Publications by authors named "Hai-Wei Xu"

54 Publications

Intravitreally injected ranibizumab versus photodynamic therapy for CNV secondary to choroidal osteoma: a 7-year follow-up case report.

Int J Ophthalmol 2021 18;14(6):940-944. Epub 2021 Jun 18.

Southwest Hospital, Southwest Eye Hospital, the Third Military Medical University (Army Medical University), Chongqing 400038, China.

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http://dx.doi.org/10.18240/ijo.2021.06.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165613PMC
June 2021

LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells.

Front Oncol 2021 16;11:658608. Epub 2021 Apr 16.

Key Laboratory of Advanced Technology for Drug Preparation, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.

Gastric cancer is a global health problem. In this study, we investigate the role of a novel Indole derivative, named LCT-3d, in inhibiting the growth of gastric cancer cells by MTT assay. The Western blotting results showed that LCT-3d modulated the mitochondrial-related proteins and Cleaved-Caspases 3/9, to induce cell apoptosis. The up-regulation of Death receptor 5 (DR5) in MGC803 cells was observed with LCT-3d treatment. Knockdown of DR5 on MGC803 cells partially reversed the LCT-3d-induced mitochondrial apoptosis. The level of Reactive Oxygen Species (ROS) in MGC803 cells was increased with LCT-3d treatment and could be blocked with the pretreatment of the ROS inhibitor N-Acetylcysteine (NAC). The results demonstrate that the elevating ROS can up-regulate the expression of DR5, resulting in apoptosis mitochondrial pathway. Although the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway served an important role in protecting gastric cancer cells against the injury of ROS, it can't reverse LCT-3d-induced cell apoptosis. Taken together, our study showed that LCT-3d induced apoptosis DR5-mediated mitochondrial apoptotic pathway in gastric cancer cells. LCT-3d could be a novel lead compound for development of anti-cancer activity in gastric cancer.
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http://dx.doi.org/10.3389/fonc.2021.658608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085419PMC
April 2021

Functional assessment of cryopreserved clinical grade hESC-RPE cells as a qualified cell source for stem cell therapy of retinal degenerative diseases.

Exp Eye Res 2021 01 17;202:108305. Epub 2020 Oct 17.

Southwest Hospital/ Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, 400038, PR China. Electronic address:

The biosafety and efficiency of transplanting retinal pigment epithelial (RPE) cells derived from both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) have been evaluated in phase I and phase II clinical trials. For further large-scale application, cryopreserved RPE cells must be used; thus, it is highly important to investigate the influence of cryopreservation and thawing on the biological characteristics of hESC-RPE cells and their post-transplantation vision-restoring function. Here, via immunofluorescence, qPCR, transmission electron microscopy, transepithelial electrical resistance, and enzyme-linked immunosorbent assays (ELISAs), we showed that cryopreserved hESC-RPE cells retained the specific gene expression profile, morphology, ultrastructure, and maturity-related functions of induced RPE cells. Additionally, cryopreserved hESC-RPE cells exhibited a polarized monolayer, tight junction, and gap junction structure and an in vitro nanoparticle phagocytosis capability similar to those of induced hESC-RPE cells. However, the level of pigment epithelium-derived factor (PEDF) secretion was significantly decreased in cryopreserved hESC-RPE cells. Royal College of Surgeons rats with cryopreserved hESC-RPE cells engrafted into the subretinal space exhibited a significant decrease in the b-wave amplitude compared with rats engrafted with induced hESC-RPE cells at 4 weeks post transplantation. However, the difference disappeared at 8 weeks and 12 weeks post operation. No significant difference in the outer nuclear layer (ONL) thickness was observed between the two groups. Our data showed that even after cryopreservation and thawing, cryopreserved hESC-RPE cells are still qualified as a donor cell source for cell-based therapy of retinal degenerative diseases.
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http://dx.doi.org/10.1016/j.exer.2020.108305DOI Listing
January 2021

Biosafety of a 3D-printed intraocular lens made of a poly(acrylamide-co-sodium acrylate) hydrogel and .

Int J Ophthalmol 2020 18;13(10):1521-1530. Epub 2020 Oct 18.

Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.

Aim: To assess the biosafety of a poly(acrylamide-co-sodium acrylate) hydrogel (PAH) as a 3D-printed intraocular lens (IOL) material.

Methods: The biosafety of PAH was first evaluated using human lens epithelial cells (LECs) and the ARPE19 cell line, and a cell counting kit-8 (CCK-8) assay was performed to investigate alterations in cell proliferation. A thin film of PAH and a conventional IOL were intraocularly implanted into the eyes of New Zealand white rabbits respectively, and a sham surgery served as control group. The anterior segment photographs, intraocular pressure (IOP), blood parameters and electroretinograms (ERG) were recorded. Inflammatory cytokines in the aqueous humor, such as TNFα and IL-8, were examined by ELISA. Cell apoptosis of the retina was investigated by TUNEL assay, and macroPAHge activation was detected by immunostaining.

Results: PAH did not slow cell proliferation when cocultured with human LECs or ARPE19 cells. The implantation of a thin film of a 3D-printed IOL composed of PAH did not affect the IOP, blood parameters, ERG or optical structure in any of the three experimental groups (=3 for each). Both TNFα and IL-8 in the aqueous humor of PAH group were transiently elevated 1wk post-operation and recovered to normal levels at 1 and 3mo post-operation. Iba1 macroPAHges in the anterior chamber angle in PAH group were increased markedly compared to those of the control group; however, there was no significant difference compared to those in the IOL group.

Conclusion: PAH is a safe material for 3D printing of personal IOLs that hold great potential for future clinical applications.
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http://dx.doi.org/10.18240/ijo.2020.10.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511391PMC
October 2020

A low toxic CRM1 degrader: Synthesis and anti-proliferation on MGC803 and HGC27.

Eur J Med Chem 2020 Nov 7;206:112708. Epub 2020 Aug 7.

Key Laboratory of Advanced Technology for Drug Preparation, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou University, No. 100, KeXueDaDao, Zhengzhou, 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province, 450052, PR China. Electronic address:

Chromosome region maintenance 1 (CRM1) is the sole nuclear exporter of several tumor suppressor, a growth regulatory protein as an attractive cancer drug target. In the present work, a novel CRM1 degrader was discovered from newly synthesized α, β-unsaturated-δ-lactone based on a natural product Goniothalamin. It induces apoptosis of both MGC803 and HGC27 cell lines via degrading CRM1. Selective inhibition was observed for the proliferation of gastric cancer cell lines MGC803, HGC27 comparing to Human Gastric Mucosal Epithelial Cell Line (GES1). For the first time, CRM1 inhibitor or degrader inducing apoptosis in gastric carcinoma was investigated.
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http://dx.doi.org/10.1016/j.ejmech.2020.112708DOI Listing
November 2020

Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing.

Biosci Rep 2020 01;40(1)

Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, (Army Medical University), Chongqing 400038, China.

Background: The USH2A gene encodes usherin, a basement membrane protein that is involved in the development and homeostasis of the inner ear and retina. Mutations in USH2A are linked to Usher syndrome type II (USH II) and non-syndromic retinitis pigmentosa (RP). Molecular diagnosis can provide insight into the pathogenesis of these diseases, facilitate clinical diagnosis, and identify individuals who can most benefit from gene or cell replacement therapy. Here, we report 21 pathogenic mutations in the USH2A gene identified in 11 Chinese families by using the targeted next-generation sequencing (NGS) technology.

Methods: In all, 11 unrelated Chinese families were enrolled, and NGS was performed to identify mutations in the USH2A gene. Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations in these families.

Results: We identified 21 pathogenic mutations, of which 13, including 5 associated with non-syndromic RP and 8 with USH II, have not been previously reported. The novel variants segregated with disease phenotype in the affected families and were absent from the control subjects. In general, visual impairment and retinopathy were consistent between the USH II and non-syndromic RP patients with USH2A mutations.

Conclusions: These findings provide a basis for investigating genotype-phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.
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http://dx.doi.org/10.1042/BSR20193536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974426PMC
January 2020

Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors.

Eur J Med Chem 2019 Aug 29;175:357-372. Epub 2019 Apr 29.

Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Science, Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China. Electronic address:

Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC of 1.230 μM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.
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http://dx.doi.org/10.1016/j.ejmech.2019.04.065DOI Listing
August 2019

CT-based Morphometric Analysis of Approach of Percutaneous Transforaminal Endoscopic Lumbar Interbody Fusion.

Orthop Surg 2019 Apr 21;11(2):212-220. Epub 2019 Mar 21.

Department of Minimally Invasive Spine Surgery, Tianjin Hospital, Tianjin, China.

Objectives: A radiographic study was designed to measure the relationship of the exiting nerve root and its surroundings to the corresponding intervertebral disc for percutaneous transforaminal endoscopic lumbar interbody fusion to better understand the regional anatomy and to improve clinical applications.

Methods: A retrospective study from January 2017 to October 2017 was conducted at Tianjin Hospital. CT images were obtained from patients presenting low back pain (110 patients), and analysis was performed bilaterally from L to L S . In the rotating coronal plane we analyzed: the nerve root-dural sac distance at the superior and inferior margins of the disc (Js, Ji); the nerve root-pedicle distance at the medial, middle, and lateral borders of the pedicle (Pa, Pb, Pc); the pedicle width (W); and the safe working zone, defined as a trapezoid bounded by the inferior pedicle and the exiting nerve root (S). In the transverse plane, the nerve root-articular process and the shortest distance for the nerve root-articular process joint surface were analyzed at the superior and inferior margins of the disc (Gs, Gi), respectively. The groups were analyzed using ANOVA, and paired t-tests were used to compare the left and right sides.

Results: From L to L S , the distance of the nerve root to the dural sac was larger at the inferior margin of the disc. From L to L S , each segment of the vertebral nerve root-pedicle distance gradually decreased from medial to lateral. From L to L S , the distance from the exiting nerve root to the middle and lateral margins of the pedicle gradually decreased, with L S being the minimum. Some significant differences were observed between the left and right sides for L and L S . The pedicle width of the vertebral body and the mean area for the safe working zone gradually increased from L to L S . In the axial plane, the shortest distance between the nerve root and articular process joint surface at the inferior margin of the disc was greater than the distance for the nerve root to the articular process at the superior margin of the disc from L to L S . There were no significant differences between the two sides.

Conclusions: It is more difficult to implant a cage with a width of 10 mm above the L level. By removing part of the superior articular process, the safe working area can be expanded, and damage to the nerve or other structures can be avoided when implanting a cage.
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http://dx.doi.org/10.1111/os.12434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594482PMC
April 2019

Human embryonic stem cell-derived retinal pigment epithelium transplants as a potential treatment for wet age-related macular degeneration.

Cell Discov 2018 11;4:50. Epub 2018 Sep 11.

1Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Amy Medical University), Chongqing, 400038 China.

Stem cell therapy may provide a safe and promising treatment for retinal diseases. Wet age-related macular degeneration (wet-AMD) is a leading cause of blindness in China. We developed a clinical-grade human embryonic stem cell (hESC) line, Q-CTS-hESC-2, under xeno-free conditions that differentiated into retinal pigment epithelial cells (Q-CTS-hESC-2-RPE). A clinical trial with three wet-AMD patients was initiated in order to study the safety and tolerance to Q-CTS-hESC-2-RPE cell transplants. The choroidal neovascularization membrane was removed and then a suspension of 1 × 10 Q-CTS-hESC-2-RPE cells were injected into a subfoveal pocket. The patients were followed for 12 months during which no adverse effects resulting from the transplant were observed. Anatomical evidence suggested the existence of new RPE-like cell layer in the previously damaged area. Visual and physiological testing indicated limited functional improvement, albeit to different degrees between patients. This study provides some promising early results concerning the use of transplanted hESC-RPE cells to alleviate wet-AMD.
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http://dx.doi.org/10.1038/s41421-018-0053-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143607PMC
September 2018

Long-term safety of human retinal progenitor cell transplantation in retinitis pigmentosa patients.

Stem Cell Res Ther 2017 09 29;8(1):209. Epub 2017 Sep 29.

Key Laboratory of Visual Damage, Regeneration and Repair, Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, China.

Background: Retinitis pigmentosa is a common genetic disease that causes retinal degeneration and blindness for which there is currently no curable treatment available. Vision preservation was observed in retinitis pigmentosa animal models after retinal stem cell transplantation. However, long-term safety studies and visual assessment have not been thoroughly tested in retinitis pigmentosa patients.

Methods: In our pre-clinical study, purified human fetal-derived retinal progenitor cells (RPCs) were transplanted into the diseased retina of Royal College of Surgeons (RCS) rats, a model of retinal degeneration. Based on these results, we conducted a phase I clinical trial to establish the safety and tolerability of transplantation of RPCs in eight patients with advanced retinitis pigmentosa. Patients were studied for 24 months.

Results: After RPC transplantation in RCS rats, we observed moderate recovery of vision and maintenance of the outer nuclear layer thickness. Most importantly, we did not find tumor formation or immune rejection. In the retinis pigmentosa patients given RPC injections, we also did not observe immunological rejection or tumorigenesis when immunosuppressive agents were not administered. We observed a significant improvement in visual acuity (P < 0.05) in five patients and an increase in retinal sensitivity of pupillary responses in three of the eight patients between 2 and 6 months after the transplant, but this improvement did not appear by 12 months.

Conclusion: Our study for the first time confirmed the long-term safety and feasibility of vision repair by stem cell therapy in patients blinded by retinitis pigmentosa.

Trial Registration: WHO Trial Registration, ChiCTR-TNRC-08000193 . Retrospectively registered on 5 December 2008.
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http://dx.doi.org/10.1186/s13287-017-0661-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622579PMC
September 2017

Thoracic Endoscopic-Assisted Mini-Open Surgery for Thoracic and Thoracolumbar Spinal Cord Compression.

Orthop Surg 2016 Nov;8(4):523-526

Cell Engineering Laboratory of Orthopaedic Institute, Tianjin Hospital, Tianjin, China.

Intervertebral disc herniation is a common cause of spinal cord compression, especially for the thoracic and thoracolumbar spinal cord, which has limited buffer space in the spinal canal. Spinal cord compression usually causes decreased sensation and paralysis of limbs below the level of compression, urinary and fecal incontinence, and/or urinary retention, which brings great suffering to the patients and usually requires surgical intervention. Thoracotomy or abdominothoracic surgery is usually performed for the thoracolumbar cord compression caused by hard intervertebral disc herniation. However, there is high risk of trauma and complications with this surgery. To reduce the surgical trauma and obtain good visibility, we designed athoracic endoscopic-assisted mini-open surgery for thoracic and thoracolumbar disc herniation, and performed this procedure on 10 patients who suffered from hard thoracic or thoracolumbar spinal cord compression. During the procedure, the thoracic endoscopy provided clear vision of the surgical field with a good light source. The compression could be fully exposed and completely removed, and no nerve root injury or spinal cord damage occurred. All patients achieved obvious recovery of neurological function after this procedure. This technique possesses the merits of minimal trauma, increased safety, and good clinical results. The aim of this study is to introduce this thoracic endoscopic-assisted mini-open surgery technique, and we believe that this technique will be a good choice for the thoracic and thoracolumbar cord compression caused by hard intervertebral disc herniation.
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http://dx.doi.org/10.1111/os.12281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584088PMC
November 2016

Promotion of axon regeneration and inhibition of astrocyte activation by alpha A-crystallin on crushed optic nerve.

Int J Ophthalmol 2016 18;9(7):955-66. Epub 2016 Jul 18.

Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China.

Aim: To explore the effects of αA-crystallin in astrocyte gliosis after optic nerve crush (ONC) and the mechanism of α-crystallin in neuroprotection and axon regeneration.

Methods: ONC was established on the Sprague-Dawley rat model and αA-crystallin (10(-4) g/L, 4 µL) was intravitreously injected into the rat model. Flash-visual evoked potential (F-VEP) was examined 14d after ONC, and the glial fibrillary acidic protein (GFAP) levels in the retina and crush site were analyzed 1, 3, 5, 7 and 14d after ONC by immunohistochemistry (IHC) and Western blot respectively. The levels of beta Tubulin (TUJ1), growth-associated membrane phosphoprotein-43 (GAP-43), chondroitin sulfate proteoglycans (CSPGs) and neurocan were also determined by IHC 14d after ONC.

Results: GFAP level in the retina and the optic nerve significantly increased 1d after ONC, and reached the peak level 7d post-ONC. Injection of αA-crystallin significantly decreased GFAP level in both the retina and the crush site 3d after ONC, and induced astrocytes architecture remodeling at the crush site. Quantification of retinal ganglion cell (RGC) axons indicated αA-crystallin markedly promoted axon regeneration in ONC rats and enhanced the regenerated axons penetrated into the glial scar. CSPGs and neurocan expression also decreased 14d after αA-crystallin injection. The amplitude (N1-P1) and latency (P1) of F-VEP were also restored.

Conclusion: Our results suggest α-crystallin promotes the axon regeneration of RGCs and suppresses the activation of astrocytes.
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http://dx.doi.org/10.18240/ijo.2016.07.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951673PMC
August 2016

Intervertebral Fusion with Mobile Microendoscopic Discectomy for Lumbar Degenerative Disc Disease.

Orthop Surg 2016 May;8(2):241-5

Orthopaedic Oncology, Tianjin Hospital, Tianjin, China.

The aim of this article is to introduce a technique for lumbar intervertebral fusion that incorporates mobile microendoscopic discectomy (MMED) for lumbar degenerative disc disease. Minimally invasive transforaminal lumbar interbody fusion is frequently performed to treat degenerative diseases of the lumbar spine; however, the scope of such surgery and vision is limited by what the naked eye can see through the expanding channel system. To expand the visual scope and reduce trauma, we perform lumbar intervertebral fusion with the aid of a MMED system that provides a wide field through freely tilting the surgical instrument and canals. We believe that this technique is a good option for treating lumbar degenerative disc disease that requires lumbar intervertebral fusion.
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http://dx.doi.org/10.1111/os.12235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584144PMC
May 2016

Construction Strategy and Progress of Whole Intervertebral Disc Tissue Engineering.

Orthop Surg 2016 Feb;8(1):11-8

Department of Minimally Invasive Spine Surgery, Tianjin, China.

Degenerative disc disease (DDD) is the major cause of low back pain, which usually leads to work absenteeism, medical visits and hospitalization. Because the current conservative procedures and surgical approaches to treatment of DDD only aim to relieve the symptoms of disease but not to regenerate the diseased disc, their long-term efficiency is limited. With the rapid developments in medical science, tissue engineering techniques have progressed markedly in recent years, providing a novel regenerative strategy for managing intervertebral disc disease. However, there are as yet no ideal methods for constructing tissue-engineered intervertebral discs. This paper reviews published reports pertaining to intervertebral disc tissue engineering and summarizes data concerning the seed cells and scaffold materials for tissue-engineered intervertebral discs, construction of tissue-engineered whole intervertebral discs, relevant animal experiments and effects of mechanics on the construction of tissue-engineered intervertebral disc and outlines the existing problems and future directions. Although the perfect regenerative strategy for treating DDD has not yet been developed, great progress has been achieved in the construction of tissue-engineered intervertebral discs. It is believed that ongoing research on intervertebral disc tissue engineering will result in revolutionary progress in the treatment of DDD.
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http://dx.doi.org/10.1111/os.12218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584151PMC
February 2016

Novel compound heterozygous mutation in the CNGA1 gene underlie autosomal recessive retinitis pigmentosa in a Chinese family.

Biosci Rep 2016 22;36(1):e00289. Epub 2016 Jan 22.

Southwest Hospital, Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China Department of Ophthalmology, General Hospital of Chinese PLA, Beijing 100853, China Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China

Retinitis pigmentosa (RP) describes a group of inherited retinopathies that are characterized by the progressive degeneration of photoreceptor neurons, which causes night blindness, a reduction in the peripheral visual field and decreased visual acuity. More than 50 RP-related genes have been identified. In the present study, we analysed a Chinese family with autosomal recessive RP. We identified a compound heterozygous mutation, c.265delC and c.1537G>A, in CNGA1 using targeted next-generation sequencing (NGS) of RP-causing genes. The mutations were validated in the family members by Sanger sequencing. The mutations co-segregated with the RP phenotype and were absent from ethnically-matched control chromosomes. The mutant (mut) CNGA1 p.(G513R) protein caused by the mis-sense novel mutation c.1537G>A was expressed in vitro. The mut CNGA1 p.(G513R) protein was largely retained inside the cell rather than being targeted to the plasma membrane, suggesting the absence of cGMP-gated cation channels in the plasma membrane would be deleterious to rod photoreceptors, leading lead to RP.
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http://dx.doi.org/10.1042/BSR20150131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725244PMC
October 2016

Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.

Proc Natl Acad Sci U S A 2015 Apr 6;112(16):5225-30. Epub 2015 Apr 6.

Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing 400042, China;

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aβ aggregation and attenuating Aβ-induced oxidation in vitro. When given before or after the onset of Aβ deposition via i.p. injection, Edaravone substantially reduces Aβ deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.
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http://dx.doi.org/10.1073/pnas.1422998112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413288PMC
April 2015

Base-promoted transannulation of heterocyclic enamines and 2,3-epoxypropan-1-ones: regio- and stereoselective synthesis of fused pyridines and pyrroles.

J Org Chem 2015 Mar 25;80(5):2781-9. Epub 2015 Feb 25.

School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University , Xuzhou 221116, P. R. China.

Base-promoted transannulation of heterocyclic enamines and 2,3-epoxypropan-1-ones has been successfully achieved, providing a new access to structurally diverse fused pyridines and pyrroles with excellent regio- and stereoselectivity. Treatment with N-aryl 4-aminofuran-2(5H)-ones and 2,3-epoxypropan-1-ones under microwave heating resulted in functional furo[3,2-b]pyridines in good yields. The N-aryl 4-aminopyrrol-2(5H)-ones bearing an electron-withdrawing group engaged in the reaction afforded pyrrolo[3,2-b]pyridines, whereas their counterparts with an electron-neutral or an electron-donating group underwent a different reaction pathway to form pyrrolo[3,2-b]pyrroles through C-C bond cleavage.
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http://dx.doi.org/10.1021/acs.joc.5b00067DOI Listing
March 2015

Identification of novel CYP4V2 gene mutations in 92 Chinese families with Bietti's crystalline corneoretinal dystrophy.

Mol Vis 2014 31;20:1806-14. Epub 2014 Dec 31.

Southwest Hospital, Southwest Eye Hospital, Third Military Medical University, Chongqing, China ; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, PR China.

Purpose: To characterize the spectrum of CYP4V2 gene mutations in 92 unrelated Chinese probands with Bietti's crystalline dystrophy (BCD) and to describe the molecular and clinical characteristics of four novel CYP4V2 mutations associated with BCD.

Methods: All study participants underwent a complete ophthalmological examination. Mutational screening of CYP4V2 coding regions and flanking intron sequences was examined via directional Sanger sequencing, with allele separation confirmed by screening other family members. Subsequent in silico analysis of the mutational consequence on protein function was undertaken, with the impact of the novel mutation on pre-mRNA splicing examined via RT-PCR.

Results: Fifteen disease-causing variants were identified in 92 probands with BCD, including four novel mutations and eleven previously reported mutations. The most prevalent mutation was c.802_810del17insGC, which was detected in 69 unrelated families, with an allele frequency of 52.7% (97/184). Homozygosity was revealed in 35 unrelated families, and compound heterozygosity was observed in 43 subjects. Four patients harbored four novel variants, with these mutations cosegregated within all affected individuals and were not found in unaffected family members and 100 unrelated controls. Transcriptional analysis of a novel splice mutation revealed altered RNA splicing. In silico analysis predicted that the missense variant, p.Tyr343Asp, disrupted the CYP4V2 surface electrostatic potential distribution and spatial conformation. Among the patients with four novel mutations, genotype did not always correlate with age at onset, disease course, or electroretinogram (ERG) changes, with phenotypic variations even noted within the same genotype.

Conclusions: The c.802_810del17insCG mutation was the most common mutation in the 92 Chinese probands with BCD examined. Four novel mutations were identified, contributing to the spectrum of CYP4V2 mutations associated with BCD, with no clear link established between disease phenotype and genotype.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287718PMC
December 2015

Oridonin suppress cell migration via regulation of nonmuscle myosin IIA.

Cytotechnology 2016 May 9;68(3):389-97. Epub 2014 Oct 9.

School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, People's Republic of China.

Oridonin, which is isolated from Chinese herb Rabdosia rubescens (Hemsl.) Hara, has been implicated in regulation of tumor cell migration and invasion. In this study, treatment with oridonin enhanced the phosphorylation of myosin regulatory light chain (T18/S19) that regulates the ATPase activity of myosin IIA. Meanwhile, stress fibers were significantly more prominent after oridonin incubation, which impaired cell migration in transwell migration assays. All of these effects may be caused by the decreased interaction between myosin IIA and myosin phosphatase complex, but not kinases. Our data provide clear evidence of this novel pharmacological function for oridonin in treating cancer cell migration.
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http://dx.doi.org/10.1007/s10616-014-9790-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846644PMC
May 2016

Detecting novel genetic mutations in Chinese Usher syndrome families using next-generation sequencing technology.

Mol Genet Genomics 2015 Feb 25;290(1):353-63. Epub 2014 Sep 25.

Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing, 400038, China.

Usher syndrome (USH) is the most common cause of combined blindness and deafness inherited in an autosomal recessive mode. Molecular diagnosis is of great significance in revealing the molecular pathogenesis and aiding the clinical diagnosis of this disease. However, molecular diagnosis remains a challenge due to high phenotypic and genetic heterogeneity in USH. This study explored an approach for detecting disease-causing genetic mutations in candidate genes in five index cases from unrelated USH families based on targeted next-generation sequencing (NGS) technology. Through systematic data analysis using an established bioinformatics pipeline and segregation analysis, 10 pathogenic mutations in the USH disease genes were identified in the five USH families. Six of these mutations were novel: c.4398G > A and EX38-49del in MYO7A, c.988_989delAT in USH1C, c.15104_15105delCA and c.6875_6876insG in USH2A. All novel variations segregated with the disease phenotypes in their respective families and were absent from ethnically matched control individuals. This study expanded the mutation spectrum of USH and revealed the genotype-phenotype relationships of the novel USH mutations in Chinese patients. Moreover, this study proved that targeted NGS is an accurate and effective method for detecting genetic mutations related to USH. The identification of pathogenic mutations is of great significance for elucidating the underlying pathophysiology of USH.
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http://dx.doi.org/10.1007/s00438-014-0915-4DOI Listing
February 2015

Detecting genetic variations in hereditary retinal dystrophies with next-generation sequencing technology.

Mol Vis 2014 26;20:553-60. Epub 2014 Apr 26.

Southwest Hospital, Southwest Eye Hospital, Third Military Medical University, Chongqing, China ; Department of Ophthalmology, Chinese PLA General Hospital, Beijing, China ; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China.

Purpose: To identify pathogenic mutations responsible for retinal dystrophies (RDs) in three unrelated Chinese families.

Methods: Three probands from unrelated families with RDs were recruited. Genomic DNA prepared from leukocytes was analyzed using gene chip-based next-generation sequencing (NGS) to capture and sequence all of the exons of 100 known RD-associated genes. Candidate variants were validated with PCR and Sanger sequencing in the respective families. Thorough ophthalmic examinations including best-corrected visual acuity, funduscopic examination, and full-field electroretinograms were performed in the affected individuals.

Results: We successfully identified causative mutations in patients from the Chinese families with RDS: the known mutation IMPDH1 c.942_944delGAA in a family with retinitis pigmentosa, the novel mutation ABCA4 c.1924T>A in a family with Stargardt disease, and the novel mutation NMNAT1 c.272A>G and known mutation NMNAT1 c.196C>T in a family with Leber congenital amaurosis. All variations segregated with the disease phenotypes in the respective families and were absent from ethnically matched control chromosomes. Prediction analysis demonstrated the two novel missense mutations might be damaging.

Conclusions: The results strongly suggested these mutations were responsible for different RD phenotypes in the Chinese families. NGS technology provides an accurate and economic method for identifying causative genes for RDs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000715PMC
September 2014

Effect of optogenetic stimulus on the proliferation and cell cycle progression of neural stem cells.

J Membr Biol 2014 Jun 19;247(6):493-500. Epub 2014 Apr 19.

Southwest Eye Hospital/Southwest Hospital, Key Laboratory of Visual Damage and Regeneration and Restoration of Chongqing, Third Military Medical University, Chongqing, 400038, China,

Modulation of stem cell proliferation is a crucial aspect of neural developmental biology and regenerative medicine. To investigate the effect of optical stimulation on neural stem cell proliferation, cells transduced with channelrhodopsin-2 (ChR2) were used to analyze changes in cell proliferation and cell cycle distribution after light stimulation. Blue light significantly inhibited cell proliferation and affected the cell cycle, which increased the percentage of cells in G1 phase and reduced the percentage in S phase. It is likely that the influence of blue light on cell proliferation and the cell cycle was mediated by membrane depolarization, which induced accumulation of p21 and p27 proteins. Our data provide additional specific evidence that membrane depolarization may inhibit neural stem cell proliferation.
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http://dx.doi.org/10.1007/s00232-014-9659-7DOI Listing
June 2014

Synthesis and anti-BVDV activity of novel δ-sultones in vitro: implications for HCV therapies.

Bioorg Med Chem Lett 2014 May 17;24(10):2388-91. Epub 2014 Mar 17.

New Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, No. 100, KeXue DaDao, Zheng zhou, Henan Province 450001, PR China.

In this study we report the synthesis and activity against bovine viral diarrhea virus (BVDV) of a novel series of bicycle δ-sultones containing γ-lactones. BVDV is responsible for major losses in cattle. Some of the synthesized δ-sultones showed pronounced anti-BVDV activity with EC50 values of 0.12-1.0μM and no significant cytotoxicity. Among them, the ortho bromosubstituted derivative 4f (EC50=0.12μM) showed better antiviral activity than other derivatives and was 10 fold more that of than positive control ribavirin (EC50=1.3μM). BVDV is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. The above results provided a novel candidate for the development of anti-HCV agents.
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http://dx.doi.org/10.1016/j.bmcl.2014.03.012DOI Listing
May 2014

New synthetic antibiotics for the treatment of Enterococcus and Campylobacter infection.

Curr Top Med Chem 2014 ;14(1):21-39

New Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, No. 100, KeXue DaDao, Zhengzhou 450001, China.

Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. This review focuses on antibiotic resistance mechanisms of Enterococcus and Campylobacter, and new antibacterial agents against Enterococcus and Campylobacter through de novo or semi- synthesis in the period from 2003 until mid- 2013.
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http://dx.doi.org/10.2174/1568026613666131113145544DOI Listing
August 2014

Improved inhibitory activities against tumor-cell migration and invasion by 15-benzylidene substitution derivatives of andrographolide.

Bioorg Med Chem Lett 2013 Dec 25;23(23):6421-6. Epub 2013 Sep 25.

Department of Biotechnology, Zhengzhou University, Zhengzhou 450001, PR China.

In the present study, andrographolide (Andro, 1) derivatives were screened to identify potent inhibitors against tumor-cell migration and invasion, and associated structure-activity relationships were studied. Compared to 1, compounds 8a-8d exhibited more potent activities against migration in SGC-7901, PC-3, A549, HT-29 and Ec109 cell lines. Improved activities against tumor-cell migration and invasion were proved to be associated with the down-regulation of MMPs.
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http://dx.doi.org/10.1016/j.bmcl.2013.09.049DOI Listing
December 2013

Stereoselective synthesis and anti-proliferative effects on prostate cancer evaluation of 5-substituted-3,4-diphenylfuran-2-ones.

Eur J Med Chem 2013 Jul 14;65:323-36. Epub 2013 May 14.

School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan 450046, PR China.

Series of 5-substituted-3,4-diphenylfuran-2-ones were stereoselectively prepared. Their potential anti-proliferative effects on prostate cancer and some of their cyclooxygenases (COXs) inhibitory activities were evaluated. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position and ortho-position of the C-3 phenyl ring and 5-substituted modification of the central furanone, showed that 3-(2-chloro-phenyl)-4-(4-methanesulfonyl-phenyl)-5-(1-methoxy-ethyl)-5H-furan-2-one (13p) was the most potent compound and could effectively reduce the proliferation of prostate cancer cells (PC3 cell IC50 = 20 μM; PC3 PCDNA cell IC50 = 5 μM; PC3 SKP2 cell IC50 = 5 μM; DU145 cell IC50 = 25 μM). The cell cycle analysis for 13p in DU145 indicated that 13p may induce G1 phase arrest.
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http://dx.doi.org/10.1016/j.ejmech.2013.04.062DOI Listing
July 2013

A novel domino strategy for forming poly-substituted quaternary imidazoles through a Cs2CO3-promoted aryl migration process.

Org Biomol Chem 2013 Jun;11(22):3603-7

School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, 211116, P. R. China.

A new domino strategy for the synthesis of highly functionalized quaternary imidazole derivatives via [3 + 2] heterocyclization, involving aryl migration and ring-opening of oxirane, has been developed. This domino reaction enables the successful assembly of three new sigma bonds including two C-N bonds in a simple operation. Features of this strategy include the mild conditions, convenient operation, and short reaction periods (15-20 min).
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http://dx.doi.org/10.1039/c3ob40666kDOI Listing
June 2013

Perineuronal nets increase inhibitory GABAergic currents during the critical period in rats.

Int J Ophthalmol 2013 18;6(2):120-5. Epub 2013 Apr 18.

Southwest Eye Hospital, Southwest Hospital, Third Military Medical University, Chongqing 400038, China ; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China.

Aim: To investigate inhibitory γ-aminobutyric acid (GABA) ergic postsynaptic currents (IPSCs) and postsynaptic currents (PSCs) in layer IV of the rat visual cortex during the critical period and when plasticity was extended through dissolution of the perineuronal nets (PNNs).

Methods: We employed 24 normal Long-Evans rats to study GABAA-PSC characteristics of neurons within layer IV of the visual cortex during development. The animals were divided into six groups of four rats according to ages at recording: PW3 (P21-23d), PW4 (P28-30d), PW5 (P35-37d), PW6 (P42-44d), PW7 (P49-51d), and PW8 (56-58d). An additional 24 chondroitin sulfate proteoglycan (CSPG) degradation rats (also Long-Evans) were generated by making a pattern of injections of chondroitinase ABC (chABC) into the visual cortex 1 week prior to recording at PW3, PW4, PW5, PW6, PW7, and PW8. Immunohistochemistry was used to identify the effect of chABC injection on CSPGs. PSCs were detected with whole-cell patch recordings, and GABAA receptor-mediated IPSCs were pharmacologically isolated.

Results: IPSC peak current showed a strong rise in the age-matched control group, peaked at PW5 and were maintained at a roughly constant value thereafter. Although there was a small increase in peak current for the chABC group with age, the peak currents continued to decrease with the delayed highest value at PW6, resulting in significantly different week-by-week comparison with normal development. IPSC decay time continued to increase until PW7 in the control group, while those in the chABC group were maintained at a stable level after an initial increase at PW4. Compared with normal rats, the decay times recorded in the chABC rats were always shorter, which differed significantly at each age. We did not observe any differences in IPSC properties between the age-matched control and penicillinase (P-ase) group. However, the change in IPSCs after chABC treatment was not reflected in the total PSCs or in basic membrane properties in layer IV of the rat visual cortex.

Conclusion: Our results demonstrate that rather than rapidly increasing during the critical period for neuronal plasticity, IPSCs in layer IV of rat visual cortex are maintained at an immature level when PNNs are removed by chABC. This suggests that GABA receptor maturation involves the conformation of the CSPGs in PNNs.
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http://dx.doi.org/10.3980/j.issn.2222-3959.2013.02.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633745PMC
May 2013

Novel double [3 + 2 + 1] heteroannulation for forming unprecedented dipyrazolo-fused 2,6-naphthyridines.

Org Lett 2013 May 18;15(9):2258-61. Epub 2013 Apr 18.

School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, 221116 Jiangsu, PR China.

A novel four-component strategy for the efficient synthesis of unprecedented dipyrazolo-fused 2,6-naphthyridines through a double [3 + 2+1] heteroannulation has been described. The bond-forming efficiency, accessibility, and generality of this synthesis make it highly valuable to assemble tetra-heterocyclic scaffolds.
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http://dx.doi.org/10.1021/ol4008266DOI Listing
May 2013

Highly selective domino multicyclizations for forming polycyclic fused acridines and azaheterocyclic skeletons.

Org Lett 2013 Apr 18;15(7):1540-3. Epub 2013 Mar 18.

School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou, 221116, Jiangsu, PR China.

Highly selective four-component domino multicyclizations for the synthesis of new fused acridines and azaheterocyclic skeletons have been established by mixing common reactants in isobutyric acid under microwave irradiation. The reactions proceeded at fast rates and were conducted to completion within 20-30 min. Up to seven new chemical bonds, four rings, and four stereocenters were assembled in a convenient one-pot operation. The resulting hexacyclic and pentacyclic fused acridines and their stereochemistry have been fully characterized and determined by X-ray structural analysis.
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http://dx.doi.org/10.1021/ol400322vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635953PMC
April 2013
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