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1.
Molecules ; 27(13)2022 Jun 23.
Article in English | MEDLINE | ID: mdl-35807286

ABSTRACT

As a typical dibenzylisoquinoline alkaloid, tetrandrine (TET) is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. Recent investigations have demonstrated the outstanding anticancer activity of this structure, but its poor aqueous solubility severely restricts its further development. Herein, a series of its 14-N-amino acid-substituted derivatives with improved anticancer effects and aqueous solubility were designed and synthesized. Among them, compound 16 displayed the best antiproliferative activity against human colorectal cancer (HCT-15) cells, with an IC50 value of 0.57 µM. Compared with TET, 16 was markedly improved in terms of aqueous solubility (by 5-fold). Compound 16 significantly suppressed the colony formation, migration, and invasion of HCT-15 cells in a concentration-dependent manner, with it being more potent in this respect than TET. Additionally, compound 16 markedly impaired the morphology and motility of HCT-15 cells and induced the death of colorectal cancer cells in double-staining and flow cytometry assays. Western blot results revealed that 16 could induce the autophagy of HCT-15 cells by significantly decreasing the content of p62/SQSTM1 and enhancing the Beclin-1 level and the ratio of LC3-II to LC3-I. Further study showed that 16 effectively inhibited the proliferation, migration, and tube formation of umbilical vein endothelial cells, manifesting in a potent anti-angiogenesis effect. Overall, these results revealed the potential of 16 as a promising candidate for further preclinical studies.


Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Amino Acids/pharmacology , Antineoplastic Agents/chemistry , Apoptosis , Benzylisoquinolines , Cell Line, Tumor , Cell Proliferation , Colorectal Neoplasms/drug therapy , Drug Screening Assays, Antitumor , Endothelial Cells , Humans , Molecular Structure , Structure-Activity Relationship
2.
Eur J Med Chem ; 222: 113573, 2021 Oct 15.
Article in English | MEDLINE | ID: mdl-34091209

ABSTRACT

A series of 2,4-diamino pyrimidine (DAPY) derivatives were designed, synthesized, and evaluated as inhibitors of focal adhesion kinase (FAK) with antitumor and anti-angiogenesis activities. Most compounds effectively suppressed the enzymatic activities of FAK, and the IC50s of 11b and 12f were 2.75 and 1.87 nM, respectively. 11b and 12f exhibited strong antiproliferative effects against seven human cancer cells, with IC50 values against two FAK-overexpressing pancreatic cancer cells (PANC-1 and BxPC-3) of 0.98 µM, 0.55 µM, and 0.11 µM, 0.15 µM, respectively. Moreover, 11b and 12f obviously suppressed the colony formation, migration, and invasion of PANC-1 cells in a dose-dependent manner. Meanwhile, these two compounds could induce the apoptosis of PANC-1 cells and arrest the cell cycle in G2/M phase according to the flow cytometry assay. Western blot revealed that 11b and 12f effectively inhibited the FAK/PI3K/Akt signal pathway and significantly decreased the expression of cyclin D1 and Bcl-2. In addition, compounds 11b and 12f potently inhibited the antiproliferative of HUVECs and obviously altered the cell morphology. 11b and 12f also significantly inhibited the migration, tube formation of HUVECs and severely impaired the angiogenesis in the zebrafish model. Overall, these results revealed the potential of compounds 11b and 12f as promising candidates for further preclinical studies.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Drug Design , Focal Adhesion Kinase 1/antagonists & inhibitors , Neovascularization, Pathologic/drug therapy , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Focal Adhesion Kinase 1/metabolism , Humans , Molecular Structure , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
3.
Sci Rep ; 8(1): 7675, 2018 05 16.
Article in English | MEDLINE | ID: mdl-29769573

ABSTRACT

Interleukin-15 (IL-15) can promote both innate and adaptive immune reactions by stimulating CD8+/CD4+ T cells and natural killer cells (NK) while showing no effect in activating T-regulatory (Treg) cells or inducing activation-associated death among effector T cells and NK cells. Thus, IL-15 is considered as one of the most promising molecules for antitumor immune therapy. To improve the drug-like properties of natural IL-15, we create an IL-15-based molecule, named P22339, with the following characteristics: 1) building a complex of IL-15 and the Sushi domain of IL-15 receptor α chain to enhance the agonist activity of IL-15 via transpresentation; 2) through a rational structure-based design, creating a disulfide bond linking the IL-15/Sushi domain complex with an IgG1 Fc to augment its half-life. P22339 demonstrates excellent developability, pharmacokinetic and pharmacodynamic properties as well as antitumor efficacy in both in vitro assessments and in vivo studies. It significantly suppresses tumor growth and metastasis in rodent models, and activates T effector cells and NK cells in cynomolgus monkey. Overall, these data suggest that P22339 has a great potential for cancer immunotherapy.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Immunotherapy/methods , Interleukin-15 Receptor alpha Subunit/chemistry , Interleukin-15/metabolism , Lung Neoplasms/therapy , Melanoma, Experimental/therapy , Animals , Antineoplastic Agents/chemistry , Apoptosis , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Drug Design , Female , Humans , Interleukin-15/chemistry , Interleukin-15/pharmacokinetics , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Macaca fascicularis , Male , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Tissue Distribution , Tumor Cells, Cultured
4.
Anal Chim Acta ; 955: 67-78, 2017 Feb 22.
Article in English | MEDLINE | ID: mdl-28088282

ABSTRACT

Trastuzumab-MCC-DM1 (T-DM1) is an antibody-drug conjugate (ADC) that consists of a monoclonal antibody (mAb) trastuzumab non-cleavably linked to a cytotoxic drug DM1. During production, the DM1 agents were conjugated to the lysine residues of the mAb in a non-specific manner, yielding a heterogeneous mixture of ADC molecules that differ with respect to both the number and the conjugation sites of DM1 per mAb molecule. Since drug conjugation sites of ADC can significantly impact properties such as stability and pharmacokinetic behaviors, a rapid and reliable approach for conjugation site analysis of ADCs is highly demanded. Herein, we have employed a signature ion fingerprinting approach to specifically determine lysine residues with DM1 conjugation, and developed a normalized peak area quantitation method to characterize the percentage of DM1-conjugated lysine for each putative site using a T-DM1 biosimilar as a model drug. With this integrative approach, 38 lysine residues were identified with DM1 conjugation among 90 possible sites. More interestingly, we found that the T-DM1 biosimilar exhibited a specific preference of DM1-conjugation for several lysine residues, and such preference was consistent among three production batches. A molecular modeling approach was subsequently utilized to analyze all the conjugation sites, and revealed an intriguing correlation of the conjugated residue's microenvironment with the conjugation level. In summary, our study introduced an approach that is widely applicable to ADCs of interest for conjugation site analysis. Moreover, it suggests the necessity of performing conjugation site analysis for product and process characterization and also for routine use in lot release and stability testing of manufactured ADCs.


Subject(s)
Immunoconjugates/chemistry , Maytansine/chemistry , Trastuzumab/chemistry , Chromatography, Liquid , Mass Spectrometry
5.
J Chem Inf Model ; 56(10): 1979-1994, 2016 10 24.
Article in English | MEDLINE | ID: mdl-27529495

ABSTRACT

The discovery of unique substrates is important for developing potential applications of enzymes. However, the experimental procedures for substrate identification are laborious, time-consuming, and expensive. Although in silico structure-based approaches show great promise, recent extensive studies have shown that these approaches remain a formidable challenge for current biocomputational methodologies. Here we present an open-source, extensible, and flexible software platform for predicting enzyme substrates called THEMIS, which performs in silico virtual screening for potential catalytic targets of an enzyme on the basis of the enzyme's catalysis mechanism. On the basis of a generalized transition state theory of enzyme catalysis, we introduce a modified docking procedure called "mechanism-based restricted docking" (MBRD) for novel substrate recognition from molecular docking. Comprising a series of utilities written in C/Python, THEMIS automatically executes parallel-computing MBRD tasks and evaluates the results with various molecular mechanics (MM) criteria such as energy, distance, angle, and dihedral angle to help identify desired substrates. Exhaustive sampling and statistical measures were used to improve the robustness and reproducibility of the method. We used Candida antarctica lipase B (CALB) as a test system to demonstrate the effectiveness of our computational prediction of (non)substrates. A novel MM score function for CALB substrate identification derived from the near-attack conformation was used to evaluate the possibility of chemical transformation. A highly positive rate of 93.4% was achieved from a CALB substrate library with 61 known substrates and 35 nonsubstrates, and the screening rate has reached 103 compounds/day (96 CPU cores, 100 samples/compound). The performance shows that the present method is perhaps the first reported scheme to meet the requirement for practical applicability to enzyme studies. An additional study was performed to validate the universality of our method. In this verification we employed two distinct enzymes, nitrilase Nit6803 and SDR Gox2181, where the correct rates of both enzymes exceeded 90%. The source code used will be released under the GNU General Public License (GPLv3) and will be free to download. We believe that the present method will provide new insights into enzyme research and accelerate the development of novel enzyme applications.


Subject(s)
Candida/enzymology , Fungal Proteins/metabolism , Lipase/metabolism , Binding Sites , Candida/chemistry , Candida/metabolism , Fungal Proteins/chemistry , Lipase/chemistry , Molecular Docking Simulation , Software , Substrate Specificity
7.
FEBS J ; 282(12): 2339-51, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25817922

ABSTRACT

Coenzyme engineering, especially for altered coenzyme specificity, has been a research hotspot for more than a decade. In the present study, a novel computational strategy that enhances the hydrogen-bond interaction between an enzyme and a coenzyme was developed and utilized to alter the coenzyme preference. This novel computational strategy only required the structure of the target enzyme. No other homologous enzymes were needed to achieve alteration in the coenzyme preference of a certain enzyme. Using our novel strategy, Gox2181 was reconstructed from exhibiting complete NADPH preference to exhibiting dual cofactor specificity for NADH and NADPH. Structure-guided Gox2181 mutants were designed in silico and molecular dynamics simulations were performed to evaluate the strength of hydrogen-bond interactions between the enzyme and the coenzyme NADPH. Three Gox2181 mutants displaying high structure stability and structural compatibility to NADH/NADPH were chosen for experimental confirmation. Among the three Gox2181 mutants, Gox2181-Q20R&D43S showed the highest enzymatic activity by utilizing NADPH as its coenzyme, which was even better than the wild-type enzyme. In addition, isothermal titration calorimetry analysis further verified that Gox2181-Q20R&D43S was able to interact with NADPH but the wild-type enzyme could not. This novel computational strategy represents an insightful approach for altering the cofactor preference of target enzymes.


Subject(s)
Coenzymes/metabolism , Models, Molecular , Mutant Proteins/metabolism , NADP/metabolism , NAD/metabolism , Oxidoreductases/metabolism , Protein Engineering/methods , Amino Acid Sequence , Amino Acid Substitution , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Coenzymes/chemistry , Computational Biology , Conserved Sequence , Databases, Protein , Enzyme Stability , Expert Systems , Gluconobacter oxydans/enzymology , Hydrogen Bonding , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Mutant Proteins/chemistry , NAD/chemistry , NADP/chemistry , Oxidoreductases/chemistry , Oxidoreductases/genetics , Protein Conformation
8.
Protein Sci ; 23(11): 1540-9, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25131535

ABSTRACT

An aldo-keto reductase AKR5C3 from Gluconobacter oxydans (designated as Gox0644) is a useful enzyme with various substrates, including aldehydes, diacetyl, keto esters, and α-ketocarbonyl compounds. The crystal structures of AKR5C3 in apoform in complex with NADPH and the D53A mutant (AKR5C3(-D53A) ) in complex with NADPH are presented herein. Structure comparison and site-directed mutagenesis combined with biochemical kinetics analysis reveal that the conserved Asp53 in the AKR5C3 catalytic tetrad has a crucial role in securing active pocket conformation. The gain-of-function Asp53 to Ala mutation triggers conformational changes on the Trp30 and Trp191 side chains, improving NADPH affinity to AKR5C3, which helps increase catalytic efficiency. The highly conserved Trp30 and Trp191 residues interact with the nicotinamide moiety of NADPH and help form the NADPH-binding pocket. The AKR5C3(-W30A) and AKR5C3(-W191Y) mutants show decreased activities, confirming that both residues facilitate catalysis. Residue Trp191 is in the loop structure, and the AKR5C3(-W191Y) mutant does not react with benzaldehyde, which might also determine substrate recognition. Arg192, which is involved in the substrate binding, is another important residue. The introduction of R192G increases substrate-binding affinity by improving hydrophobicity in the substrate-binding pocket. These results not only supplement the AKRs superfamily with crystal structures but also provide useful information for understanding the catalytic properties of AKR5C3 and guiding further engineering of this enzyme.


Subject(s)
Gluconobacter oxydans/enzymology , Sugar Alcohol Dehydrogenases/chemistry , Sugar Alcohol Dehydrogenases/metabolism , Amino Acid Sequence , Binding Sites/genetics , Escherichia coli Proteins , Gluconobacter oxydans/genetics , Models, Molecular , Molecular Sequence Data , Mutation/genetics , NADP/chemistry , NADP/metabolism , Protein Binding , Sequence Alignment , Sugar Alcohol Dehydrogenases/genetics
9.
Proteins ; 82(11): 2925-35, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24825769

ABSTRACT

Gox2253 from Gluconobacter oxydans belongs to the short-chain dehydrogenases/reductases family, and catalyzes the reduction of heptanal, octanal, nonanal, and decanal with NADPH. To develop a robust working platform to engineer novel G. oxydans oxidoreductases with designed coenzyme preference, we adopted a structure based rational design strategy using computational predictions that considers the number of hydrogen bonds formed between enzyme and docked coenzyme. We report the crystal structure of Gox2253 at 2.6 Å resolution, ternary models of Gox2253 mutants in complex with NADH/short-chain aldehydes, and propose a structural mechanism of substrate selection. Molecular dynamics simulation shows that hydrogen bonds could form between 2'-hydroxyl group in the adenosine moiety of NADH and the side chain of Gox2253 mutant after arginine at position 42 is replaced with tyrosine or lysine. Consistent with the molecular dynamics prediction, Gox2253-R42Y/K mutants can use both NADH and NADPH as a coenzyme. Hence, the strategies here could provide a practical platform to engineer coenzyme selectivity for any given oxidoreductase and could serve as an additional consideration to engineer substrate-binding pockets.


Subject(s)
Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Gluconobacter oxydans/chemistry , Aldehydes/metabolism , Amino Acid Sequence , Bacterial Proteins/genetics , Catalytic Domain , Coenzymes/metabolism , Crystallography, X-Ray , Hydrogen Bonding , Kinetics , Models, Molecular , Molecular Dynamics Simulation , Molecular Sequence Data , Mutation , NADP/chemistry , NADP/metabolism , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Protein Conformation , Sequence Homology, Amino Acid , Substrate Specificity
10.
Protein Sci ; 23(1): 110-6, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24353171

ABSTRACT

We report a suite of enzyme redesign protocol based on the surface charge-charge interaction calculation, which is potentially applied to improve the stability of an enzyme without compromising its catalytic activity. Together with the experimental validation, we have released a suite of enzyme redesign algorithm Enzyme Thermal Stability System, written based on our model, for open access to meet the needs in wet labs. Lipk107, a lipase of a versatile industrial use, was chosen to test our software. Our calculation determined that four residues, D113, D149, D213, and D253, located on the surface of LipK107 were critical to the stability of the enzyme. The model was validated with mutagenesis at these four residues followed by stability and activity tests. LipK107 mutants D113A and D149K were more resistant to thermal inactivation with ∼10°C higher half-inactivation temperature than wild-type LipK107. Moreover, mutant D149K exhibited significant retention in residual activity under constant heat, showing a 14-fold increase in the half-inactivation time at 50°C. Activity tests showed that these mutants retained the equal or higher specific activity, among which noteworthy was the mutant D253A with as much as 20% higher activity. We suggest that our protocol could be used as a general guideline to redesign protein enzymes with increased stabilities and enhanced activities.


Subject(s)
Catalytic Domain , Enzyme Stability , Lipase/chemistry , Mutagenesis, Site-Directed , Proteus/enzymology , Algorithms , Hot Temperature , Lipase/genetics , Models, Chemical , Reproducibility of Results , Surface Properties
11.
J Biotechnol ; 167(4): 386-92, 2013 Sep 20.
Article in English | MEDLINE | ID: mdl-23916946

ABSTRACT

Short-chain dehydrogenase Gox2181 from Gluconobacter oxydans catalyzes the reduction of 2,3-pentanedione by using NADH as the physiological electron donor. To realize its synthetic biological application for coenzyme recycling use, computational design and site-directed mutagenesis have been used to engineer Gox2181 to utilize not only NADH but also NADPH as the electron donor. Single and double mutations at residues Q20 and D43 were made in a recombinant expression system that corresponded to Gox2181-D43Q and Gox2181-Q20R&D43Q, respectively. The design of mutant Q20R not only resolved the hydrogen bond interaction and electrostatic interaction between R and 2'-phosphate of NADPH, but also could enhance the binding with 2'-phophated of NADPH by combining with D43Q. Molecular dynamics simulation has been carried out to testify the hydrogen bond interactions between mutation sites and 2'-phosphate of NADPH. Steady-state turnover measurement results indicated that Gox2181-D43Q could use both NADH and NADPH as its coenzyme, and so could Gox2181-Q20R&D43Q. Meanwhile, compared to the wild-type enzyme, Gox2181-D43Q exhibited dramatically reduced enzymatic activity while Gox2181-Q20R&D43Q successfully retained the majority of enzymatic activity.


Subject(s)
Coenzymes/chemistry , Fatty Acid Synthases/genetics , Gluconobacter oxydans/enzymology , NADH, NADPH Oxidoreductases/genetics , Protein Engineering , Bacterial Proteins/metabolism , Coenzymes/metabolism , Fatty Acid Synthases/chemistry , Fatty Acid Synthases/metabolism , Hydrogen/metabolism , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Mutant Proteins/chemistry , Mutant Proteins/metabolism , NAD/metabolism , NADH, NADPH Oxidoreductases/chemistry , NADH, NADPH Oxidoreductases/metabolism , NADP/metabolism
12.
Chembiochem ; 13(15): 2234-42, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22961947

ABSTRACT

A polyene macrolide antibiotic tetramycin biosynthetic gene cluster was identified by genome mining and isolated from Streptomyces hygrospinosus var. beijingensis. Genetic and in silico analyses gave insights into the mechanism of biosynthesis of tetramycin, and a model of the tetramycin biosynthetic pathway is proposed. Inactivation of a cytochrome P450 monooxygenase gene, tetrK, resulted in the production of a tetramycin B precursor: tetramycin A, which lacks a hydroxy group in its polyol region. TetrK was subsequently overexpressed heterologously in E. coli with a His(6) tag, and purified TetrK efficiently hydroxylated tetramycin A to afford tetramycin B. Kinetic studies revealed no inhibition of TetrK by substrate or product. Surprisingly, sequence-alignment analysis showed that TetrK, as a hydroxylase, has much higher homology with epoxidase PimD than with hydroxylases NysL and AmphL. The 3D structure of TetrK was then constructed by homology modeling with PimD as reference. Although TetrK and PimD catalyzed different chemical reactions, homology modeling indicated that they might share the same catalytic sites, despite also possessing some different sites correlated with substrate binding and substrate specificity. These findings offer good prospects for the production of improved antifungal polyene analogues.


Subject(s)
Anti-Bacterial Agents/metabolism , Cytochrome P-450 Enzyme System/metabolism , Macrolides/metabolism , Multigene Family , Polyenes/metabolism , Streptomyces/enzymology , Streptomyces/genetics , Amino Acid Sequence , Cytochrome P-450 Enzyme System/genetics , Genes, Bacterial , Hydroxylation , Models, Molecular , Molecular Sequence Data , Sequence Alignment , Streptomyces/metabolism
13.
Zhonghua Yi Xue Za Zhi ; 91(26): 1847-51, 2011 Jul 12.
Article in Chinese | MEDLINE | ID: mdl-22093789

ABSTRACT

OBJECTIVE: To explore the therapeutic effect and the mechanism of marrow mesenchymal stem cells (MMSCs) transfected with vascular endothelial growth factor (VEGF) gene in the treatment of pulmonary hypertension in rats. METHODS: MMSCs from the bone marrow of Sprague-Dawley rats were isolated, cultured and propagated in vitro. pIRES2-EGFP-VEGF165 was transfected into MMSC. The healthy male SD rats were divided randomly into 4 groups: normal control group, pulmonary hypertension model group, MMSCs transplantation group and transfer gene transplantation group. A single subcutaneous monocrotaline (50 mg/kg) was injected to induce the model of pulmonary hypertension. The normal control group received a single subcutaneous dose of L-DMEM (low glucose Dulbecco's modified Eagle's medium). All four groups of rats were fed similarly. At Day 21 post-modeling, 5 × 10(6) MMSCs in l ml L-DMEM were injected into the MMSC group. 5 × 10(5) MMSC transfected by pIRES2-EGFP-VEGF165 were injected into the gene transplantation group. A same volume L-DMEM solution was also injected into the pulmonary hypertension model group and normal control group. The parameters of right ventricular systolic pressure (RVSP), right ventricular hypertrophy index, blood gas analysis and microstructure as well as pulmonary microvascular changes were observed after 30 days. RESULTS: At Day 30 post-transplantation of MMSCs, the outcomes were as follows: RVSP was (30.2 ± 2.1) and (29.2 ± 1.1) mm Hg (1 mm Hg = 0.133 kPa) in the MMSCs transplantation and gene transplantation groups respectively. The right ventricular hypertrophy indices were (37.9 ± 3.2)% and (27.2 ± 3.4)% respectively. The media thickness of pulmonary artery (MT) was (21.3 ± 3.4) and (14.3 ± 2.8) µm respectively. The ratios of vascular area to total arterial area (V/T) were (39.3 ± 4.3)% and (43.0 ± 1.5)% respectively. As compare with the pulmonary hypertension model group, the above parameters were of statistical significances (P < 0.01). A comparison of right ventricle hypertrophy index, MT and V/T was of statistical significance between MMSC and gene transplantation groups (P < 0.05). The blood gas analysis of the MMSCs transplantation and gene transplantation groups were better than the pulmonary hypertension mode group. Ultramicrostructure showed that neovascularization and small pulmonary arterial repair appeared in two transplantation groups. CONCLUSION: MMSCs transfected by pIRES2-EGFP-VEGF165 transplantation may improve and reverse the MCT-induced progress of pulmonary hypertension in rats. And it is better than the MMSC transplantation. The potential mechanism is through arterial repair and neovascularization.


Subject(s)
Hypertension, Pulmonary/surgery , Mesenchymal Stem Cell Transplantation/methods , Vascular Endothelial Growth Factor A/genetics , Animals , Bone Marrow Cells/cytology , Cells, Cultured , Male , Rats , Rats, Sprague-Dawley , Transfection
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