JOURNAL OF MOLECULAR MEDICINE-JMM
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2023
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IF 4.7
Chen Yinghui,Wu Yizhuo,Feng Weiqi,Luo Xueyang,Xiao Bing,Ding Xiaowei,Gu Yongjia,Lu Yanan,Yu Yu
Abstract The ductus arteriosus (DA), bridging the aorta and pulmonary artery, immediately starts closing after birth. Remodeling of DA leads to anatomic obstruction to prevent repatency. Several histological changes, especially extracellular matrices (ECMs) deposition and smooth muscle cells (SMCs) migration bring to anatomic closure. The genetic etiology and mechanism of DA closure remain elusive. We have previously reported a novel copy number variant containing Vav2 in patent ductus arteriosus (PDA) patients, but its specific role in DA closure remains unknown. The present study revealed that the expression of Vav2 was reduced in human patent DA, and it was less enrichment in the adjacent aorta. Matrigel experiments demonstrated that Vav2 could promote SMC migration from PDA patient explants. Smooth muscle cells with Vav2 overexpression also presented an increased capacity in migration and downregulated contractile-related proteins. Meanwhile, SMCs with Vav2 overexpression exhibited higher expression of collagen III and lessened protein abundance of lysyl oxidase, and both changes are beneficial to DA remodeling. Overexpression of Vav2 resulted in increased activity of Rac1, Cdc42, and RhoA in SMCs. Further investigation noteworthily found that the above alterations caused by Vav2 overexpression were particularly reversed by Rac1 inhibitor. A heterozygous, rare Vav2 variant was identified in PDA patients. Compared with the wild type, this variant attenuated Vav2 protein expression and weakened the activation of downstream Rac1, further impairing its functions in SMCs. In conclusion, Vav2 functions as an activator for Rac1 in SMCs to promote SMCs migration, dedifferentiation, and ECMs production. Deleterious variant potentially induces Vav2 loss of function, further providing possible molecular mechanisms about Vav2 in PDA pathogenesis. These findings enriched the current genetic etiology of PDA, which may provide a novel target for prenatal diagnosis and treatment. Key messages
Although we have proposed the potential association between Vav2 and PDA incidence through whole exome sequencing, the molecular mechanisms underlying Vav2 in PDA have never been reported. This work, for the first time, demonstrated that Vav2 was exclusively expressed in closed DAs.
Moreover, we found that Vav2 participated in the process of anatomic closure by mediating SMCs migration, dedifferentiation, and ECMs deposition through Rac1 activation.
Our findings first identified a deleterious Vav2 c.701C>T variant that affected its function in SMCs by impairing Rac1 activation, which may lead to PDA defect. Vav2 may become an early diagnosis and an effective intervention target for PDA clinical therapy.
研究领域:
心血管生物学
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遗传学
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分子生物学
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发育生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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2023
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IF 3
Dan Xiao,Ying Jin,Mengyu Zhang,Xiangjie Di,Lisha Fu,Changke Jiang,Zhuoli Lai,Yating Ge,Shanmian Ji,Yuming Zhang,Li Zheng,Zhenlei Wang,Fang Gong
Persistent patent ductus arteriosus (PDA) is generally observed in preterm neonates. Oral ibuprofen is the standard treatment for closing PDA in China. To investigate the chiral pharmacokinetics of ibuprofen enantiomers in Chinese premature infants with PDA, a simple, fast, and sensitive analytical enantioselective technology was developed with ultra-performance liquid chromatography (UPLC) – tandem mass spectrometry (MS/MS). Chromatographic separation of (R)-ibuprofen and (S)-ibuprofen was accomplished on a Lux® 3 µm Cellulose-3 (150 mm × 2.0 mm, 3 μm) at a flow rate of 0.2 mL/min within 6 min. UPLC separation was achieved by isocratic elution with a mobile phase consisting of formic acid:water (75:1000000, v/v) and acetonitrile:methanol (1:1, v/v). Only 50 µL of plasma samples were pre-treated with acetonitrile precipitation. Ibuprofen-d 3 was used as an internal standard. The standard curves of both enantiomers were linear over a concentration range of 0.0500 μg/mL to 50.00 μg/mL. The method has been validated for selectivity, carryover effect, lower limit of quantification, precision, accuracy, matrix effect, extraction recovery, dilution integrity, and stability based on the existing guidelines of the National Medical Products Administration, the United States Food and Drug Administration, and the European Medicines Agency. This method has been successfully applied to investigate the pharmacokinetics of ibuprofen enantiomers in 9 preterm infants with PDA. Our results showed that a high chiral inversion ratio of (R)- to (S)-ibuprofen exists in Chinese preterm neonates. Further studies should be conducted to monitor drug concentration following oral administration of ibuprofen and to consider the effect of individual variations and ethnic differences in metabolizing enantiomers of ibuprofen in premature neonates with PDA.
研究领域:
药理学
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新生儿医学
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分析化学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
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IF 10.6
Majid Sharifi,Majid Salehi,Somayeh Ebrahimi-Barough,Morteza Alizadeh,Hossein Kargar Jahromi,Mohammad Kamalabadi-Farahani
Numerous conduits have been developed to improve peripheral nerve regeneration. However, challenges remain, including remote control of conduit function, and programmed cell behaviors like orientation. We synthesized Fe 3 O 4 -MnO 2 @Zirconium-based Metal-organic frameworks@Retinoic acid (FMZMR) core-shell and assessed their impact on Schwann cell function and behavior within conduits made from decellularized human umbilical arteries (DHUCA) under magnetic field (MF). FMZMR core-shell, featuring a spherical porous structure and catalytic properties, effectively scavenges radicals and facilitates controlled drug release under MF. The histology of the DHUCA indicates effective decellularization with adequate tensile strength and Young’s modulus for sciatic nerve regeneration. In-vitro results demonstrate that FMZMR core-shell is biocompatible and promotes Schwann cell proliferation through remotely controlled drug release. Furthermore, its synergy with MF enhances cell orientation and increases neurite length by ~ 1.93-fold. Functional and histological evaluations indicate that the FMZMR core-shell combined with MF promotes nerve regeneration, decreases muscle atrophy, and enhances new neuron growth and myelin formation, without negatively affecting vital tissues. This study suggests that the synergistic effect of FMZMR core-shell with MF can alleviate some of the treatment challenges.
研究领域:
生物材料学
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神经科学
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组织工程学
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DOI
PubMed
高影响因子
Nano Today
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2025
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IF 10.9
Majid Sharifi,Majid Salehi,Somayeh Ebrahimi-Barough,Mohammad Kamalabadi-Farahani
Neuroma formation following the repair of nerve injuries exceeding 0.9 cm in length severely impedes functional recovery. To overcome this challenge, we engineered magnetically responsive core-shell nanoparticles (MnFe 2 O 4 @ZIF-8@Retinoic acid, MFZR; 90–360 nm) to guide regeneration within a decellularized umbilical cord artery (DUCA) conduit. We investigated the synergistic effect of MFZR under an external magnetic field (MF) on Schwann cell behavior in vitro and on sciatic nerve repair in a rat model. Under MF exposure, MFZR significantly enhanced Schwann cell migration, alignment, and elongation on DUCA conduits. In-vivo , the MFZR+MF combination potently promoted functional recovery, as measured by the sciatic functional index, muscle compound action potential, and nerve conduction velocity, without inducing DUCA-related inflammation. Histological analysis demonstrated robust regeneration, characterized by increased axon diameter, an improved G-ratio, and elevated expression of S100 and NF-200. This regeneration was facilitated by a healing-promoting M2 macrophage polarization at the injury site. Critically, the strategy exhibited no systemic toxicity. These findings establish that magnetically guided MFZR effectively prevents neuroma in the DUCA conduits, orchestrates a pro-regenerative microenvironment, and achieves significant functional recovery, offering a promising translatable strategy for nerve repair.
研究领域:
生物医学工程
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神经生物学
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组织工程
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纳米医学
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再生医学
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免疫调节
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转化医学
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产品关联
DOI
高影响因子
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