secondary damage but only by palliative therapies.Nerve growth factor is a neurotrophin targeting neuronal and non-neuronal cells,potentially useful in preventing/limiting the outcomes of secondary damage in traumatic brain injury.This potential has further increased in the last two decades since the possibility of reaching neurotrophin targets in the brain through its intranasal delivery has been exploited.Indeed,molecules intranasally delivered to the brain parenchyma may easily bypass the blood-brain barrier and reach their therapeutic targets in the brain,with favorable kinetics,dynamics,and safety profile.In the first part of this review,we aimed to report the traumatic brain injury-induced dysfunctional mechanisms that may benefit from nerve growth factor treatment.In the second part,we then exposed the experimental evidence relating to the action of nerve growth factor(both in vitro and in vivo,after administration routes other than intranasal)on some of these mechanisms.In the last part of the work,we,therefore,discussed the few manuscripts that analyze the effects of treatment with nerve growth factor,intranasally delivered to the brain parenchyma,on the outcomes of traumatic brain injury.展开更多
AIM:To characterize changes of corneal nerve morphology and tear indices in patients with neurotrophic keratitis(NK)treated with recombinant human nerve growth factor(rhNGF).METHODS:In a prospective observational stud...AIM:To characterize changes of corneal nerve morphology and tear indices in patients with neurotrophic keratitis(NK)treated with recombinant human nerve growth factor(rhNGF).METHODS:In a prospective observational study,six patients(nine eyes)were locally treated with rhNGF.Visual acuity,corneal fluorescein staining score,the heights of the tear river,lipid layer thickness(LLT),tear ferning(TF)test,conjunctival impression cytology(CIC)examination,the densities of cornea subbasal nerve fibers were determined before and after treatment.RESULTS:Compared with baseline,there was a significant difference in corneal fluorescence staining scores(P<0.01);all patient corneal epithelial defects recovered completely within 8wk,but there was no significant improvement in the height of the tear river(P=0.202).LLT was significantly increased when compared with baseline(P=0.042);however,the function of conjunctival goblet cells and mucin content did not significantly improve using the TF test and CIC examination(P=0.557,P=0.539).After 8wk of treatment,the average corneal subbasal nerve fiber density increased significantly(P<0.01),as did the number of corneal nerve fiber branches(P=0.001).CONCLUSION:RhNGF can increase the density of corneal subbasal nerve fibers,promote the healing of persistent corneal epithelial defects and corneal ulcers in patients with NK,also improving tear function partially.展开更多
BACKGROUND:Studies have demonstrated that oxyhemoglobin(OxyHb)can induce brain cell apoptosis in vivo. OBJECTIVE:To observe the effects of exogenous nerve growth factor(NGF)on cerebral cortical neuronal Bcl-2 and Bax ...BACKGROUND:Studies have demonstrated that oxyhemoglobin(OxyHb)can induce brain cell apoptosis in vivo. OBJECTIVE:To observe the effects of exogenous nerve growth factor(NGF)on cerebral cortical neuronal Bcl-2 and Bax expression in mice with OxyHb-induced subarachnoid hemorrhage. DESIGN,TIME AND SETTING:A completely randomized grouping,controlled animal experiment was performed at the Experimental Center for Biomedicine,College of Medicine,Xi’an Jiaotong University between February and April 2005. MATERIALS:Fifty-four healthy,male,adult,ICR mice were included in this study.Subarachnoid hemorrhage was induced by a subarachnoid injection of OxyHb in 48 mice.Mouse NGF was obtained from Xiamen Beidazhilu Bioengineering Co.,Ltd.,China. METHODS:All 54 mice were randomly divided into three groups:control(n=6),injury(n=24),and NGF (n=24).The NGF group received a subarachnoidal administration of OxyHb,immediately followed by a caudal vein injection of NGF(1μg).The injury group was injected with OxyHb,and subsequently with physiological saline.The control group only received intravenous physiological saline. MAIN OUTCOME MEASURES:At 1,6,24,and 48 hours following subarachnoid hemorrhage induction, expression levels of Bcl-2 and Bax were detected by immunohistochemistry in the cerebral cortex 3 mm anterior and posterior to the injection site. RESULTS:At all time points following OxyHb injection,cerebral cortical Bax levels were significantly higher in the injured group than in the control and NGF groups(P<0.01).During the first 24 hours following OxyHb injection,cerebral cortical Bcl-2 levels were significantly lower in the injury group compared to the control group(P<0.05-0.01).Between 1 and 48 hours,Bcl-2 levels were significantly higher in the NGF group than in the injury group(P<0.01). CONCLUSION:Exogenous NGF can inhibit increased neuronal Bax expression and decreased Bcl-2 expression in the cerebral cortex of mice with OxyHb-induced subarachnoid hemorrhage.展开更多
Lead exposure is a known potential risk factor for neurodegenerative diseases such as Alzheimer's disease(AD). Exposure to lead during the critical phase of brain development has been linked with mental retardatio...Lead exposure is a known potential risk factor for neurodegenerative diseases such as Alzheimer's disease(AD). Exposure to lead during the critical phase of brain development has been linked with mental retardation and hypophrenia in later life. This study was aimed to investigate the effects of lead exposure of pregnant mice on the expressions of insulin-degrading enzyme(IDE) and nerve growth factor(NGF) in the hippocampus of their offspring. Blood samples were collected from the tail vein, and after anesthetizing the pups, the brain was excised on postnatal day 21. Lead concentrations were determined by graphite furnace atomic absorption spectrophotometry, and the expressions of IDE and NGF were determined by immunohistochemistry and Western blotting. Results showed that the reduction in IDE and NGF expression in the hippocampus of pups might be associated with impairment of learning and memory and dementia induced by maternal lead exposure during pregnancy and lactation.展开更多
BACKGROUND: Nerve growth factor (NGF) attenuates glutamate-induced injury to hippocampal neurons, and the human tumor suppressor gene phosphatase and tensin homologue deleted on chromosome 10 (PTEN) promotes neuronal ...BACKGROUND: Nerve growth factor (NGF) attenuates glutamate-induced injury to hippocampal neurons, and the human tumor suppressor gene phosphatase and tensin homologue deleted on chromosome 10 (PTEN) promotes neuronal apoptosis. However, effects of PTEN in NGF-mediated neuroprotection against glutamate excitotoxicity remain poorly understood. OBJECTIVE: To investigate the relationship between NGF inhibition of glutamate-induced injury and PTEN. DESIGN, TIME AND SETTING: The randomized, controlled, in vitro study was performed at the Department of Pathophysiology, Medical School of Nantong University, China from October 2007 to March 2008. MATERIALS: Glutamate, NGF, 4, 6-diamidino-2-phenyl-indolediacetate, 3-[4, 5-dimethylthiazol-2-yl]- 2, 5-diphenyl tetrazoliumbromide (MTT), and lactate dehydrogenase kit (Sigma, USA), fluorescence microscope and inverted phase contrast microscope (Olympus, Japan) were used in this study. METHODS: Hippocampal neurons were obtained from newborn (< 24 hours) Sprague Dawley rats and cultured for 7 days. The control group was not treated with any intervention factor, the glutamate group was treated with glutamate (0.2 mmol/L), and NGF groups were treated with NGF (10, 50, 100, and 200 μg/L, respectively) prior to glutamate treatment. MAIN OUTCOME MEASURES: The MTT and lactate dehydrogenase assays were applied to evaluate viability of hippocampal neurons. Morphological changes in hippocampal neurons were observed using an inverted phase-contrast microscope, and neuronal apoptosis was detected by 4, 6-diamidino-2-phenyl-indolediacetate staining. PTEN mRNA and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot analysis, respectively. RESULTS: Glutamate (0.2 mmol/L) induced significantly decreased neuronal viability and greater lactate dehydrogenase efflux compared with the control group (P < 0.01). However, compared with the glutamate group, cell viability significantly increased and lactate dehydrogenase efflux decreased in the NGF group with increasing NGF concentrations (P < 0.05 or P < 0.01). The apoptotic ratio and PTEN mRNA and protein expression decreased in the NGF group compared with the glutamate group (P < 0.01). CONCLUSION: Pretreatment with NGF exerted neuroprotective effects against glutamate-induced injury, partially through inhibition of PTEN expression and neuronal apoptosis.展开更多
BACKGROUND: Studies have shown that abnormal innervation is an important factor impacting occurrence and development of pathological pain in endometriosis. OBJECTIVE: To observe uterine innervation of adenomyosis mice...BACKGROUND: Studies have shown that abnormal innervation is an important factor impacting occurrence and development of pathological pain in endometriosis. OBJECTIVE: To observe uterine innervation of adenomyosis mice and to analyze the cause of innervation changes due to nerve growth factor (NGF) expression, inflammation, and vascularization. DESIGN, TIME AND SETTING: This randomized, controlled, animal experiment was performed at the Research Institute of Obstetrics and Gynecology Hospital, and Central Laboratory of Zhong- shan Hospital, Fudan University from March to December 2008. MATERIALS: Tamoxifen was provided by Fudan Forward, China. Rabbit anti-mouse NGF was purchased from Santa Cruz Corporation, USA; rabbit anti-protein gene product 9.5 (PGP9.5) and rabbit antisubstance P (SP) were purchased from Chemicon, USA. METHODS: A total of 40 newborn ICR mice were randomly assigned to adenomyosis model and control groups, with 20 animals in each group. Mice in the adenomyosis model group were orally administrated 2.7 μmol/kg tamoxifen on days 2-5 after birth, while the controls were not treated. MAIN OUTCOME MEASURES: Both uteri from all mice were harvested at days 135-145 after birth. Expressions of polyclonal PGP9.5 and SP were immunohistochemically detected to demonstrate pan- and sensory nerve fibers. Microvessel density was quantified in the endometrium and myometrium using immunochemical staining for polyclonal rabbit anti-CD31, which stained vessels. Gene expression for NGF, high-affinity tyrosine kinase receptor (trkA), p75 neurotrophin receptor (p75NTR), bradykinin receptor-1 (BKR-1), and 2 (BKR-2), as well as substance P receptor (neurokinin1 receptor, NK1-R), were detected by reverse transcription-polymerase chain reaction. NGF-β protein expression was detected by Western blot analysis. RESULTS: More nerve fibers were stained with PGP9.5 in the endometrium and myometrium, and with SP in the endometrium, in adenomyosis mice compared with controls (P < 0.01 and P < 0.05). Microvessel density in the myometrium of adenomyosis mice was significantly greater than the controls (P < 0.01). In the uterus of adenomyosis mice, mRNA expression of NGF and its two receptors (trkA and p75 NTR), BKR-1, and NK1-R, as well as protein expression of NGF-β, were greater than the control mice (P < 0.01 or P < 0.05). CONCLUSION: Uterine innervation in the adenomyosis mice was increased compared with the controls. Moreover, NGF expression, inflammation, and vascularization, which have been shown to be impact factors of innervation, were abnormal in the uteri of adenomyosis mice.展开更多
Nerve growth factor(NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors...Nerve growth factor(NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors contributing significantly to inflammatory pain and neuropathic pain after tissue injury. As such anti-NGF based therapies represent a promising strategy for pain management. Because of dose-dependent serious side effects such as back pain, injection site hyperalgesia, clinical trials of using NGF to treat various disorders such as diabetic neuropathies, chemotherapy-induced and human immunodeficiency virus-associated peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V(HSAN V) is an extremely rare disease. Genetic analyses have revealed that HSAN V is associated with autosomal recessive mutations in NGF. One of the mutations occurred at the 100^(th) position of mature NGF resulting in a change of residue from arginine to tryptophan(R100W). Although those HSAN V patients associated with the NGF^(R100W) mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGF^(R100W) mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGF^(R100W) provides an ideal tool to uncouple the two important functions of NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGF^(R100W) no longer induced pain. More importantly, the trophic function seemed to be largely preserved in NGF harboring the R100W mutation. On the mechanistic level, we found that the NGF^(R100W) mutation was capable of binding to and signaling through the tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa neurotrophic factor was significantly diminished. The significance of these findings is at least two folds: 1) the NGF^(R100W) mutation can be used as an alternative to the wildtype NGF to treat human conditions without eliciting pain; and 2) the 75 kDa neurotrophic factor may serve as a novel target for pain management. We will discuss all the details in this mini-review.展开更多
The regenerative capacity of peripheral nerves is limited after nerve injury.A number of growth factors modulate many cellular behaviors,such as proliferation and migration,and may contribute to nerve repair and regen...The regenerative capacity of peripheral nerves is limited after nerve injury.A number of growth factors modulate many cellular behaviors,such as proliferation and migration,and may contribute to nerve repair and regeneration.Our previous study observed the dynamic changes of genes in L4–6 dorsal root ganglion after rat sciatic nerve crush using transcriptome sequencing.Our current study focused on upstream growth factors and found that a total of 19 upstream growth factors were dysregulated in dorsal root ganglions at 3,9 hours,1,4,or 7 days after nerve crush,compared with the 0 hour control.Thirty-six rat models of sciatic nerve crush injury were prepared as described previously.Then,they were divided into six groups to measure the expression changes of representative genes at 0,3,9 hours,1,4 or 7 days post crush.Our current study measured the expression levels of representative upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin genes,and explored critical signaling pathways and biological process through bioinformatic analysis.Our data revealed that many of these dysregulated upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin,participated in tissue remodeling and axon growth-related biological processes Therefore,the experiment described the expression pattern of upstream growth factors in the dorsal root ganglia after peripheral nerve injury.Bioinformatic analysis revealed growth factors that may promote repair and regeneration of damaged peripheral nerves.All animal surgery procedures were performed in accordance with Institutional Animal Care Guidelines of Nantong University and ethically approved by the Administration Committee of Experimental Animals,China(approval No.20170302-017)on March 2,2017.展开更多
Objective: To study the effect of surgery combined with nerve growth factor preparation treatment of acute cerebral hemorrhage on nerve cytokines and nerve injury. Methods: 68 patients with acute cerebral hemorrhage w...Objective: To study the effect of surgery combined with nerve growth factor preparation treatment of acute cerebral hemorrhage on nerve cytokines and nerve injury. Methods: 68 patients with acute cerebral hemorrhage who received emergency minimally invasive evacuation of hematoma in Zigong No. 4 People's Hospital between August 2014 and September 2016 were selected and randomly divided into mNGF group and control group, mNGF group received postoperative mouse nerve growth factor preparation combined with conventional therapy, and control group accepted routine postoperative treatment. 10d, 20d and 30d after treatment, the serum was collected to determine the levels of nerve cytokines and nerve injury molecules. Results: 10d, 20d and 30d after treatment, serum BDNF (5.29±0.88 vs. 3.58±0.61, 6.94±0.93 vs. 3.78±0.55, 9.28±1.13 vs. 4.57±0.62 ng/ml), NTF-α (2.94±0.52 vs. 1.35±0.18, 3.88±0.58 vs. 1.51±0.20, 5.21±0.72 vs. 2.95±0.46 ng/ml), NGF (0.89±0.11 vs. 0.62±0.08, 1.02±0.15 vs. 0.78±0.09, 1.45±0.18 vs. 0.92±0.12 ng/ml) and VEGF (147.53±19.52 vs. 110.38±14.28, 184.95±22.51 vs. 121.29±17.85, 237.49±31.28 vs. 145.38±18.31 pg/ml) levels of mNGF group were significantly higher than those of control group while S100β (1.27±0.20 vs. 2.19±0.33, 0.94±0.14 vs. 1.76±0.25, 0.71±0.09 vs. 1.32±0.17 ng/ml), GFAP (2.08±0.36 vs. 4.42±0.55, 1.65±0.25 vs. 3.57±0.51, 1.31±0.17 vs. 2.93±0.42 pg/ml), NSE (34.21±5.82 vs. 73.19±9.35, 27.58±4.12 vs. 58.76±8.28, 22.12±3.25 vs. 39.52±5.28 ng/ml), MBP (5.28±0.93 vs. 11.28±1.86, 3.89±0.51 vs. 9.12±1.14, 3.12±0.41 vs. 6.79±0.94 ng/ml), MDA (6.97±0.93 vs. 14.21±1.87, 5.02±0.78 vs. 11.75±1.76, 3.57±0.62 vs. 8.12±0.99 μmol/L), AOPP(65.19±9.68 vs. 155.62±19.63, 48.59±7.21 vs. 118.75±16.85, 37.83±5.28 vs. 82.11±10.18 μmol/L) and 8-OHdG (4.77±0.67 vs. 10.28±1.52, 3.52±0.51 vs. 9.38±1.15, 2.33±0.41 vs. 6.52±0.92 ng/ml) levels were significantly lower than those of control group. Conclusion: Surgery combined with nerve growth factor preparation treatment of acute cerebral hemorrhage can improve neural nutritional status and reduce nerve injury degree, and it is beneficial to the recovery of neural function.展开更多
AIM:To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase(NGF-TrkA)signaling pathway and prognosis in intrahepatic cholangiocarcinoma(IHCC).METHODS:NGF and TrkA expression in 83 sample...AIM:To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase(NGF-TrkA)signaling pathway and prognosis in intrahepatic cholangiocarcinoma(IHCC).METHODS:NGF and TrkA expression in 83 samples of IHCC was assessed by immunohistochemistry.Correlations between NGF-TrkA expression and clinicopathological features were analyzed byχ2 test.Moreover,we evaluated the association between NGF-TrkA and overall survival by univariate and multivariate analysis.With experiments in vitro,we investigated the crucial role of NGF-TrkA on proliferation and invasion of IHCC cells with recombinant NGF-βstimulation.RESULTS:We found that NGF and TrkA expression was significantly related with differentiation(P=0.024)and intraneural invasion(P=0.003),respectively.Additionally,double higher expression of NGF and TrkA was identified as an independent prognostic factor in IHCC(P=0.003).Moreover,we demonstrated that NGF-TrkA signaling pathway can promote IHCC proliferation and invasion.CONCLUSION:NGF-TrkA double higher expression is an independent prognostic factor in IHCC.NGF-TrkA pathway can promote IHCC progression,indicating that NGF-TrkA may become a potential drug target.展开更多
Electroacupuncture(EA)has been shown to reduce blood lipid level and improve cerebral ischemia in rats with hyperlipemia complicated by cerebral ischemia.However,there are few studies on the results and mechanism of t...Electroacupuncture(EA)has been shown to reduce blood lipid level and improve cerebral ischemia in rats with hyperlipemia complicated by cerebral ischemia.However,there are few studies on the results and mechanism of the effect of EA in reducing blood lipid level or promoting neural repair after stroke in hyperlipidemic subjects.In this study,EA was applied to a rat model of hyperlipidemia and middle cerebral artery thrombosis and the condition of neurons and astrocytes after hippocampal injury was assessed.Except for the normal group,rats in other groups were fed a high-fat diet throughout the whole experiment.Hyperlipidemia models were established in rats fed a high-fat diet for 6 weeks.Middle cerebral artery thrombus models were induced by pasting 50%FeCl3 filter paper on the left middle cerebral artery for 20 minutes on day 50 as the model group.EA1 group rats received EA at bilateral ST40(Fenglong)for 7 days before the thrombosis.Rats in the EA1 and EA2 groups received EA at GV20(Baihui)and bilateral ST40 for 14 days after model establishment.Neuronal health was assessed by hematoxylin-eosin staining in the brain.Hyperlipidemia was assessed by biochemical methods that measured total cholesterol,triglyceride,low-density lipoprotein and high-density lipoprotein in blood sera.Behavioral analysis was used to confirm the establishment of the model.Immunohistochemical methods were used to detect the expression of glial fibrillary acidic protein and nerve growth factor in the hippocampal CA1 region.The results demonstrated that,compared with the model group,blood lipid levels significantly decreased,glial fibrillary acidic protein immunoreactivity was significantly weakened and nerve growth factor immunoreactivity was significantly enhanced in the EA1 and EA2 groups.The repair effect was superior in the EA1 group than in the EA2 group.These findings confirm that EA can reduce blood lipid,inhibit glial fibrillary acidic protein expression and promote nerve growth factor expression in the hippocampal CA1 region after hyperlipidemia and middle cerebral artery thrombosis.All experimental procedures and protocols were approved by the Animal Use and Management Committee of Beijing University of Chinese Medicine,China(approval No.BUCM-3-2018022802-1002)on April 12,2018.展开更多
Although autogenous nerve transplantation is the gold standard for treating peripheral nerve defects of considerable length,it still has some shortcomings,such as insufficient donors and secondary injury.Composite chi...Although autogenous nerve transplantation is the gold standard for treating peripheral nerve defects of considerable length,it still has some shortcomings,such as insufficient donors and secondary injury.Composite chitosan scaffolds loaded with controlled release of nerve growth factor can promote neuronal survival and axonal regeneration after short-segment sciatic nerve defects.However,the effects on extended nerve defects remain poorly understood.In this study,we used chitosan scaffolds loaded with nerve growth factor for 8 weeks to repair long-segment(20 mm)sciatic nerve defects in adult rats.The results showed that treatment markedly promoted the recovery of motor and sensory functions.The regenerated sciatic nerve not only reconnected with neurons but neural circuits with the central nervous system were also reconstructed.In addition,the regenerated sciatic nerve reconnected the motor endplate with the target muscle.Therefore,this novel biomimetic scaffold can promote the regeneration of extended sciatic nerve defects and reconstruct functional circuits.This provides a promising method for the clinical treatment of extended peripheral nerve injury.This study was approved by the Animal Ethics Committee of Capital Medical University,China(approval No.AEEI-2017-033)on March 21,2017.展开更多
Neurotrophins are a family of proteins that support neuronal proliferation, survival, and differentiation in the central and peripheral nervous systems, and are regulators of neuronal plasticity. Nerve growth factor i...Neurotrophins are a family of proteins that support neuronal proliferation, survival, and differentiation in the central and peripheral nervous systems, and are regulators of neuronal plasticity. Nerve growth factor is one of the best-described neurotrophins and has advanced to clinical trials for treatment of ocular and brain diseases due to its trophic and regenerative properties. Prior trials over the past few decades have produced conflicting results, which have principally been ascribed to adverse effects of systemic nerve growth factor administration, together with poor penetrance of the blood-brain barrier that impairs drug delivery. Contrastingly, recent studies have revealed that topical ocular and intranasal nerve growth factor administration are safe and effective, suggesting that topical nerve growth factor delivery is a potential alternative to both systemic and invasive intracerebral delivery. The therapeutic effects of local nerve growth factor delivery have been extensively investigated for different ophthalmic diseases, including neurotrophic keratitis, glaucoma, retinitis pigmentosa, and dry eye disease. Further, promising pharmacologic effects were reported in an optic glioma model, which indicated that topically administered nerve growth factor diffused far beyond where it was topically applied. These findings support the therapeutic potential of delivering topical nerve growth factor preparations intranasally for acquired and degenerative brain disorders. Preliminary clinical findings in both traumatic and non-traumatic acquired brain injuries are encouraging, especially in pediatric patients, and clinical trials are ongoing. The present review will focus on the therapeutic effects of both ocular and intranasal nerve growth factor delivery for diseases of the brain and eye.展开更多
Several studies have shown that fibroblast growth factor-2(FGF2) can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the ef...Several studies have shown that fibroblast growth factor-2(FGF2) can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the effect of recombinant human FGF-2(rh FGF2) treatment on damaged mental nerves. The mental nerves of 6-week-old male Sprague-Dawley rats were crush-injured for 1 minute and then treated with 10 or 50 μg/m L rh FGF2 or PBS in crush injury area with a mini Osmotic pump. Sensory test using von Frey filaments at 1 week revealed the presence of sensory degeneration based on decreased gap score and increased difference score. However, at 2 weeks, the gap score and difference score were significantly rebounded in the mental nerve crush group treated with 10 μg/m L rh FGF2. Interestingly, treatment with 10 μg/m L rh FGF had a more obviously positive effect on the gap score than treatment with 50 μg/m L rh FGF2. In addition, retrograde neuronal tracing with Dil revealed a significant increase in nerve regeneration in the trigeminal ganglion at 2 and 4 weeks in the rh FGF2 groups(10 μg/m L and 50 μg/m L) than in the PBS group. The 10 μg/m L rh FGF2 group also showed an obviously robust regeneration in axon density in the mental nerve at 4 weeks. Our results demonstrate that 10 μg/m L rh FGF induces mental nerve regeneration and sensory recovery after mental nerve crush injury.展开更多
BACKGROUND: Neuronal apoptosis in perihematomal brain tissues following intracerebral hemorrhage is strongly related to the formation of a compound signal pathway between nerve growth factor precursor (proNGF), p75NTR...BACKGROUND: Neuronal apoptosis in perihematomal brain tissues following intracerebral hemorrhage is strongly related to the formation of a compound signal pathway between nerve growth factor precursor (proNGF), p75NTR, and sortilin receptor. Sortilin acts as a co-receptor and molecular switch governing the p75NTR-mediated pro-apoptotic signal induced by proNGF. OBJECTIVE: To investigate proNGF and sortilin expressions in perihematomal brain tissues following intracerebral hemorrhage, and to study the effects of proNGF and sortilin on secondary cell apoptosis. DESIGN, TIME AND SETTING: A paired, comparison study was performed at the Laboratory of Histology and Embryology, Xi'an Jiaotong University from October 2007 to September 2008. MATERIALS: Brain tissue samples were obtained from 15 patients with intracerebral hemorrhage, who were treated at the Department of Neurosurgery, First Affiliated Hospital, Medical College of Xi'an Jiaotong University from October 2007 to March 2008. Rabbit anti-proNGF polyclonal antibody was provided by Chemicon, USA; rabbit antisortilin polyclonal antibody by Abcam, UK; and TUNEL kit by Promega, USA. METHODS: Perihematomal brain tissues selected 0.5 cm from the hemorrhage area were considered to be the hemorrhage group, while brain tissues from the middle temporal gyrus served as the control group. MAIN OUTCOME MEASURES: Histopathological changes were detected using hematoxylin-eosin staining, cell apoptosis was determined using the TUNEL method, and proNGF and sortilin ex- pressions were determined using immunohistochemistry. RESULTS: Edema was clearly observed in perihematomal brain tissues, and infiltration of inflammatory cells was visible, with the presence of irregular and necrotic bodies. The apoptotic rate in the hemorrhage group was significantly greater than in the control group (P < 0.01). Moreover, sortilin expression significantly increased (P < 0.01), but proNGF expression remained unchanged (P > 0.05). Correlation analysis suggested that sortilin expression positively correlated with apoptosis (rs = 0.648, P < 0.01). CONCLUSION: proNGF expression was stable, but sortilin expression increased in perihematomal brain tissues following intracerebral hemorrhage, suggesting that sortilin acted as a co-receptor and molecular switch to govern p75NTR-mediated cell apoptosis.展开更多
AIM:To clarify the mechanism by which bone marrow cells promote angiogenesis around transplanted islets.METHODS: Streptozotocin induced diabetic BALB/ c mice were transplanted syngeneically under the kidney capsule wi...AIM:To clarify the mechanism by which bone marrow cells promote angiogenesis around transplanted islets.METHODS: Streptozotocin induced diabetic BALB/ c mice were transplanted syngeneically under the kidney capsule with the following: (1) 200 islets (islet group: n=12), (2) 1-5×106 bone marrow cells (bone marrow group: n=11), (3) 200 islets and 1-5×106 bone marrow cells (islet + bone marrow group: n= 13), or (4) no cells (sham group:n=5). All mice were evaluated for blood glucose, serum insulin, serum nervegrowth factor (NGF) and glucose tolerance (GTT) up to postoperative day (POD) 14. Histological assessment for insulin, von Willebrand factor (vWF) and NGF was performed at POD 3, 7 and 14.RESULTS: Blood glucose level was lowest and serum insulin was highest in the islet + bone marrow group. Serum NGF increased in islet, bone marrow, and islet + bone marrow groups after transplantation, and there was a significant difference (P=0.0496, ANOVA) between the bone marrow and sham groups. The number of vessels within the graft area was signif icantly increased in both the bone marrow and islet + bone marrow groups at POD 14 as compared to the islet alone group (21.2 ± 3.6 in bone marrow, P=0.01, vs islet group, 22.6 ± 1.9 in islet + bone marrow, P = 0.0003, vs islet group, 5.3 ± 1.6 in islet-alone transplants). NGF was more strongly expressed in bone marrow cells compared with islets. CONCLUSION: Bone marrow cells produce NGF and promote angiogenesis. Islet co-transplantation with bone marrow is associated with improvement of islet graft function.展开更多
文摘Objective:To study the influence of mouse nerve growth factor (mNGF) combined with hyperbaric oxygen on serum cytokines and cognitive function in patients with delayed encephalopathy after carbon monoxide poisoning (DEACMP).Methods: 218 patients with DEACMP who were treated in our hospital between June 2012 and September 2016 were chosen as research subjects and retrospectively divided into the control group (n=100) who underwent hyperbaric oxygen treatment and the observation group (n=118) who underwent mouse nerve growth factor combined with hyperbaric oxygen treatment. Serum contents of nerve injury indexes and inflammatory mediators were compared between two groups of patients and cognitive function was assessed.Results:Before treatment, differences in serum levels of nerve injury indexes and inflammatory mediators, total MMSE score and each dimension score were not statistically significant between two groups of patients. After treatment, serum contents of nerve injury indexes creatine kinase-BB (CK-BB), neuron-specific enolase (NSE), S-100β protein (S-100β) and lactate (Lac) in observation group were lower than those in control group;serum contents of inflammatory mediators interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-18 (IL-18), hypersensitive C-reactive protein (hs-CRP) and tumor necrosis factor (TNF-α) were lower than those in control group;total MMSE score and each dimension score were higher than those of control group.Conclusion:mNGF combined with hyperbaric oxygen treatment of DEACMP is helpful to reduce the nerve injury and systemic inflammatory response, and improve the cognitive function.
基金supported by PLA General Hospital Program,No.LB20201A010024(to LW).
文摘Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.
基金supported by Science and Technology Research Project of Jilin Provincial Department of Education,No.JJKH20220072KJ(to XL)Science and Technology Development Program of Jilin Province,No.20200201495JC(to YL)。
文摘The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting vision.The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation.However,although the macular thickness can be normalized with each of these two therapies used alone,the vision does not improve in many patients.This might result from the incomplete recovery of retinal ganglion cell injury.Therefore,a prospective,non-randomized,controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery.In this trial,150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods,followed by treatment with anti-vascular endothelial growth factor drugs,laser photocoagulation therapy,and their combination.All patients will be followed up for 12 months.The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment.The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1,3,6,and 9 months after treatment,retinal nerve fiber layer thickness,best-corrected visual acuity,macular area thickness,and choroidal thickness before and 1,3,6,9,and 12 months after treatment.Safety measure is the incidence of adverse events at 1,3,6,9,and 12 months after treatment.The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period.The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity.The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No.(2023)(26)on April 25,2023,and was registered with the Chinese Clinical Trial Registry(registration number:ChiCTR2300072478,June 14,2023,protocol version:2.0).
基金supported by the National Key Research and Development Program of China, No. 2016YFC1101603 (to DYZ)the National Natural Science Foundation of China, Nos. 31640045 (to YHW), 81901251 (to ML)the Natural Science Foundation of Beijing of China, No. 7204323 (to ML)
文摘We previously prepared nerve growth factor poly-lactide co-glycolid sustained-release microspheres to treat rat sciatic nerve injury using the small gap sleeve technique.Multiple growth factors play a synergistic role in promoting the repair of peripheral nerve injury;as a result,in this study,we added basic fibroblast growth factors to the microspheres to further promote nerve regeneration.First,in an in vitro biomimetic microenvironment,we developed and used a drug screening biomimetic microfluidic chip to screen the optimal combination of nerve growth factor/basic fibroblast growth factor to promote the regeneration of Schwann cells.We found that 22.56 ng/mL nerve growth factor combined with 4.29 ng/mL basic fibroblast growth factor exhibited optimal effects on the proliferation of primary rat Schwann cells.The successfully prepared nerve growth factor-basic fibroblast growth factor-poly-lactide-co-glycolid sustained-release microspheres were used to treat rat sciatic nerve transection injury using the small gap sleeve bridge technique.Compared with epithelium sutures and small gap sleeve bridging alone,the small gap sleeve bridging technique combined with drug-free sustained-release microspheres has a stronger effect on rat sciatic nerve transfection injury repair at the structural and functional level.
基金funded by the Italian Ministry of Health Grant:RF-2018-12366594“Nerve growth factor in paediatric severe traumatic brain injury:translational and clinical studies on a candidate biomarker and therapeutic drug”(to AC)。
文摘Traumatic brain injury is one of the main causes of mortality and disability worldwide.Traumatic brain injury is characterized by a primary injury directly induced by the impact,which progresses into a secondary injury that leads to cellular and metabolic damages,starting in the first few hours and days after primary mechanical injury.To date,traumatic brain injury is not targetable by therapies aimed at preventing and/or limiting the outcomes of secondary damage but only by palliative therapies.Nerve growth factor is a neurotrophin targeting neuronal and non-neuronal cells,potentially useful in preventing/limiting the outcomes of secondary damage in traumatic brain injury.This potential has further increased in the last two decades since the possibility of reaching neurotrophin targets in the brain through its intranasal delivery has been exploited.Indeed,molecules intranasally delivered to the brain parenchyma may easily bypass the blood-brain barrier and reach their therapeutic targets in the brain,with favorable kinetics,dynamics,and safety profile.In the first part of this review,we aimed to report the traumatic brain injury-induced dysfunctional mechanisms that may benefit from nerve growth factor treatment.In the second part,we then exposed the experimental evidence relating to the action of nerve growth factor(both in vitro and in vivo,after administration routes other than intranasal)on some of these mechanisms.In the last part of the work,we,therefore,discussed the few manuscripts that analyze the effects of treatment with nerve growth factor,intranasally delivered to the brain parenchyma,on the outcomes of traumatic brain injury.
基金Supported by the Shaanxi Provincial Department of Science and Technology(No.2021SF-331)。
文摘AIM:To characterize changes of corneal nerve morphology and tear indices in patients with neurotrophic keratitis(NK)treated with recombinant human nerve growth factor(rhNGF).METHODS:In a prospective observational study,six patients(nine eyes)were locally treated with rhNGF.Visual acuity,corneal fluorescein staining score,the heights of the tear river,lipid layer thickness(LLT),tear ferning(TF)test,conjunctival impression cytology(CIC)examination,the densities of cornea subbasal nerve fibers were determined before and after treatment.RESULTS:Compared with baseline,there was a significant difference in corneal fluorescence staining scores(P<0.01);all patient corneal epithelial defects recovered completely within 8wk,but there was no significant improvement in the height of the tear river(P=0.202).LLT was significantly increased when compared with baseline(P=0.042);however,the function of conjunctival goblet cells and mucin content did not significantly improve using the TF test and CIC examination(P=0.557,P=0.539).After 8wk of treatment,the average corneal subbasal nerve fiber density increased significantly(P<0.01),as did the number of corneal nerve fiber branches(P=0.001).CONCLUSION:RhNGF can increase the density of corneal subbasal nerve fibers,promote the healing of persistent corneal epithelial defects and corneal ulcers in patients with NK,also improving tear function partially.
文摘BACKGROUND:Studies have demonstrated that oxyhemoglobin(OxyHb)can induce brain cell apoptosis in vivo. OBJECTIVE:To observe the effects of exogenous nerve growth factor(NGF)on cerebral cortical neuronal Bcl-2 and Bax expression in mice with OxyHb-induced subarachnoid hemorrhage. DESIGN,TIME AND SETTING:A completely randomized grouping,controlled animal experiment was performed at the Experimental Center for Biomedicine,College of Medicine,Xi’an Jiaotong University between February and April 2005. MATERIALS:Fifty-four healthy,male,adult,ICR mice were included in this study.Subarachnoid hemorrhage was induced by a subarachnoid injection of OxyHb in 48 mice.Mouse NGF was obtained from Xiamen Beidazhilu Bioengineering Co.,Ltd.,China. METHODS:All 54 mice were randomly divided into three groups:control(n=6),injury(n=24),and NGF (n=24).The NGF group received a subarachnoidal administration of OxyHb,immediately followed by a caudal vein injection of NGF(1μg).The injury group was injected with OxyHb,and subsequently with physiological saline.The control group only received intravenous physiological saline. MAIN OUTCOME MEASURES:At 1,6,24,and 48 hours following subarachnoid hemorrhage induction, expression levels of Bcl-2 and Bax were detected by immunohistochemistry in the cerebral cortex 3 mm anterior and posterior to the injection site. RESULTS:At all time points following OxyHb injection,cerebral cortical Bax levels were significantly higher in the injured group than in the control and NGF groups(P<0.01).During the first 24 hours following OxyHb injection,cerebral cortical Bcl-2 levels were significantly lower in the injury group compared to the control group(P<0.05-0.01).Between 1 and 48 hours,Bcl-2 levels were significantly higher in the NGF group than in the injury group(P<0.01). CONCLUSION:Exogenous NGF can inhibit increased neuronal Bax expression and decreased Bcl-2 expression in the cerebral cortex of mice with OxyHb-induced subarachnoid hemorrhage.
基金supported by the National Natural Science Foundation of China(NSFC),No.31201878,81172716,and U1204804Post Doctoral Foundation of China,No.2015M572109Post Doctoral Fund of Henan province,No.2014049
文摘Lead exposure is a known potential risk factor for neurodegenerative diseases such as Alzheimer's disease(AD). Exposure to lead during the critical phase of brain development has been linked with mental retardation and hypophrenia in later life. This study was aimed to investigate the effects of lead exposure of pregnant mice on the expressions of insulin-degrading enzyme(IDE) and nerve growth factor(NGF) in the hippocampus of their offspring. Blood samples were collected from the tail vein, and after anesthetizing the pups, the brain was excised on postnatal day 21. Lead concentrations were determined by graphite furnace atomic absorption spectrophotometry, and the expressions of IDE and NGF were determined by immunohistochemistry and Western blotting. Results showed that the reduction in IDE and NGF expression in the hippocampus of pups might be associated with impairment of learning and memory and dementia induced by maternal lead exposure during pregnancy and lactation.
基金the Natural Science Foundation of Jiangsu Province, No. BK2004048the Social Development and Technology Plan of Nantong City, No. K2008009
文摘BACKGROUND: Nerve growth factor (NGF) attenuates glutamate-induced injury to hippocampal neurons, and the human tumor suppressor gene phosphatase and tensin homologue deleted on chromosome 10 (PTEN) promotes neuronal apoptosis. However, effects of PTEN in NGF-mediated neuroprotection against glutamate excitotoxicity remain poorly understood. OBJECTIVE: To investigate the relationship between NGF inhibition of glutamate-induced injury and PTEN. DESIGN, TIME AND SETTING: The randomized, controlled, in vitro study was performed at the Department of Pathophysiology, Medical School of Nantong University, China from October 2007 to March 2008. MATERIALS: Glutamate, NGF, 4, 6-diamidino-2-phenyl-indolediacetate, 3-[4, 5-dimethylthiazol-2-yl]- 2, 5-diphenyl tetrazoliumbromide (MTT), and lactate dehydrogenase kit (Sigma, USA), fluorescence microscope and inverted phase contrast microscope (Olympus, Japan) were used in this study. METHODS: Hippocampal neurons were obtained from newborn (< 24 hours) Sprague Dawley rats and cultured for 7 days. The control group was not treated with any intervention factor, the glutamate group was treated with glutamate (0.2 mmol/L), and NGF groups were treated with NGF (10, 50, 100, and 200 μg/L, respectively) prior to glutamate treatment. MAIN OUTCOME MEASURES: The MTT and lactate dehydrogenase assays were applied to evaluate viability of hippocampal neurons. Morphological changes in hippocampal neurons were observed using an inverted phase-contrast microscope, and neuronal apoptosis was detected by 4, 6-diamidino-2-phenyl-indolediacetate staining. PTEN mRNA and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot analysis, respectively. RESULTS: Glutamate (0.2 mmol/L) induced significantly decreased neuronal viability and greater lactate dehydrogenase efflux compared with the control group (P < 0.01). However, compared with the glutamate group, cell viability significantly increased and lactate dehydrogenase efflux decreased in the NGF group with increasing NGF concentrations (P < 0.05 or P < 0.01). The apoptotic ratio and PTEN mRNA and protein expression decreased in the NGF group compared with the glutamate group (P < 0.01). CONCLUSION: Pretreatment with NGF exerted neuroprotective effects against glutamate-induced injury, partially through inhibition of PTEN expression and neuronal apoptosis.
基金the Construction Program of Shanghai Medical Intensive Subject (Obstetrics and Gynaecology), No. 05-111-0165
文摘BACKGROUND: Studies have shown that abnormal innervation is an important factor impacting occurrence and development of pathological pain in endometriosis. OBJECTIVE: To observe uterine innervation of adenomyosis mice and to analyze the cause of innervation changes due to nerve growth factor (NGF) expression, inflammation, and vascularization. DESIGN, TIME AND SETTING: This randomized, controlled, animal experiment was performed at the Research Institute of Obstetrics and Gynecology Hospital, and Central Laboratory of Zhong- shan Hospital, Fudan University from March to December 2008. MATERIALS: Tamoxifen was provided by Fudan Forward, China. Rabbit anti-mouse NGF was purchased from Santa Cruz Corporation, USA; rabbit anti-protein gene product 9.5 (PGP9.5) and rabbit antisubstance P (SP) were purchased from Chemicon, USA. METHODS: A total of 40 newborn ICR mice were randomly assigned to adenomyosis model and control groups, with 20 animals in each group. Mice in the adenomyosis model group were orally administrated 2.7 μmol/kg tamoxifen on days 2-5 after birth, while the controls were not treated. MAIN OUTCOME MEASURES: Both uteri from all mice were harvested at days 135-145 after birth. Expressions of polyclonal PGP9.5 and SP were immunohistochemically detected to demonstrate pan- and sensory nerve fibers. Microvessel density was quantified in the endometrium and myometrium using immunochemical staining for polyclonal rabbit anti-CD31, which stained vessels. Gene expression for NGF, high-affinity tyrosine kinase receptor (trkA), p75 neurotrophin receptor (p75NTR), bradykinin receptor-1 (BKR-1), and 2 (BKR-2), as well as substance P receptor (neurokinin1 receptor, NK1-R), were detected by reverse transcription-polymerase chain reaction. NGF-β protein expression was detected by Western blot analysis. RESULTS: More nerve fibers were stained with PGP9.5 in the endometrium and myometrium, and with SP in the endometrium, in adenomyosis mice compared with controls (P < 0.01 and P < 0.05). Microvessel density in the myometrium of adenomyosis mice was significantly greater than the controls (P < 0.01). In the uterus of adenomyosis mice, mRNA expression of NGF and its two receptors (trkA and p75 NTR), BKR-1, and NK1-R, as well as protein expression of NGF-β, were greater than the control mice (P < 0.01 or P < 0.05). CONCLUSION: Uterine innervation in the adenomyosis mice was increased compared with the controls. Moreover, NGF expression, inflammation, and vascularization, which have been shown to be impact factors of innervation, were abnormal in the uteri of adenomyosis mice.
文摘Nerve growth factor(NGF) is a powerful trophic factor that provides essential support for the survival and differentiation of sympathetic and sensory neurons during development. However, NGF also activates nociceptors contributing significantly to inflammatory pain and neuropathic pain after tissue injury. As such anti-NGF based therapies represent a promising strategy for pain management. Because of dose-dependent serious side effects such as back pain, injection site hyperalgesia, clinical trials of using NGF to treat various disorders such as diabetic neuropathies, chemotherapy-induced and human immunodeficiency virus-associated peripheral neuropathies were all discontinued. Thus far, worldwide clinical applications of NGF in treating patients are very limited except in China. Hereditary sensory autonomic neuropathy type V(HSAN V) is an extremely rare disease. Genetic analyses have revealed that HSAN V is associated with autosomal recessive mutations in NGF. One of the mutations occurred at the 100^(th) position of mature NGF resulting in a change of residue from arginine to tryptophan(R100W). Although those HSAN V patients associated with the NGF^(R100W) mutation suffer from severe loss of deep pain, bone fractures and joint destruction, interestingly patients with the NGF^(R100W) mutation do not show apparent cognitive deficits, suggesting important trophic support function is preserved. We believe that NGF^(R100W) provides an ideal tool to uncouple the two important functions of NGF: trophic versus nociceptive. Studies from investigators including ourselves have indeed confirmed in animal testing that the NGF^(R100W) no longer induced pain. More importantly, the trophic function seemed to be largely preserved in NGF harboring the R100W mutation. On the mechanistic level, we found that the NGF^(R100W) mutation was capable of binding to and signaling through the tyrosine receptor kinase A receptor. But its ability to bind to and activate the 75 kDa neurotrophic factor was significantly diminished. The significance of these findings is at least two folds: 1) the NGF^(R100W) mutation can be used as an alternative to the wildtype NGF to treat human conditions without eliciting pain; and 2) the 75 kDa neurotrophic factor may serve as a novel target for pain management. We will discuss all the details in this mini-review.
基金supported by the Natural Science Foundation of Jiangsu Higher Education Institutions of China(Major Program),No.16KJA310005(to SYL)the Natural Science Foundation of Nantong City of China,No.JC2018058(to TMQ)the Priority Academic Program Development of Jiangsu Higher Education Institutions of China
文摘The regenerative capacity of peripheral nerves is limited after nerve injury.A number of growth factors modulate many cellular behaviors,such as proliferation and migration,and may contribute to nerve repair and regeneration.Our previous study observed the dynamic changes of genes in L4–6 dorsal root ganglion after rat sciatic nerve crush using transcriptome sequencing.Our current study focused on upstream growth factors and found that a total of 19 upstream growth factors were dysregulated in dorsal root ganglions at 3,9 hours,1,4,or 7 days after nerve crush,compared with the 0 hour control.Thirty-six rat models of sciatic nerve crush injury were prepared as described previously.Then,they were divided into six groups to measure the expression changes of representative genes at 0,3,9 hours,1,4 or 7 days post crush.Our current study measured the expression levels of representative upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin genes,and explored critical signaling pathways and biological process through bioinformatic analysis.Our data revealed that many of these dysregulated upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin,participated in tissue remodeling and axon growth-related biological processes Therefore,the experiment described the expression pattern of upstream growth factors in the dorsal root ganglia after peripheral nerve injury.Bioinformatic analysis revealed growth factors that may promote repair and regeneration of damaged peripheral nerves.All animal surgery procedures were performed in accordance with Institutional Animal Care Guidelines of Nantong University and ethically approved by the Administration Committee of Experimental Animals,China(approval No.20170302-017)on March 2,2017.
文摘Objective: To study the effect of surgery combined with nerve growth factor preparation treatment of acute cerebral hemorrhage on nerve cytokines and nerve injury. Methods: 68 patients with acute cerebral hemorrhage who received emergency minimally invasive evacuation of hematoma in Zigong No. 4 People's Hospital between August 2014 and September 2016 were selected and randomly divided into mNGF group and control group, mNGF group received postoperative mouse nerve growth factor preparation combined with conventional therapy, and control group accepted routine postoperative treatment. 10d, 20d and 30d after treatment, the serum was collected to determine the levels of nerve cytokines and nerve injury molecules. Results: 10d, 20d and 30d after treatment, serum BDNF (5.29±0.88 vs. 3.58±0.61, 6.94±0.93 vs. 3.78±0.55, 9.28±1.13 vs. 4.57±0.62 ng/ml), NTF-α (2.94±0.52 vs. 1.35±0.18, 3.88±0.58 vs. 1.51±0.20, 5.21±0.72 vs. 2.95±0.46 ng/ml), NGF (0.89±0.11 vs. 0.62±0.08, 1.02±0.15 vs. 0.78±0.09, 1.45±0.18 vs. 0.92±0.12 ng/ml) and VEGF (147.53±19.52 vs. 110.38±14.28, 184.95±22.51 vs. 121.29±17.85, 237.49±31.28 vs. 145.38±18.31 pg/ml) levels of mNGF group were significantly higher than those of control group while S100β (1.27±0.20 vs. 2.19±0.33, 0.94±0.14 vs. 1.76±0.25, 0.71±0.09 vs. 1.32±0.17 ng/ml), GFAP (2.08±0.36 vs. 4.42±0.55, 1.65±0.25 vs. 3.57±0.51, 1.31±0.17 vs. 2.93±0.42 pg/ml), NSE (34.21±5.82 vs. 73.19±9.35, 27.58±4.12 vs. 58.76±8.28, 22.12±3.25 vs. 39.52±5.28 ng/ml), MBP (5.28±0.93 vs. 11.28±1.86, 3.89±0.51 vs. 9.12±1.14, 3.12±0.41 vs. 6.79±0.94 ng/ml), MDA (6.97±0.93 vs. 14.21±1.87, 5.02±0.78 vs. 11.75±1.76, 3.57±0.62 vs. 8.12±0.99 μmol/L), AOPP(65.19±9.68 vs. 155.62±19.63, 48.59±7.21 vs. 118.75±16.85, 37.83±5.28 vs. 82.11±10.18 μmol/L) and 8-OHdG (4.77±0.67 vs. 10.28±1.52, 3.52±0.51 vs. 9.38±1.15, 2.33±0.41 vs. 6.52±0.92 ng/ml) levels were significantly lower than those of control group. Conclusion: Surgery combined with nerve growth factor preparation treatment of acute cerebral hemorrhage can improve neural nutritional status and reduce nerve injury degree, and it is beneficial to the recovery of neural function.
基金Supported by National Natural Science Foundation of China,No.81172044
文摘AIM:To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase(NGF-TrkA)signaling pathway and prognosis in intrahepatic cholangiocarcinoma(IHCC).METHODS:NGF and TrkA expression in 83 samples of IHCC was assessed by immunohistochemistry.Correlations between NGF-TrkA expression and clinicopathological features were analyzed byχ2 test.Moreover,we evaluated the association between NGF-TrkA and overall survival by univariate and multivariate analysis.With experiments in vitro,we investigated the crucial role of NGF-TrkA on proliferation and invasion of IHCC cells with recombinant NGF-βstimulation.RESULTS:We found that NGF and TrkA expression was significantly related with differentiation(P=0.024)and intraneural invasion(P=0.003),respectively.Additionally,double higher expression of NGF and TrkA was identified as an independent prognostic factor in IHCC(P=0.003).Moreover,we demonstrated that NGF-TrkA signaling pathway can promote IHCC proliferation and invasion.CONCLUSION:NGF-TrkA double higher expression is an independent prognostic factor in IHCC.NGF-TrkA pathway can promote IHCC progression,indicating that NGF-TrkA may become a potential drug target.
基金This study was funded by the National Natural Science Foundation of China,No.81470200(to XJR).
文摘Electroacupuncture(EA)has been shown to reduce blood lipid level and improve cerebral ischemia in rats with hyperlipemia complicated by cerebral ischemia.However,there are few studies on the results and mechanism of the effect of EA in reducing blood lipid level or promoting neural repair after stroke in hyperlipidemic subjects.In this study,EA was applied to a rat model of hyperlipidemia and middle cerebral artery thrombosis and the condition of neurons and astrocytes after hippocampal injury was assessed.Except for the normal group,rats in other groups were fed a high-fat diet throughout the whole experiment.Hyperlipidemia models were established in rats fed a high-fat diet for 6 weeks.Middle cerebral artery thrombus models were induced by pasting 50%FeCl3 filter paper on the left middle cerebral artery for 20 minutes on day 50 as the model group.EA1 group rats received EA at bilateral ST40(Fenglong)for 7 days before the thrombosis.Rats in the EA1 and EA2 groups received EA at GV20(Baihui)and bilateral ST40 for 14 days after model establishment.Neuronal health was assessed by hematoxylin-eosin staining in the brain.Hyperlipidemia was assessed by biochemical methods that measured total cholesterol,triglyceride,low-density lipoprotein and high-density lipoprotein in blood sera.Behavioral analysis was used to confirm the establishment of the model.Immunohistochemical methods were used to detect the expression of glial fibrillary acidic protein and nerve growth factor in the hippocampal CA1 region.The results demonstrated that,compared with the model group,blood lipid levels significantly decreased,glial fibrillary acidic protein immunoreactivity was significantly weakened and nerve growth factor immunoreactivity was significantly enhanced in the EA1 and EA2 groups.The repair effect was superior in the EA1 group than in the EA2 group.These findings confirm that EA can reduce blood lipid,inhibit glial fibrillary acidic protein expression and promote nerve growth factor expression in the hippocampal CA1 region after hyperlipidemia and middle cerebral artery thrombosis.All experimental procedures and protocols were approved by the Animal Use and Management Committee of Beijing University of Chinese Medicine,China(approval No.BUCM-3-2018022802-1002)on April 12,2018.
基金supported by the National Natural Science Foundation of China,Nos.31900749(to PH),31730030(to XGL),81941011(to XGL),31971279(to ZYY),31771053(to HMD)the Natural Science Foundation of Beijing of China,No.7214301(to FH)。
文摘Although autogenous nerve transplantation is the gold standard for treating peripheral nerve defects of considerable length,it still has some shortcomings,such as insufficient donors and secondary injury.Composite chitosan scaffolds loaded with controlled release of nerve growth factor can promote neuronal survival and axonal regeneration after short-segment sciatic nerve defects.However,the effects on extended nerve defects remain poorly understood.In this study,we used chitosan scaffolds loaded with nerve growth factor for 8 weeks to repair long-segment(20 mm)sciatic nerve defects in adult rats.The results showed that treatment markedly promoted the recovery of motor and sensory functions.The regenerated sciatic nerve not only reconnected with neurons but neural circuits with the central nervous system were also reconstructed.In addition,the regenerated sciatic nerve reconnected the motor endplate with the target muscle.Therefore,this novel biomimetic scaffold can promote the regeneration of extended sciatic nerve defects and reconstruct functional circuits.This provides a promising method for the clinical treatment of extended peripheral nerve injury.This study was approved by the Animal Ethics Committee of Capital Medical University,China(approval No.AEEI-2017-033)on March 21,2017.
文摘Neurotrophins are a family of proteins that support neuronal proliferation, survival, and differentiation in the central and peripheral nervous systems, and are regulators of neuronal plasticity. Nerve growth factor is one of the best-described neurotrophins and has advanced to clinical trials for treatment of ocular and brain diseases due to its trophic and regenerative properties. Prior trials over the past few decades have produced conflicting results, which have principally been ascribed to adverse effects of systemic nerve growth factor administration, together with poor penetrance of the blood-brain barrier that impairs drug delivery. Contrastingly, recent studies have revealed that topical ocular and intranasal nerve growth factor administration are safe and effective, suggesting that topical nerve growth factor delivery is a potential alternative to both systemic and invasive intracerebral delivery. The therapeutic effects of local nerve growth factor delivery have been extensively investigated for different ophthalmic diseases, including neurotrophic keratitis, glaucoma, retinitis pigmentosa, and dry eye disease. Further, promising pharmacologic effects were reported in an optic glioma model, which indicated that topically administered nerve growth factor diffused far beyond where it was topically applied. These findings support the therapeutic potential of delivering topical nerve growth factor preparations intranasally for acquired and degenerative brain disorders. Preliminary clinical findings in both traumatic and non-traumatic acquired brain injuries are encouraging, especially in pediatric patients, and clinical trials are ongoing. The present review will focus on the therapeutic effects of both ocular and intranasal nerve growth factor delivery for diseases of the brain and eye.
基金supported by a grant from the Korea Healthcare Technology R&D Project,Ministry for Health,Welfare&Family Affairs,Republic of Korea,No.A101578
文摘Several studies have shown that fibroblast growth factor-2(FGF2) can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the effect of recombinant human FGF-2(rh FGF2) treatment on damaged mental nerves. The mental nerves of 6-week-old male Sprague-Dawley rats were crush-injured for 1 minute and then treated with 10 or 50 μg/m L rh FGF2 or PBS in crush injury area with a mini Osmotic pump. Sensory test using von Frey filaments at 1 week revealed the presence of sensory degeneration based on decreased gap score and increased difference score. However, at 2 weeks, the gap score and difference score were significantly rebounded in the mental nerve crush group treated with 10 μg/m L rh FGF2. Interestingly, treatment with 10 μg/m L rh FGF had a more obviously positive effect on the gap score than treatment with 50 μg/m L rh FGF2. In addition, retrograde neuronal tracing with Dil revealed a significant increase in nerve regeneration in the trigeminal ganglion at 2 and 4 weeks in the rh FGF2 groups(10 μg/m L and 50 μg/m L) than in the PBS group. The 10 μg/m L rh FGF2 group also showed an obviously robust regeneration in axon density in the mental nerve at 4 weeks. Our results demonstrate that 10 μg/m L rh FGF induces mental nerve regeneration and sensory recovery after mental nerve crush injury.
基金Scientific and Technological Research Developing Program of Shaanxi Province, No. 2007K15-01
文摘BACKGROUND: Neuronal apoptosis in perihematomal brain tissues following intracerebral hemorrhage is strongly related to the formation of a compound signal pathway between nerve growth factor precursor (proNGF), p75NTR, and sortilin receptor. Sortilin acts as a co-receptor and molecular switch governing the p75NTR-mediated pro-apoptotic signal induced by proNGF. OBJECTIVE: To investigate proNGF and sortilin expressions in perihematomal brain tissues following intracerebral hemorrhage, and to study the effects of proNGF and sortilin on secondary cell apoptosis. DESIGN, TIME AND SETTING: A paired, comparison study was performed at the Laboratory of Histology and Embryology, Xi'an Jiaotong University from October 2007 to September 2008. MATERIALS: Brain tissue samples were obtained from 15 patients with intracerebral hemorrhage, who were treated at the Department of Neurosurgery, First Affiliated Hospital, Medical College of Xi'an Jiaotong University from October 2007 to March 2008. Rabbit anti-proNGF polyclonal antibody was provided by Chemicon, USA; rabbit antisortilin polyclonal antibody by Abcam, UK; and TUNEL kit by Promega, USA. METHODS: Perihematomal brain tissues selected 0.5 cm from the hemorrhage area were considered to be the hemorrhage group, while brain tissues from the middle temporal gyrus served as the control group. MAIN OUTCOME MEASURES: Histopathological changes were detected using hematoxylin-eosin staining, cell apoptosis was determined using the TUNEL method, and proNGF and sortilin ex- pressions were determined using immunohistochemistry. RESULTS: Edema was clearly observed in perihematomal brain tissues, and infiltration of inflammatory cells was visible, with the presence of irregular and necrotic bodies. The apoptotic rate in the hemorrhage group was significantly greater than in the control group (P < 0.01). Moreover, sortilin expression significantly increased (P < 0.01), but proNGF expression remained unchanged (P > 0.05). Correlation analysis suggested that sortilin expression positively correlated with apoptosis (rs = 0.648, P < 0.01). CONCLUSION: proNGF expression was stable, but sortilin expression increased in perihematomal brain tissues following intracerebral hemorrhage, suggesting that sortilin acted as a co-receptor and molecular switch to govern p75NTR-mediated cell apoptosis.
基金Supported by National Institutes of Health/National Instituteof Diabetes and Digestive and Kidney Diseases (NIH/NIDDK)Grant # 1R01-DK077541 (to Hathout E)a grant from the National Medical Test Bed (to Hathout E)
文摘AIM:To clarify the mechanism by which bone marrow cells promote angiogenesis around transplanted islets.METHODS: Streptozotocin induced diabetic BALB/ c mice were transplanted syngeneically under the kidney capsule with the following: (1) 200 islets (islet group: n=12), (2) 1-5×106 bone marrow cells (bone marrow group: n=11), (3) 200 islets and 1-5×106 bone marrow cells (islet + bone marrow group: n= 13), or (4) no cells (sham group:n=5). All mice were evaluated for blood glucose, serum insulin, serum nervegrowth factor (NGF) and glucose tolerance (GTT) up to postoperative day (POD) 14. Histological assessment for insulin, von Willebrand factor (vWF) and NGF was performed at POD 3, 7 and 14.RESULTS: Blood glucose level was lowest and serum insulin was highest in the islet + bone marrow group. Serum NGF increased in islet, bone marrow, and islet + bone marrow groups after transplantation, and there was a significant difference (P=0.0496, ANOVA) between the bone marrow and sham groups. The number of vessels within the graft area was signif icantly increased in both the bone marrow and islet + bone marrow groups at POD 14 as compared to the islet alone group (21.2 ± 3.6 in bone marrow, P=0.01, vs islet group, 22.6 ± 1.9 in islet + bone marrow, P = 0.0003, vs islet group, 5.3 ± 1.6 in islet-alone transplants). NGF was more strongly expressed in bone marrow cells compared with islets. CONCLUSION: Bone marrow cells produce NGF and promote angiogenesis. Islet co-transplantation with bone marrow is associated with improvement of islet graft function.
