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Supervisor: Ministry of Education of the People's Republic of China

Sponsor: Sichuan University

Host unit: Editorial Board of Journal of Sichuan University (Medical Science Edition)

Editor-in-Chief: Yuquan Wei

CN 51-1644/R

ISSN 1672-173X

Postal code: 62-72

Establishment Time: 1959

Address: 17,Section 3,Renmin Nanlu,Chengdu,Sichuan,610041,People's Republic of China

Tel: 028-85501320

Email: scuxbyxb@scu.edu.cn


A 5+-day-old male patient was hospitalized due to significant increase of urine protein for 5+ days. A 36+4 weeks preterm male infant was found with III° polluted amniotic fluid and excessive placenta, presented with proteinuria, hypoproteinemia, and progressive edema after birth. Two heterozygous mutations of NPHS1 gene, c.3325C>T (p.Arg1109*) and c.2479C>T (p.Arg827*), were found through the whole exon gene detection. The latter has not been reported domestically andthe diagnosis of congenitalnephrotic syndrome of the Finnish type (CNF) is definite. The report of c.2479C>T mutation gene will expand the mutation spectrum of CNF gene data in China. Early genetic testing is recommended for cryptogenic congenital nephrotic syndrome (CNS) and early genetic diagnosis of CNF is important for prognostic evaluation, genetic counseling and clinical management.
Motor function injuries mostly block or interfere with motor nerve conduction pathways. Theinnovative multi-target magnetic stimulation (MS) technology stimulates the cortex and nerve roots to activate the human central and peripheral nervous system, and has achieved preliminary results in scientificand clinical exploration. The mechanismsof these researches involve the activation of neurons, nerve conduction, the regulation of the microenvironment of the injured area, and gene regulation. However, how to make the multi-target MS technology achieve more accurate and effective nerve repair in rehabilitation is a bottleneck problem, which may need to break through neural circuit reconstruction and task-oriented training. This topic focuses on Nerve Regeneration Modulation and Rehabilitation, aiming to apply the concepts of nerve regeneration and neuromodulation totreatment of rehabilitation, and to supportfor exploring the neurobiological mechanism of rehabilitation. This review will explore the important role of multi-target synergistic enhanced neural circuit modulation technology in neural circuit reconstruction, and establish more accurate and effective multi-target innovative technologies and clinical pathways, so as to promote the basic and clinical research of neuromodulation.
Transcranial magnetic stimulation (TMS), as a non-invasive neuromodulation technique, has achieved certain results in the study of brain function localization, treatment of nervous and mental diseases, but its mechanism of action and physiological effects are difficult to be clarified. The signals in blood oxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI) is capable of reflecting the activities of brain tissue neurons. TMS-fMRI combines the advantages of two techniques to monitor changes in excitability of the TMS stimulation site and the distal brain region with which it is functionally linked. In this review, we elaborates the advances, limitations and future expectations of real-time interleaved TMS-fMRI. From the perspective of application progress, in the field of brain functional connectivity network research, TMS-fMRI can observe the dynamic connection between brain networks with a resolution of 100 ms, which is an important progress in the exploration of time-specific functional connectivity of brain regions. However, the TMS-fMRI on spatial specificity of functional connectivity of brain regions is still unclear, and future studies can focus on this aspect. In addition, TMS-fMRI can assess the effect of TMS on the cerebral cortex and the interaction between brain regions, help us understand the neural mechanism behind attention control, and study the brain's processing of somatosensory sensation. Nevertheless, TMS-fMRI can only observe the correlation between excitability of different brain regions under the stimulation of TMS, but the mechanism of this phenomenon and whether the correlation between brain regions is specific needs more research. Futhermore, TMS-fMRI can also be used to study the pathogenesis and therapeutic effect of neurological and psychiatric diseases, and the effects of psychoactive compounds on brain regions. Nonetheless, currently TMS-fMRI is still difficult to be widely used in clinical practice, so more efforts are needed in the study of clinical indications of TMS-fMRI. There are two major technical problems of TMS-fMRI. One major problem is that it is difficult for TMS coils to accurately position specific areas of cerebral cortex in MRI scanner. Another major problem is that TMS coils affect the static magnetic field (B0), resulting in image artifacts, spatial distortion and local signal loss of echo-Planar (EP) images. Nowadays, researchers have solved the two major problems through continuous technical updates, but TMS-fMRI still has problems in parameter setting, user experience, simplicity and universality of application and other aspects, which is the direction of future technological progress.
Objective To study the effect of bone marrow mesenchyml stem cell (BMSC) exosomes (Exo) on the proliferation and migration of brain microvascular endothelial cells in rats. Methods BMSCs were extracted from rats and identified. The BMSCs were co-cultured with bEnd.3 cells in Transwell chamber for 24 h (BMSCs group). Extracted and identified the BMSCs exosomes (BMSC-Exo). Observed and qualitatively evaluated the cells’ abilities on swallowing the BMSC-Exo under a fluorescence microscope. The optimal work concentration of BMSC-Exo was selected by detecting the cell vitality under different BMSC-Exo concentrations by CCK8 method. bEnd.3 cells were co-cultured with BMSC-Exo for 24 h (BMSC-Exo group). bEnd.3 cells cultured alone was set as control group. The proliferation and migration of bEnd.3 cells in the three groups were respectively detected by EDU and cell scratching experiment after 24 h of culture. Results Flow cytometry showed that P3 BMSCs were CD90 and CD29 positive and CD45 negative, with osteogenic differentiation and adipogenesis differentiation, indicating the extracted BMSCs high purity. The BMSC-Exo under transmission electron microscopy was round-shaped with a diameter of about 100 nm; NTA analysis found the diameter distribution of BMSC-Exo ranged from 50 to 600 nm, with a peak size of 150 nm. Immunofluorescence showed that the endothelial cells could swallow BMSC-Exo. CCK8 showed that supplement of 20 μg/mL BMSC-Exo had the best effect on cell proliferation. EDU results showed that BMSCs group and BMSC-Exo group could promote the proliferation of bEnd.3 cells compared with the control group (P<0.05), and there was no difference between BMSCs group and BMSC-Exo group (P>0.05). Cell scratch test showed that the cell mobility of the BMSC-Exo group was higher than that of the control group (P<0.05), but there was no significant difference between the BMSC-Exo group and the BMSCs group (P>0.05). Conclusion BMSC-Exo can replace BMSCs in effectively promoting the proliferation and migration of cerebral microvascular endothelial cells, which provide a new potential treatment for angiogenesis after stroke.
Objective To investigate the effects of exosomes of mouse astrocytes on the viability of neural stem cells. Methods Cultured and isolated the mouse astrocytes, and collected the cell supernatant for obtain the exosomes by ultracentrifugation. Neural stem cells that primary cultured for 2nd to 6th generation were obtained and treated with medium contained 0, 20, 40, 60 μg/mL of exosomes respectively. Screening the optimal exosome concentration for culturing neural stem cells by CCK-8 method. The optimal exosome concentration for neural stem cells was 40 μg/mL according to CCK-8 results. Then cells were intervened with 40 μg/mL of exosome in experimental group for 72 h, and the control group was added with the same volume of PBS. After intervention, the positive stem cells were labeled with EdU kit. Using the Transwell model, the number of nucleus stained by DAPI in the lower chamber in 40 μg/mL exosome treatment group and the control group were counted under a fluorescence microscope. Results ① Identification of astrocyte exosomes: The successful obtain of exosomes of cell supernatant were confirmed by techniques such as electron microscopy, Western blot, exosome concentration and particle size measurement. ② CCK8 experiment: As the increasement of the concentration of exosomes, cell proliferation of primary neural stem cells gradually increased. Compared with the control group, proliferation of the cells in 40 μg/mL and 60 μg/mL exosome treatment groups was significantly enhanced, but there was no significant difference between the two groups. So, 40 μg/mL was selected as the best intervention concentration. ③ EdU detection: Number of EdU positive labeled cells in the 40 μg/mL exosome group was higher than that in the control group (P<0.05). ④ Transwell experiment: In the Transwell model, more neural stem cells in the 40 μg/mL exosome group migrated from the upper layer to the lower layer of the Transwell membrane, and the number was higher than that of the control group (P<0.05). Conclusion Mouse astrocyte exosomes can improve the viability of neural stem cells.
Objective To study the effect and mechanism of modified constraint-induced movement therapy (mCIMT) on motor function recovery in cerebral ischemia-reperfusion rats. Methods The rats were randomly divided into the control group and the mCIMT group, with 12 rats in each group. The left middle cerebral artery occlusion (MCAO) model was established by the Longa suture method. In the mCIMT group, the rats started continuous training for 14 d on the 7th day after modeling. The unaffected limb was tied to the chest with elastic bandages, and the affected limb was trained in the compulsory runner equipment. In the control group, rats moved freely in the cage. The body mass of rats was recorded within 20 d after modeling, and behavior was assessed by the foot-fault test. Some of the rats were euthanized 18 d after modeling, and high performance liquid chromatography (HPLC) was used to detect monoamine neurotransmitters (5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIVV), homovanillic acid (HVA) ), and amino acid neurotransmitters (glutamic acid (Glu), asparaginic acid (ASP), glutamine (Gln), glycine (Gly), taurine (Tau), gamma aminobutyric acid (GABA) ) in the motor cortex and striatum, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of total P70 ribosomal protein S6 kinase (p70s6k) and p70s6k phosphorylated protein (p-p70s6k) in motor cortex and striatum, respectively. Results Compared with the control group, the body mass of rats in the mCIMT group was comparable (P>0.05) within 21 d after modeling, foot-fault rate of the mCIMT group was significantly lower at 17 d after modeling (P<0.05). At 18 d after modeling, compared with the control group, the level of 5-HIVV in the motor cortex increased significantly (P<0.05), and the relative content of amino acid neurotransmitters (the ratio of Glu) in the motor cortex including Gln, Gly, Tau and GABA to Glu increased significantly (P<0.05 or P<0.01) except for decreased ASP/Glu (P<0.05). Moreover, compared with the control group, the expression of p-p70s6k in the motor cortex of the mCIMT was significantly decreased (P<0.05). There were no significant differences in monoamine neurotransmitters and amino acid neurotransmitters in the striatum between two groups (P>0.05). Conclusion mCIMT improved the motor function of MCAO rats, and the mechanism might be related to the increase of amino acid neurotransmitters and 5-HIVV and decrease of p-p70s6k expression in the motor cortex.
This article reports a patient with spinal cord injury who was treated with conventional rehabilitation therapy plus repeated transcranial magnetic stimulation (rTMS) during the postoperative rehabilitation, and to observe the effects of rTMS on dystonia. A 66-year-old male patient fell from the bed 8 months ago. At that time, he felt pain in his neck, dysfunction in limbs movement, and loss of sensation in trunk and limbs. Magnetic resonance imaging (MRI) revealed spinal cord injury. Under general anesthesia, anterior cervical decompression and bone graft fusion (ACDF) and cervical spine internal fixation of C3-C6 were performed. Postoperative hyperbaric oxygen chamber and conventional rehabilitation treatment were performed. Eight months after surgery, he was admitted to the hospital due to motor function, balance dysfunction, neurogenic bladder/rectal dysfunction. After admission, the patient was treated with rTMS plus rehabilitation treatment, once per day, 5 times/week, for 4 weeks. rTMS worked by wearing a positioning cap for transcranial magnetic stimulation (80% resting motor threshold, 1 Hz, 30 min), and then conduct walking, balance proprioception, muscle strength training, and coordination training. After 4 weeks, MEP, sEMG and H reflex were improved. Therefore, rTMS on the premotor cortex to improve the dystonia after spinal cord injury is effective in this case, which can be further studied.
Objective To investigate the effects of human bone marrow mesenchymal stem cells/vascular endothelial growth factor (hBMSCs/VEGF) transplantation on early brain edema in rats with cerebral hemorrhage. Methods Cultured the hBMSCs in vitro, transducted the cells with VEGF recombinant lentivirus vector to abtain the hBMSCs/VEGF cells. Intracerebral hemorrhage (ICH) rat model was established by injection of type Ⅰ collagenase and heparin into the caudate putamen. 2 h after the operation, the rats were evaluated with modified nerve function defect (mNSS) score to ensure whether the model was successfully established. At the third day after the injection, SD rats were randomly divided into sham group (only injected with empty needle), cerebral hemorrhage group, saline group, hBMSCs group and hBMSCs/VEGF group. Saline group, hBMSCs group and hBMSCs/VEGF group mice were injected with normal saline, hBMSCs (2×106 cells/kg body mass) and hBMSCs/VEGF (2×106 cells/kg body mass) respectively; sham group and model group did not perform intervention. On day 3 and 7 after injection, the rats were evaluated with modified neurological function score (mNSS). Then rats were sacrificed, and brain tissue specimens from the right caudate putamen area were separated. The wet and dry weighing method was used to measure the water content, and HE staining was used to evaluate pathological and functional changes. The expressions of VEGF, matrix metalloproteinase 9 (MMP-9) and aquaporin 4 (AQP-4) proteins were detected by immunofluorescence and Western blot. Results 2 h after injection, compared with rats in sham operation group, mNSS scores of rats in model group were increased, indicating that the models have successfully established. 3 d and 7 d after intervention, the mNSS score, the content of brain water, the expression level of VEGF, MMP-9 and AQP-4 proteins in model group and NS group were significantly higher than those of sham group (P<0.05), while the above values in hBMSCs group were significantly lower than those in saline group and model group (P<0.001), and the above values in hBMSCs/VEGF group were significantly higher than those of hBMSCs group (P<0.05). There were obvious hemorrhage and infarction in the brain tissue in the model group and NS group rats observed under the light microscope. Besides, the brain tissue developed loose structure and edema change. However, the bleeding and infarction in the brain tissue of hBMSCs group mice were reduced. Compared with the hBMSCs group mice, the brain tissue of hBMSCs/VEGF group mice was looser, more vacuoles occurred, and many neurons showed apoptosis changes such as nuclear deflation. Conclusion hBMSCs transplantation could improve neurological function and relieve brain edema. But hBMSCs/VEGF will increase the vascular permeability and then aggravate the early cerebral edema in rats with cerebral hemorrhage.
Objective To investigate the effect of overexpression of miR-382-5p overexpression on malignant biological behavior of human glioma U251 cells. Methods U251 cells were transfected with miR-382-5pmimic. Then miR-382-5p and PTEN mRNA levels were detected by reverse transcription-polymerase chain reaction (RT-PCR) after transfection. Used bioinformatics to predicted the presence of base binding sites between miR-382-5p and PTEN, and constructed PTEN pcDNA vector overexpression plasmid was constructed. Luciluciase reporting experiment was used to detect the targeting relationship between miR-382-5p and PTEN. Cells were randomly divided into four groups: control group, mimics group, pc-PTEN group and mimics+pc-PTEN group for follow-up experiments. RT-PCR was carried out to detect the level of PTEN mRNA in each group. Cell proliferation was detected by clone formation method. The mRNA levels of Ki67, Survivin and c-Myc were detected by RT-PCR. Transwell experiment was used to assayed cell invasion ability. The expression levels of E-cadherin, N-cadherin and Vimentin were determined by Western blot. Results Results showed that miR-382-5p directly targeted PTEN. Compared with the control group, miR-382-5p and c-Myc mRNA levels and E-cadherin protein level were increased (P<0.05), PTEN, Ki67 and Survivin mRNA levels were decreased (P<0.05), cell clonal formation rate and cell invasion number were decreased (P<0.05), N-cadherin and Vimentin protein levels were decreased (P<0.05) in the mimics group; In pc-PTEN group, miR-382-5p mRNA and c-Myc mRNA levels and E-cadherin protein level were decreased (P<0.05), PTEN, Ki67 and Survivin mRNA levels were increased (P<0.05), cell clonal formation rate and cell invasion number were increased (P<0.05), N-cadherin and Vimentin protein levels were increased (P<0.05). Compared with pc-PTEN group, PTEN, Ki67 and Survivin mRNA levels, the cell clone formation rate, the number of invasion cells and the N-cadherin and Vimentin levels of mimics+PC-PTEN group decreased significantly (P<0.05), while the c-Myc mRNA level and E-cadherin protein level increased significantly (P<0.05). Conclusion Overexpression of miR-382-5p mediates the downregulation of PTEN expression, causing the inhibition of the proliferation, invasion, growth and EMT of U251 glioma cells.
Objective To study the neuroprotective effect of inhalation of volatile oil of Cang Ai (VOCA) on cerebral ischemia-reperfusion injury model by MRI diffusion tensor imaging. Methods Twenty-four healthy adult male SD rats were randomly divided into sham operation group, model (middle cerebral artery occlusion (MCAO) ) group and VOCA group. Evaluated the degree of neurological impairment of rats in each group immediately after successful establishment of model or 7 d later according to Zea Longa scoring. Coronal diffusion tensor imaging (DTI) scan was performed at 3 h, 3 d, and 7 d after the model successfully established by using 7.0 T magnetic resonance imaging. Measured the apparent diffusion coefficient (ADC) and anisotropy score (FA) of the DTI in the striatal region and the motion flat zone of the maximum infarct level and then calculate the relative apparent diffusion coefficient (rADC) and relative anisotropy score (rFA). TTC staining was used to evaluate the cerebral infarction volume of rats in each group at 7 d post model establishment, and the correlation analysis of rFA, rADC and neural score was performed. Results No neurological defect was detected in mice in the sham operation group. The MCAO group and the VOCA group showed neurological defect to different degrees. The neurological function score of the VOCA group was obviously lower than that of MCAO group at 7th day (P<0.05). The DTI scan results showed that the rADC value of striatum of rats in VOCA group was higher than that in MCAO group at 3 h and 3 d after modeling (P<0.05), while there was no significant difference between the three groups at 7th day. The rADC value of the motor cortex in the VOCA group was higher than that in the MCAO group at 3 h after modeling (P<0.01), and there was no significant difference at 3rd day and 7th day. The rFA value of striatum in VOCA group was higher than that in MCAO group at 3rd day and 7th day after modeling (P<0.05). There were no significant differences in rFA value between the MCAO and the VOCA group at three time points. TTC staining results showed that there was no infarcted area in the sham operation group, and the infarct volume in the VOCA group was smaller than that of the MCAO group (P<0.05). Correlation analysis showed that the striatum rFA value was highly correlated with neurological scores (r=-0.847, P<0.01). Conclusion For the first time, we found that VOCA can effectively protect the neurological function of MCAO rats by reducing the toxic edema of cells in the ischemic area and accelerating the recovery of nerve fiber bundles after cerebral ischemia and reperfusion. rFA and rADC values can be used as effective indicators to evaluate the recovery of nerve function after cerebral ischemia and reperfusion.

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