Research progress on P2X7 receptor in cancer pain / 基础医学与临床

The activation of the P2X7 receptor as an ATP-gated ion channel,triggers the release of pro-inflammato-ry cytokines in tumor carring individuals and stimulate excitation of injury-causing neurons,thereby exacerbating the transmission of pain.In preclinical cancer pain models,it has the potential to serve as a new therapeutic target for cancer pain management.

Autophagy protects neurons against facial nerve injury in rats / 中国组织工程研究

BACKGROUND:After peripheral facial nerve injury,glial cell-derived neurotrophic factor(GDNF)can play a protective role in facial neurons.It has been found that GDNF can regulate the level of autophagy through mammalian target of rapamycin(mTOR),but it is unclear whether it can regulate facial neurons through the adenylate-activated protein kinase/Unc-51-like kinase 1(AMPK/ULK1)signaling pathway after facial nerve injury. OBJECTIVE:To establish a facial nerve injury model in Sprague-Dawley rats and explore the role of autophagy in facial nerve regeneration and the mechanism by which the GDNF/AMPK/ULK1 signaling pathway promotes facial nerve repair after injury. METHODS:Seventy-two Sprague-Dawley rats were randomly divided into sham group,model group and autophagy inhibitor 3-methyladenine(3-MA)group,with 24 rats in each group.Only the main trunk of the facial nerve was exposed in the sham group,while the remaining two groups were modeled for the compression injury of the facial nerve trunk.After successful modeling,the model group was given intraperitoneal injection of normal saline(15 mg/kg),and the 3-MA group was given intraperitoneal injection of 3-MA(15 mg/kg),both once daily for 7 days.The rats in each group were scored on the Simone 10-point behavioral scale at 1,4,7,14,21 and 28 days after surgery.Nissl staining was performed to observe the morphology and number of facial neuron cells at 7,14,21,and 28 days.The expression levels of p-AMPK,p-ULK1,Beclin1 and GDNF in the facial neuron tissues of rats were detected by western blot assay. RESULTS AND CONCLUSION:Behavioral scoring showed that the improvement of facial paralysis symptoms in the 3-MA group was worse and later than that in the model group(P<0.05).Nissl staining showed that the morphology and number of Nissl bodies in facial neurons in the 3-MA group recovered poorly and the number was less than that in the model group(P<0.05).Western blot detection results showed that the expression of p-AMPK and Beclin1 in the model group was higher than that in the 3-MA group and the sham group(P<0.05).The protein expression of p-ULK1 in the model group was lower than that in the 3-MA group and the sham group(P<0.05).To conclude,autophagy inhibitor delays nerve repair after facial nerve injury,which may be related to down-regulation of GDNF expression,inactivation of AMPK,and phosphorylation of ULK1,thereby inhibiting neuronal autophagy levels.

Research progress on the involvement of adhesion molecule contactin-1 in neuropsychiatric disorders by regulating neuroinflammation / 新乡医学院学报

Contactin-1(CNTN1)is a neural cell adhesion molecule belonging to the subgroup of immunoglobulin superfamily.It is anchored on the cell surface through glycosyl phosphatidyl inositol-anchored neural membrane proteins and participates in axon guidance,synapse formation,growth and development of nervous systems,and occurrence of related disea-ses.In addition,CNTN1 can promote inflammatory response and signal communication between microglia and astrocytes through various mechanisms,playing a role in the pathological processes of various neurological and psychiatric disorders.This article discusses the role of CNTN1 in depression and cognitive dysfunction.

Research progress of retinal neurovascular unit injury in glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

Glaucoma is one of the leading causes of vision loss worldwide. More and more studies have suggested that glaucoma is a complicated retinal neurovascular disease. The homeostasis imbalance of retinal neurovascular unit(RNVU)composed of neurons, glial cells and microvascular cells not only induces changes in microvascular structure and glial cells, but also affects the nerve tissue of the retina, resulting in vision loss, which there is no effective treatment to reverse, currently. Exploring the cellular composition and molecular structure of RNVU and investigating the destruction mechanism of normal cellular environment and intercellular connections in glaucoma are of great significance in exploring the pathogenesis and the treatment of glaucoma. The research progress on structural changes and dysfunction of RNVU in glaucoma are reviewed, hoping to provide new ideas for the treatment of glaucoma.

Expression of GDNF and AR in Testicular Peritubular Cells of Surgery-induced Cryptorchidism Mice / 中山大学学报(医学科学版)

ObjectiveTo investigate the expression of glial cell line-derived neurotrophic factor （GDNF） and androgen receptor （AR） in testicular peritubular cells （TPCs） of cryptorchidism mouse models and explore the theoretical significance of cryptorchidism-induced spermatogenesis dysfunction. MethodsA total of 30 five-week-old male ICR rats were divided randomly by using random number table method into 6 groups. Cryptorchidism was surgically induced in 3 randomly selected groups and the other 3 groups underwent sham surgery as the control groups. On days 4， 7 and 14 after surgery， we harvested the mice testes of the 3 groups and their corresponding control groups， then measured the testicular volumes， analyzed the testicular histopathology and detected the mRNA and protein expression levels of AR and GDNF in TPCs by immunofluorescence， real-time PCR and Western blot. ResultsIn normal control groups， on days 4， 7 and 14 after surgery， the testicular volumes were （125.58±19.22） mm3，（123.45±20.12） mm3， （140.09±13.62） mm3 ， respectively. Clear layers of spermatogenic cells were well arranged and abundant sperm cells were found. Peritubular cells were morphologically homogeneous， with slim-spindle appearance and normal cell thickness. The mRNA expression levels of AR were 1.00±0.05， 1.06±0.07 and 1.19±0.13； GDNF mRNA 1.00±0.04， 1.09±0.05， and 1.10±0.07. The protein expression levels of AR were 1.01±0.01， 0.79±0.02 and 1.01±0.04； GDNF protein （18.68±0.43） pg/mL， （14.39±0.36） pg/mL and （16.88±0.37） pg/mL. In cryptorchidism groups， on days 4， 7 and 14 after surgery， the testicular volumes were （115.64±3.91） mm3， （69.51±14.97） mm3 and （44.86±5.56） mm3， respectively. Spermatogenic cells were disorganized， seminiferous tubules were disrupted， peritubular cells shrank， bent and fractured. The mRNA expression levels of AR were 0.76±0.06， 0.53±0.04， and 0.29±0.02； GDNF mRNA 0.72±0.05， 0.42±0.02 and 0.30±0.03. The protein expression levels of AR were 0.54±0.02， 0.98±0.04 and 0.31±0.01； GDNF protein （8.50±0.34） pg/mL， （17.44±0.32） pg/mL and （6.83±0.34） pg/mL. Statistically significant differences （P < 0.05） were found in 7-day and 14-day testicular volumes between control and cryptorchidism groups but not in the 4-day testicular volume （P > 0.05）. Testicular volumes， AR and GDNF mRNA and protein expression in control groups had no statistically significant difference （P > 0.05）， while those in cryptorchidism groups showed a trend of gradual decline in the amount and the differences between groups were statistically significant （P < 0.05）. ConclusionsIn surgery-induced cryptorchidism mice， after the induction， the expression of AR and GDNF in TPCs showed a gradual decrease over time. AR and GDNF play a major role in mediating the TPCs damage in cryptorchidism. This study provides a theoretical basis for mechanism researches of cryptorchidism-induced spermatogenesis dysfunction.

Electroacupuncture Promotes Functional Recovery after Facial Nerve Injury in Rats by Regulating Autophagy via GDNF and PI3K/mTOR Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To explore the mechanism of electroacupuncture (EA) in promoting recovery of the facial function with the involvement of autophagy, glial cell line-derived neurotrophic factor (GDNF), and phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway.@*METHODS@#Seventy-two male Sprague-Dawley rats were randomly allocated into the control, sham-operated, facial nerve injury (FNI), EA, EA+3-methyladenine (3-MA), and EA+GDNF antagonist groups using a random number table, with 12 rats in each group. An FNI rat model was established with facial nerve crushing method. EA intervention was conducted at Dicang (ST 4), Jiache (ST 6), Yifeng (SJ 17), and Hegu (LI 4) acupoints for 2 weeks. The Simone's 10-Point Scale was utilized to monitor the recovery of facial function. The histopathological evaluation of facial nerves was performed using hematoxylin-eosin (HE) staining. The levels of Beclin-1, light chain 3 (LC3), and P62 were detected by immunohistochemistry (IHC), immunofluorescence, and reverse transcription-polymerase chain reaction, respectively. Additionally, IHC was also used to detect the levels of GDNF, Rai, PI3K, and mTOR.@*RESULTS@#The facial functional scores were significantly increased in the EA group than the FNI group (P<0.05 or P<0.01). HE staining showed nerve axons and myelin sheaths, which were destroyed immediately after the injury, were recovered with EA treatment. The expressions of Beclin-1 and LC3 were significantly elevated and the expression of P62 was markedly reduced in FNI rats (P<0.01); however, EA treatment reversed these abnormal changes (P<0.01). Meanwhile, EA stimulation significantly increased the levels of GDNF, Rai, PI3K, and mTOR (P<0.01). After exogenous administration with autophagy inhibitor 3-MA or GDNF antagonist, the repair effect of EA on facial function was attenuated (P<0.05 or P<0.01).@*CONCLUSIONS@#EA could promote the recovery of facial function and repair the facial nerve damages in a rat model of FNI. EA may exert this neuroreparative effect through mediating the release of GDNF, activating the PI3K/mTOR signaling pathway, and further regulating the autophagy of facial nerves.

Effects of Baduanjin on gait parameters and serum nerve growth factor in Parkinson disease patients with freezing of gait / 中华行为医学与脑科学杂志

Objective:To explore the effect of Baduanjin on gait parameters and serum nerve growth factor in Parkinson disease (PD) patients with freezing of gait(FOG).Methods:From December 2021 to December 2022, thirty-eight PD patients with FOG who met the inclusion and exclusion criteria were randomly divided into observation group ( n=18) and control group ( n=20) by random number table.The patients in both two groups received 4 weeks of drug therapy combined with basic rehabilitation treatment respectively, and the patients in observation group received additional Baduanjin training.Efficacy was evaluated 1 day before intervention and after 4 weeks of intervention through unified Parkinson's disease rating scale-Ⅱ(UPDRS-Ⅱ) item 14, freezing of gait questionnaire (FOGQ), gait starting time, gait cycle, stride length, dynamic plantar peak pressure and average pressure, while the levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor(GDNF) in peripheral blood of patients were tested.SPSS 23.0 software was used to conduct Chi-square test, paired t-test, independent sample t-test and Mann-Whitney U test. Results:Before treatment, there were no significant differences in score of UPDRS-Ⅱ item 14, FOGQ score, gait starting time, gait cycle, stride length, dynamic planar peak pressure, average pressure, peripheral blood BDNF level and GDNF level between the two groups ( t=-0.542, 0.562, 0.490, 0.674, 0.440, 0.606, -0.835, -0.873, -0.250, all P>0.05). After treatment, compared with the control group, dynamic plantar peak pressure (control group (14.26±3.23) N/cm 2, observation group (11.40±4.13) N/cm 2, t=-2.389, P=0.022) and plantar average pressure (control group (3.34±0.72) N/cm 2, observation group (2.79±0.81) N/cm 2, t=-2.209, P=0.034) of the observation group were significantly decreased (both P<0.05). There were no significant differences in UPDRS-Ⅱ item 14, FOGQ score, gait starting time, gait cycle, stride length, BDNF and GDNF concentrations in peripheral blood between the two groups after treatment (all P>0.05). The difference between pre-treatment and post-treatment of FOGQ score (control group 1.00 (0.00, 1.00) , observation group 2.00 (0.75, 3.00), Z=-2.547, P=0.011), gait starting time (control group -1.04 (-1.86, -0.47)s, observation group -2.34 (-3.41, -1.03) s, Z=-2.280, P=0.023), gait cycle (control group 0.29 (0.08, 0.58)s, observation group 0.35 (0.16, 1.00) s, Z=-2.748, P=0.006), stride length(control group 0.19 (0.14, 0.24) m, observation group 0.26 (0.23, 0.38)m, Z=-1.360, P=0.005), the dynamic plantar peak pressure (control group -4.11 (-5.87, -2.57) N/cm 2, observation group -8.44 (-10.12, -4.81) N/cm 2, Z=-3.333, P=0.001) and average pressure (control group -0.55 (-1.00, -0.03) N/cm 2, observation group -1.11 (-1.51, -0.66) N/cm 2, Z=-2.062, P=0.009) in the observation group were better than those in the control group.After treatment, the BDNF level in peripheral blood in observation group was higher than before treatment( t=-2.315, P=0.033). Conclusion:Baduanjin can improve frozen gait score and gait parameters in PD patients with FOG, which may be related to the increase of peripheral blood BDNF.

Changes to GFAP Immunoreactive Astrocytes in Medial Prefrontal Cortex Following Exposure to Chronic Stress and Antioxidant Supplementation in Rat Model

@#Introduction: Astrocytes are responsible for many essential functions of neurons in CNS. It has been recognised that chronic stress affects the morphology of astrocyte. Natural antioxidant such as honey has been used as one of the therapeutic strategies to lessen the damaging effect of chronic stress on our body. Therefore, the aim of the study is to explore the effect of natural antioxidant, Tualang honey (TH) on the morphology of astrocytes following chronic stress exposure. Methods: Thirty-two male rats were randomly divided into the 4 groups: (i) control, (ii) stress, (iii) honey, (iv) stress plus honey groups.TH was administered via oral gavage at dose of 1.0 g/kg body weight pre and post experiment. Chronic stress was exposed to animals in group (ii) and (iv) for consecutive 21 days. Anti GFAP immunohistochemistry method was employed to label astrocytes in the medial prefrontal cortex. The number of GFAP+ astrocytes and several parameters related to astrocyte processes were measured. Results: The present study showed that chronic stress reduced the GFAP immunoreactive astrocyte number and percentage of GFAP immunoreactive material. Chronic stress also caused a reduction in astrocyte process ramification as indicated by a reduction in astrocyte total number of processes, average length of processes and maximum number of intersections. However, antioxidant treatment using TH could not reverse these stress-induced changes to the astrocytes. Conclusion: These results demonstrate that chronic stress decreases the number of GFAP immunoreactive astrocyte and cause shrinking of astrocyte processes in stress-sensitive brain region, but these changes cannot be reversed by antioxidant treatment.

Effect of Mingjing Granules on Fibrovascular Membrane of Wet Age-related Macular Degeneration Based on Macrophages and Glial Cells / 中国实验方剂学杂志

ObjectiveTo investigate the effects of Mingjing granules （MJKL） on the fibrovascular membrane of experimental wet age-related macular degeneration （nAMD） based on macrophages and glial cells and further explain the mechanism of MJKL in the treatment of nAMD. MethodThe experimental nAMD fibrovascular membrane model was established by two-stage laser photocoagulation. BN rats were randomly divided into three groups： model group， anti-vascular endothelial growth factor （VEGF） group， and MJKL + anti-VEGF group. The model group was given distilled water for intragastric administration. Anti-VEGF group was injected with leizumab injection in the vitreous cavity. MJKL + anti-VEGF group was injected with leizumab injection in the vitreous cavity， and MJKL was intragastrically administered. Ten normal BN rats were not modeled and fed as controls. After 40 days of model making， fundus lesion morphology， lesion exudation area， and MD value were observed by fundus photography （FP）， fundus angiography （FFA）， optical coherence tomography （OCT）， and retinal pigment epithelium （RPE）-choroid-sclera film. The changes in retinal structure were observed by histopathology， and the expression and distribution of F4/80， Iba-1， and GFAP were detected by immunofluorescence. The relative expression levels of F4/80， Iba-1， and GFAP mRNA were detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultThe fibrovascular membrane model was established 40d after two-stage laser modeling. The lesion exudation area， MD value， lesion height， and lesion area in the anti-VEGF group were significantly lower than those in the model group （P<0.05）， and the retinal structural damage degree was significantly improved. Compared with the anti-VEGF group， the MJKL + anti-VEGF group significantly decreased the MD value， lesion height， and lesion area （P<0.05）， and lesion area and retinal structural damage degree were significantly improved. The fluorescence intensity of F4/80 and Iba-1 in the model group was significantly higher than that in the normal group （P<0.05）， and that in the anti-VEGF group was significantly lower than that in the model group （P<0.05）. The fluorescence intensity in the MJKL + anti-VEGF group was significantly lower than that in the anti-VEGF group （P<0.05）. The fluorescence intensity of GFAP in the model group was significantly higher than that in the normal group （P<0.05）， and that in the anti-VEGF group was significantly lower than that in the model group （P<0.05）. The relative expression levels of F4/80， Iba-1， and GFAP mRNA in the model group were significantly increased compared with the normal group （P<0.05）， and the anti-VEGF group was significantly decreased compared with the model group （P<0.05）. The relative expression levels of F4/80， Iba-1， and GFAP mRNA in the MJKL + anti-VEGF group were significantly decreased compared with those in the anti-VEGF group （P<0.05）. ConclusionMJKL combined with anti-VEGF drugs can inhibit the growth of experimental nAMD fibrovascular membrane better than anti-VEGF drugs alone， and the mechanism may be related to inhibiting the participation of macrophages and glial cells in the formation of fibrovascular membrane.

Inhibition of Foxp4 Disrupts Cadherin-based Adhesion of Radial Glial Cells, Leading to Abnormal Differentiation and Migration of Cortical Neurons in Mice / 神经科学通报·英文版

Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders (NDDs) that exhibit delayed speech development, intellectual disability, and congenital abnormalities. The etiology of NDDs is unclear. Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells (RGCs), respectively, in the mouse neocortex during early gestation. Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone (VZ). Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ. The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs. The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions, the loss of which leads to periventricular heterotopias. We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.