Publications by authors named "Ai-Ping Yu"

15 Publications

  • Page 1 of 1

Environmental Monitoring of A Laboratory for New Coronavirus Nucleic Acid Testing.

Biomed Environ Sci 2020 10;33(10):771-774

Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin 300070, China;Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China;National Demonstration Center for Experimental Preventive Medicine Education (Tianjin Medical University), Tianjin 300070, China.

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http://dx.doi.org/10.3967/bes2020.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673664PMC
October 2020

A novel mouse model of contralateral C7 transfer via the pretracheal route: A feasibility study.

J Neurosci Methods 2019 12 29;328:108445. Epub 2019 Sep 29.

Department of Hand Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Department of Hand and Upper Extremity Surgery, Jing'an District Central Hospital, Shanghai, China; State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center of Brain Science, Fudan University, Shanghai, China. Electronic address:

Background: Contralateral seventh cervical nerve transfer (contralateral C7 transfer) is a novel treatment for patients with spastic paralysis, including stroke and traumatic brain injury. However, little is known on changes in plasticity that occur in the intact hemisphere after C7 transfer. An appropriate surgical model is required.

New Method: We described in detail the anatomy of the C7 in a mouse model. We designed a pretracheal route by excising the contralateral C6 lamina ventralis, and the largest nerve defect necessary for direct neurorrhaphy was compared with defect lengths in a prespinal route. To test feasibility, we performed in-vivo surgery and assessed nerve regeneration by immunofluorescence, histology, electrophysiology, and behavioral examinations.

Results: Two types of branching were found in the anterior and posterior divisions of C7, both of which were significantly larger than the sural nerve. The length of the nerve defect was drastically reduced after contralateral C6 lamina ventralis excision. Direct tension-free neurorrhaphy was achieved in 66.7% of mice. The expression of neurofilament in the distal segment of the regenerated C7 increased. Histological examination revealed remyelination. Behavioral tests and electrophysiology tests showed functional recovery in a traumatic brain injury mouse.

Comparison With Existing Methods: This is the first direct tension-free neurorrhaphy mouse model of contralateral C7 transfer which shortened the time of nerve regeneration; previous models have used nerve grafting.

Conclusions: This paper describes a simple, reproducible, and effective mouse model of contralateral C7 transfer for studying brain plasticity and exploring potential new therapies after unilateral cerebral injury.
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http://dx.doi.org/10.1016/j.jneumeth.2019.108445DOI Listing
December 2019

Simple Grading for Motor Function in Spastic Arm Paralysis: Hua-Shan Grading of Upper Extremity.

J Stroke Cerebrovasc Dis 2019 Aug 22;28(8):2140-2147. Epub 2019 May 22.

Department of Hand Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Department of Hand and Upper Extremity Surgery, Jing'an District Central Hospital, Shanghai, China; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China; State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center of Brain Science, Fudan University, Shanghai, China; Priority Among Priorities of Shanghai Municipal Clinical Medicine Center, Shanghai, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China. Electronic address:

Objective: Spastic arm paralysis after central neurological injury has a long-term effect on the patient's quality of life. Effective neurosurgical treatment for this dysfunction has been described in our previous studies. It is of great significance to determine a set of unified and concise clinical standards for motor function grading in the neurosurgical treatment and management.

Methods: We first conducted a retrospective study that included 51 hemiplegic patients from the Neurosurgery and Microsurgery outpatient database of Huashan Hospital. The neurosurgeons cooperated with rehabilitation experts to design and administer the new rating system (Hua-Shan Grading of Upper Extremity, H-S grading) after analyzing the scale scores and video records of these patients. We then randomly enrolled 64 patients with unilateral spastic arm paralysis after stroke or brain trauma. The Fugl-Meyer Assessment, the Ashworth scale and the new grading system were applied and analyzed to evaluate the participants' motor function.

Results: Based on rehabilitation medicine scales and long-term follow-up, a feasible and concise grading system was applied that was based on the patients' characteristics and the examination experiences of neurosurgeons and rehabilitation experts in clinical practice. This method could effectively grade upper extremity motor function, usually in 3-5 minutes. A significant correlation was found between H-S grading and the Fugl-Meyer score by the Spearman test (r = .937, P < .01). The mean difference between any two levels of the new grading system was significant (P < .05). And good test-retest reliability, the Cronbach's alpha coefficient and the validity indices were presented. In addition, it was more sensitive to motor function compared with the Ashworth scale.

Conclusion: As a supplement to the classic scales, H-S grading was developed in the area of spastic hemiplegia treatment. It is standardized and simplified for patients in the chronic stage after central neurological injury.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.04.006DOI Listing
August 2019

Application of CUBE-STIR MRI and high-frequency ultrasound in contralateral cervical 7 nerve transfer surgery.

Br J Neurosurg 2019 Mar 12:1-6. Epub 2019 Mar 12.

a Department of Hand Surgery, Huashan Hospital, Shanghai Medical College , Fudan University , Shanghai , China.

Objective: The objective of the study was to investigate the feasibility of CUBE-SITR MRI and high-frequency ultrasound for the structural imaging of the brachial plexus to exclude neoplastic brachial plexopathy or structural variation and measure the lengths of anterior and posterior divisions of the C7 nerve, providing guidelines for surgeons before contralateral cervical 7 nerve transfer.

Methods: A total of 30 patients with CNS and 20 with brachial plexus injury were enrolled in this retrospective study. All patients underwent brachial plexus CUBE-STIR MRI and high-frequency ultrasound, and the lengths of the anterior and posterior divisions of C7 nerve were measured before surgery. Precise length of anterior and posterior divisions of contralateral C7 nerve was measured during surgery.

Results: MRI-measured lengths of anterior and posterior divisions of C7 nerves were positively correlated with that measured during surgery (anterior division, r = 0.94, p < .01; posterior division, r = 0.92, p < .01). High agreement was found between MRI-measured and intra-surgery measured length of anterior and posterior divisions of C7 nerve by BLAD-ALTMAN analysis. Ultrasonography could feasibly image supraclavicular C7 nerve and recognize small variant branches derived from middle trunk of C7 nerve root, which could be dissected intra-operatively and confirmed by electromyography during the procedure of contralateral C7 nerve transfer.

Conclusion: CUBE-STIR MRI had advantages for the imaging of the brachial plexus and measurement of the length of root-trunk-anterior/posterior divisions of C7 nerve. The clinical role of ultrasonography may be a simple way of evaluating general condition of C7 nerve and provide guidelines for contralateral C7 nerve transfer surgery.
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http://dx.doi.org/10.1080/02688697.2019.1584661DOI Listing
March 2019

C7 transfer in a posterior intradural approach for treating hemiplegic upper-limbs: hypothesis and a cadaver feasibility study.

Br J Neurosurg 2019 Aug 25;33(4):413-417. Epub 2019 Jan 25.

a Department of Hand Surgery, Huashan Hospital, Shanghai Medical College, Fudan University , Shanghai , China.

Contralateral C7 nerve root transfer surgery has been successfully applied to rescue motor function of a hemiplegic upper extremity in patients with central neurological injury. This surgical technique is challenging, and limited anatomical space makes it difficult to manipulate tissues and may lead to higher complication rates. The authors hypothesis a new surgical route in which cervical nerve roots of both donor and recipient sides are exposed from a posterior intradural approach and neurorrhaphy is performed easily and clearly. The feasibility of this operation is tested in a cadaver model. A fresh cadaver was placed prone. After a standard midline incision and extensive cervical laminectomy, the dura and arachnoid were widely opened, and the spinal nerve roots of C6, C7, and C8 were exposed bilaterally. Nerve grafting was attempted between pairs of donor and recipient nerve roots on contralateral sides of the spinal cord. After completion of neurorrhaphy, the dura was closed. Precise neurorrhaphy could be performed intradurally between posterior and anterior nerve roots of C7 on both sides. Multiple anastomoses of C7 to various nerve roots on the contralateral side could also be performed within the same surgical field with an interposition nerve graft. The posterior intradural repair idea affords many advantages, the pathway is shorter and more straightforward, which provides more access to multiple nerve roots repair in one surgical field, and is more familiar to many neurosurgeons and spine surgeons. It may potentially be adapted for clinical use.
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http://dx.doi.org/10.1080/02688697.2018.1552754DOI Listing
August 2019

Pro-Angiogenic Activity of Monocytic-Type Myeloid-Derived Suppressor Cells from Balb/C Mice Infected with Echinococcus Granulosus and the Regulatory Role of miRNAs.

Cell Physiol Biochem 2018 27;51(3):1207-1220. Epub 2018 Nov 27.

Background/aims: This study aims to predict the pro-angiogenic functions of monocytic-type myeloid-derived suppressor cells (M-MDSCs) derived from mice infected with Echinococcus granulosus.

Methods: M-MDSCs were collected from Balb/c mice infected with E. granulosus and normal mice (control) and cultured in vitro. Human umbilical vein endothelial cells (HUVECs) were stimulated with the cell supernatant, and angiogenesis was investigated and analysed by the Angiogenesis module of the software NIH Image J. RNA was extracted from fresh isolated M-MDSCs and analysed with miRNA microarray; differentially expressed miRNAs and their potential functions were analysed through several bioinformatics tools. Finally, quantitative PCR was used to confirm the results of microarray analysis.

Results: M-MDSCs from mice infected with E. granulosus could promote the formation of tubes from HUVECs in vitro. Moreover, vascular endothelial growth factor (VEGF) showed significantly high expression, whereas soluble fms-like tyrosine kinase-1 (sFlt-1) showed low expression at the transcriptional level in M-MDSCs from mice infected with E. granulosus. Microarray analysis of miRNAs showed that 28 miRNAs were differentially expressed in M-MDSCs from the two experimental mice groups, and 272 target genes were predicted using the microRNA databases TargetScan, PITA and microRNAorg. These target genes were mainly involved in the biological processes of intracellular protein transport, protein targeting to the lysosome and protein transport, and mainly located in the cytoplasm, neuronal cell body and membrane. Moreover, they were mainly involved in the molecular functions of protein binding, metal ion binding and SH3 domain binding. Further, the differentially expressed miRNAs were mainly enriched in the endocytosis, Wnt and axon guidance pathways, as well as the MAPK, focal adhesion, PI3K-Akt, cAMP, mTOR and TGF-β signalling pathways, which are linked to immunoregulation and angiogenesis based on the results of bioinformatics analysis with DIANA-miRPath 3.0. In addition, the expression of eight miRNAs was randomly verified by quantitative PCR independently in three mice infected with E. granulosus and three normal mice.

Conclusion: M-MDSCs have a potential angiogenic role during E. granulosus infection, and miRNAs may play a role in the immune response and angiogenesis functions of M-MDSCs through regulation of the identified signalling pathways.
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http://dx.doi.org/10.1159/000495498DOI Listing
January 2019

Comparative effects of implanted electrodes with differing contact patterns on peripheral nerve regeneration and functional recovery.

Neurosci Res 2019 Aug 17;145:22-29. Epub 2018 Aug 17.

Department of Hand Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China; Department of Hand and Upper Extremity Surgery, Jing'an District Central Hospital, Shanghai, 200040, China. Electronic address:

Electrical stimulation could enhance nerve regeneration and functional recovery. The objective of this study was to evaluate the regenerative effects of implanted electrodes with different contacts in resected sciatic nerve. Sciatic nerve resection and microsurgical repair models were established and randomly divided into four groups (point contact, 1/4 circle contact; whole-circle contact; no electrodes as control). Electrical stimulation was performed and electrophysiological, morphological and histological exams (of the sciatic nerve and muscle) were conducted at 4 and 10 weeks post-implantation. Point and 1/4 circle contact groups showed significantly higher scores in the sciatic functional index (SFI), increased amplitude of compound muscle action potential (AMP) and motor nerve conduction velocity (MNCV) compared to the control group at both 4 and 10 weeks post-implantation. Point and 1/4 circle contact morphologically promoted sciatic nerve regeneration and reduced muscular atrophy with less mechanical injury to the nerve trunk observed compared with the whole-circle contact group at both 4 and 10 weeks post-implantation. Electrodes with point and 1/4 circle contacts represented an alternatively portable and effective method of electrical stimulation to facilitate injured sciatic nerve regeneration and reduce subsequent muscular atrophy, which might offer a promising approach for treating peripheral nerve injuries.
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http://dx.doi.org/10.1016/j.neures.2018.08.007DOI Listing
August 2019

Contralateral C7 to C7 nerve root transfer in reconstruction for treatment of total brachial plexus palsy: anatomical basis and preliminary clinical results.

J Neurosurg Spine 2018 Nov;29(5):491-499

1Department of Hand Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

OBJECTIVEContralateral C7 (CC7) nerve root has been used as a donor nerve for targeted neurotization in the treatment of total brachial plexus palsy (TBPP). The authors aimed to study the contribution of C7 to the innervation of specific upper-limb muscles and to explore the utility of C7 nerve root as a recipient nerve in the management of TBPP.METHODSThis was a 2-part investigation. 1) Anatomical study: the C7 nerve root was dissected and its individual branches were traced to the muscles in 5 embalmed adult cadavers bilaterally. 2) Clinical series: 6 patients with TBPP underwent CC7 nerve transfer to the middle trunk of the injured side. Outcomes were evaluated with the modified Medical Research Council scale and electromyography studies.RESULTSIn the anatomical study there were consistent and predominantly C7-derived nerve fibers in the lateral pectoral, thoracodorsal, and radial nerves. There was a minor contribution from C7 to the long thoracic nerve. The average distance from the C7 nerve root to the lateral pectoral nerve entry point of the pectoralis major was the shortest, at 10.3 ± 1.4 cm. In the clinical series the patients had been followed for a mean time of 30.8 ± 5.3 months postoperatively. At the latest follow-up, 5 of 6 patients regained M3 or higher power for shoulder adduction and elbow extension. Two patients regained M3 wrist extension. All regained some wrist and finger extension, but muscle strength was poor. Compound muscle action potentials were recorded from the pectoralis major at a mean follow-up of 6.7 ± 0.8 months; from the latissimus dorsi at 9.3 ± 1.4 months; from the triceps at 11.5 ± 1.4 months; from the wrist extensors at 17.2 ± 1.5 months; from the flexor carpi radialis at 17.0 ± 1.1 months; and from the digital extensors at 22.8 ± 2.0 months. The average sensory recovery of the index finger was S2. Transient paresthesia in the hand on the donor side, which resolved within 6 months postoperatively, was reported by all patients.CONCLUSIONSThe C7 nerve root contributes consistently to the lateral pectoral nerve, the thoracodorsal nerve, and long head of the triceps branch of the radial nerve. CC7 to C7 nerve transfer is a reconstructive option in the overall management plan for TBPP. It was safe and effective in restoring shoulder adduction and elbow extension in this patient series. However, recoveries of wrist and finger extensions are poor.
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http://dx.doi.org/10.3171/2018.3.SPINE171251DOI Listing
November 2018

[ pro - angiogenic activity of hydatid cysts from experimentally infected mice].

Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi 2017 May;29(3):320-323

National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, Ministry of Health, WHO Collaborating Center for Tropical Diseases, National Center for International Research on Tropical Diseases, Ministry of Science and Technology, Shanghai 200025, China.

Objective: To preliminarily study the pro-angiogenic activity of hydatid cysts against human umbilical vein endothelial cells and the transcriptional level of potential pro-angiogenic factors.

Methods: The hydatid cysts and protoscolex derived from experimentally infected mice were collected and cultured , then the human umbilical vein endothelial cells were stimulated by the supernatant and cyst fluid respectively, and the angiogenesis was observed and analyzed through a microscope and the angiogenesis mode of the software NIH Image J. Meanwhile, the mouse homologous proteins of matrix metalloproteinase-9 (MMP-9) and high mobility group box B1 (HMGB1) were identified in genome through sequence alignment, and their transcriptional levels in the cyst wall and protoscolex were analyzed.

Results: The culture supernatant of hydatid cysts significantly promoted human umbilical vein endothelial cells into tubes ( = 73.03, < 0.001), the transcriptions of MMP-9 and HMGB1 were detected in the cyst wall and protoscolex, and the transcriptional level of MMP-9 was higher in protoscolex ( = -11.65, < 0.001), while the level of HMGB1 was higher in hydatid cysts ( = 6.43, = 0.003).

Conclusions: Some parasite-derived pro-angiogenic molecules may exist in the supernatant of hydatid cysts, while further researches are required into their exact mechanisms.
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http://dx.doi.org/10.16250/j.32.1374.2017052DOI Listing
May 2017

Automated, highly reproducible, wide-field, light-based cortical mapping method using a commercial stereo microscope and its applications.

Biomed Opt Express 2016 Sep 16;7(9):3478-3490. Epub 2016 Aug 16.

Britton Chance Center for Biomedical Photonics, Huazhong University of Science and Technology-Wuhan National Laboratory for Optoelectronics, Wuhan, 430074, China; MoE Key Laboratory for Biomedical Photonics, Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China;

We introduce a more flexible optogenetics-based mapping system attached on a stereo microscope, which offers automatic light stimulation to individual regions of interest in the cortex that expresses light-activated channelrhodopsin-2 . Combining simultaneous recording of electromyography from specific forelimb muscles, we demonstrate that this system offers much better efficiency and precision in mapping distinct domains for controlling limb muscles in the mouse motor cortex. Furthermore, the compact and modular design of the system also yields a simple and flexible implementation to different commercial stereo microscopes, and thus could be widely used among laboratories.
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http://dx.doi.org/10.1364/BOE.7.003478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030026PMC
September 2016

[Factor Xa Promotes Differentiation of Meg-01 Cell Line].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2016 Apr;24(2):519-25

Department of Light Industry Technique and Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, Shandong Province, China. E-mail:

Objective: To investigate the effect and mechanism of Factor Xa on the differentiation of Meg-01 cells into platelet-like particles.

Methods: The Meg-01 cells were used as experimental object, Factor Xa was used as agonist. Cell proliferation was detected by CCK-8 assay. The viability of platelet-like particles was analyzed by AlamaBlue kit. MAPK/ERK pathway and PI3K/AKT pathway were assayed by Western blot. The expression of CD41b was analyzed by Western blot and flow cytometry. Cell cycle and apoptosis were detected by flow cytometry.

Results: The Factor Xa (1 µg/ml) inhibited cell viability, induced apoptosis. Factor Xa triggered cell arrest at the G(2)/M stage and down-regulated the expression of SKP2. After Meg-01 cells were stimulated by Factor Xa, the expression of CD41b was up-regulated and the MAPK/ERK pathway and PI3K/AKT pathway were activated. The platelets-like particles stimulated by FXa activation were viable.

Conclusion: The Factor Xa maybe display some effect on the differentiation of megakaryocytes into platelets.
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http://dx.doi.org/10.7534/j.issn.1009-2137.2016.02.040DOI Listing
April 2016

Thrombin Maybe Plays an Important Role in MK Differentiation into Platelets.

Biomed Res Int 2016 15;2016:9313269. Epub 2016 Mar 15.

Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850, China.

Objectives: After development and differentiation, megakaryocytes (MKs) can produce platelets. As is well known, thrombopoietin (TPO) can induce MKs to differentiate. The effect of thrombin on MKs differentiation is not clear. In this study, we used a human megakaryoblastic leukemia cell line (Meg-01) to assess the effect of thrombin on MKs differentiation.

Methods: In order to interrogate the role of thrombin in Meg-01 cells differentiation, the changes of morphology, cellular function, and expression of diverse factors were analyzed.

Results: The results show that thrombin suppresses Meg-01 cells proliferation and induces apoptosis and cell cycle arrest. Thrombin upregulates the expression of CD41b, which is one of the most important MK markers. Globin transcription factor 1 (GATA-1), an important transcriptional regulator, controls MK development and maturation. The expression of GATA-1 is also upregulated by thrombin in Meg-01 cells. The expression of B-cell lymphoma 2 (Bcl-2), an apoptosis-inhibitory protein, is downregulated by thrombin. Phosphorylated protein kinase B (p-AKT) and phosphorylated extracellular signal-regulated kinase (p-ERK) were upregulated by thrombin in Meg-01 cells. All the results are consistent with Meg-01 cells treated with TPO.

Discussion And Conclusion: In conclusion, all these data indicate that thrombin maybe plays an important role in MK differentiation into platelets. However, whether the platelet-like particles are certainly platelets remains unknown.
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http://dx.doi.org/10.1155/2016/9313269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811061PMC
January 2017

Computed tomography image analysis before and after treatment of anti-neutrophil cytoplasmic antibody-associated pulmonary interstitial fibrosis in 8 patients.

Clin Ther 2014 Dec 28;36(12):2064-2071. Epub 2014 Oct 28.

Department of Inpatient, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, PR China.

Purpose: The purpose of this study was to observe the treatment response of anti-neutrophil cytoplasmic antibody (ANCA)-associated pulmonary interstitial fibrosis in 8 patients before and after glucocorticoid or immunosuppressive therapy.

Methods: The clinical features and computed tomography imaging findings of the 8 patients in our hospital from October 2011 to October 2013, were retrospectively analyzed.

Findings: Mean age of the 8 patients was 72.6 (range 60-80) years. Five patients exhibited cough, sputum, and chest tightness, including 2 patients with fever. One patient developed hemoptysis, 1 patient exhibited abnormal urinalysis and developed renal insufficiency, and 1 patient developed limb pain. Two patients exhibited high urine erythrocytes and 2 patients had renal dysfunction and urinary abnormalities. One of the latter patients, upon renal biopsy, had focal proliferative necrotizing glomerulonephritis (consistent with vasculitis damage) with stage II to III mild nephropathy. Seven cases were anti-myeloperoxidase-ANCA, and 1 case was anti-proteinase 3-ANCA. All 8 cases exhibited streaks and grid shadows in chest imaging; 2 cases exhibited limited ground-glass patches; 1 case displayed multiple large patches of exudative shadows, indicating diffuse alveolar hemorrhage; 2 cases exhibited obvious honeycomb manifestations; and 1 case exhibited significant traction bronchiectasis. The ground-glass opacities disappeared after corticosteroid or immunosuppressive therapy; however, for streaks and grid shadows, no significant changes in the images were observed after treatment from 2 weeks to 10 months.

Implications: ANCA-associated pulmonary interstitial fibrosis most often in elderly patients with many complications. In these patients ground-glass opacities in computed tomography images, corticosteroid or immunosuppressant therapy may be effective. Clinicians should consider the poor efficacy and side effects of these therapies in the fibrosis stage of the disease.
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http://dx.doi.org/10.1016/j.clinthera.2014.09.025DOI Listing
December 2014

[Research progress in hirudin fusion protein--review].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2007 Feb;15(1):215-8

Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China.

Natural hirudin extracted from the secretion of medical leech salivary gland is a single-chain peptide containing 65 aminoacid residues with molecular weight of 7000 D, and exists in three isomers of HV1, HV2 and HV3. Hirudin possesses three disulfide bridges forming the structure of core cyclic peptides, which binds to the catalytic site of thrombin so as to inhibit the catalysis of thrombin. Its c-terminus rich in acidic aminoacid residues possesses hydrophilicity, and is free on the molecular surface, and can bind with fibrin recognition site of hirudin. The minimal segment of 12 - 16 C-terminal acidic residues keeps the minimal activity of anti-thrombosis. Thus, hirudin, as a potent and specific inhibitor of thrombin, can be used to protect from and to treat clinically thrombosis. As it has some disadvantages such as short half-life, bleeding side-effect and mono-function, and so on, hirudin has been fused with some other functional proteins in recent years. The obtained fusion proteins can prolong the half life of hirudin, or relieve it bleeding side effect, or bring new functions, such as thrombolysis, inhibiting the platelet aggregation, targeting specifically. The research progress in hirudin fusion protein was summarized in this review.
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February 2007

[Construction and expression of a fusion protein made of tissue-type plasminogen activator and hirudin in Pichia pastoris].

Sheng Wu Gong Cheng Xue Bao 2005 Jul;21(4):553-7

Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China.

To combine the fibrinolytic with anticoagulant activities for therapy of thrombotic deseases, a fusion protein made of tissue-type plasminogen activator (t-PA) and hirudin was constructed and expressed in chia pastoris. To improve thrombolytic properties of t-PA and reduce bleeding side effect of hirudin, FXa-recognition sequence was introduced between t-PA and hirudin molecules.The anticoagulant activity of hirudin can be target-released through cleavage of FXa at thrombus site. t-PA gene and hirudin gene with FXa-recognition sequence at its 5'-terminal were obtained by RT-PCR and PCR respectively. The fusion protein gene was cloned into plasmid pIC9K and electroporated into the genome of Pichia pastoris GS115. The expression of fusion protein was induced by methanol in shaking flask and secreted into the culture medium. Two forms of the fusion protein, single-chain and double-chain linked by a disulfide bond (due to the cleveage of t-PA at Arg275-Ile276), were obtained. The intact fusion protein retained the fibrinolytic activity but lacked any anticoagulant activity. After cleavage by FXa, the fusion protein liberated intact free hirudin to exert its anticoagulant activity. So, the fusion protein is a bifunctional molecule having good prospect to develop into a new targeted therapeutic agent with reduced bleeding side effect for thrombotic diseases.
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July 2005
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