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- Volume 18, Issue 27, 2012
Current Pharmaceutical Design - Volume 18, Issue 27, 2012
Volume 18, Issue 27, 2012
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Context-dependent Action of Transforming Growth Factor β Family Members on Normal and Cancer Stem Cells
Authors: Laia Caja, Kaoru Kahata and Aristidis MoustakasThe transforming growth factor β (TGFβ) family embraces many growth factors including the Activins and bone morphogenetic proteins (BMPs). The pathways mediated by these growth factors are implicated in many fundamental biological processes such as early embryonic development, organ morphogenesis and adult tissue homeostasis and in a large number of pathologies including cancer. The action of these pathways is often contextual, which means that different cell types present different physiological responses to these ligands or that the response of one cell type to a certain ligand differs depending on the presence of other signaling proteins that stimulate the target cell together with TGFβ/BMP. The latter usually reflects developmental stage or progression to a specific pathological stage. Not only diverse growth factors and cytokines can influence the response of tissues to TGFβ/BMP, but a single cell type may also show drastically different physiological outcomes to TGFβ or Activin signaling as compared to BMP signaling. This review describes differential physiological outcomes of TGFβ and BMP signaling in normal embryonic or adult stem cells and eventually in cancer stem cells and the process of epithelial-mesenchymal transition. We also summarize evidence on the mechanistic antagonism between TGFβ and BMP signaling as established in vascular differentiation and the progression of tissue fibrosis and cancer. The article ends by discussing possible advantages that the acquired knowledge of these signaling mechanisms offers to new regimes of cancer therapy and the ever-lasting problem of drug resistance elicited by tumor initiating cells.
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Deregulated Bone Morphogenetic Protein Receptor Signaling Underlies Fibrodysplasia Ossificans Progressiva
Authors: David J.J. de Gorter, Vishant Jankipersadsing and Peter ten DijkeTransforming growth factor-β family members, which include TGF-βs, activins and bone morphogenetic proteins (BMPs), play important roles in development and maintaining tissue homeostasis. The extracellular TGF-β family members signal across the plasmamembrane by activating type I and type II serine/threonine kinase receptors. Pertubation in TGF-β family receptor signaling has been implicated in certain diseases, including musculo-skeletal disorders. Fibrodysplasia ossificans progressiva (FOP) is a rare disorder characterized by progressive formation of ectopic bone and congenital malformations of the great toes. At present no curative therapy is available, therefore prevention of heterotopic ossification is the hallmark of FOP management. FOP has been linked to an autosomal dominant mutation on chromosome 2, to the gene encoding activin receptor-like kinase 2 (ALK2), a BMP type I receptor. This mutation is found in almost all classically affected FOP patients and causes the FOP phenotype. This discovery has paved the way for further investigations into the molecular basis underlying FOP and has recently pointed towards potential strategies to treat this devastating disease.
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Cellular Players in Lung Fibrosis
Authors: Annemarie N. Lekkerkerker, Jamil Aarbiou, Thomas van Es and Richard A.J. JanssenPathogenic mechanisms involved in fibrosis of various organs share many common features. Myofibroblasts are thought to play a major role in fibrosis through excessive deposition of extracellular matrix during wound healing processes. Myofibroblasts are observed in fibrotic lesions, and whereas these derive from the hepatic stellate cells in liver, in lung they appear to originate from fibroblasts. The source of these fibroblasts has been the object of numerous studies over the recent years and points towards multiple sources. First of all, resident fibroblasts are thought to differentiate into the more contractile myofibroblasts, secreting many extracellular matrix proteins. Secondly, the epithelial to mesenchymal transition (EMT) of epithelial cells may also account for increased numbers of fibroblasts, though in vivo evidence in patient tissue.is still scarce. Thirdly, the enigmatic fibrocytes, stemming from the bone marrow, may also account for increasing numbers of fibroblasts in fibrotic lesions. These pathogenic processes are further augmented by the generation of so-called alternatively activated macrophages, which have direct and indirect effects on myofibroblast accumulation and collagen deposition. TGFβ, which is produced predominantly by macrophages, plays a central role in all these processes by inducing EMT, driving differentiation of fibrocytes, and differentiation towards myofibroblasts. This review describes the potential origins and roles of these fibrotic cells in the lung and discusses models to study these cells in vitro. These models offer innovative approaches in target and drug discovery, aiming to uncover novel therapeutic targets that regulate the profibrotic phenotype of these cells.
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TGFβ Signaling in Liver Regeneration
Authors: Sofia Karkampouna, Peter ten Dijke, Steven Dooley and Marianna Kruithof-de JulioAdult organ regeneration occurs in many systems such as in liver, skin, intestine and heart, indicating that postnatal life is not a static or quiescent state but a dynamic and complex process. The liver is a spectacular organ, exhibiting high regenerative capacity crucial for homeostasis and tissue repair: injuries induced mechanically or chemically, can be completely restored. Regeneration involves extensive cell division, inflammation and extracellular matrix remodeling processes. At the molecular level, one of the key mediators of regeneration response is the secreted cytokine transforming growth factor-β (TGFβ). TGFβ is a profibrogenic and anti-proliferative protein with pleiotropic functions depending on the cellular context. In this review, we discuss the role of TGFβ in the development of the liver and in adult liver regeneration, with particular emphasis on its role in regulation of hepatocyte regeneration and in hepatic progenitor cell-induced regeneration. Finally, we give an overview of the current direction of liver research towards cell replacement therapies.
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BMPS and Liver: More Questions than Answers
Authors: Blanca Herrera, Aranzazu Sanchez and Isabel FabregatBone morphogenetic proteins (BMPs) belong to the TGF-β superfamily and were first discovered as potent bone homeostasis regulators for their ability to induce endochondral bone formation, ectopic bone formation and fracture repair. A preeminent role of BMP signaling in developmental control of cell type specification, differentiation and organogenesis is also well established. More recently, a role for BMPs in adult tissue homeostasis has started being revealed. Thus, new studies show that BMPs regulate many cellular processes such as proliferation, apoptosis, differentiation and migration in many tissues and organs. As a consequence, dysregulation of BMP activity can have pathological consequences, and there is mounting evidence for the involvement of BMPs in different human diseases. In this review, we have focused on summarizing the present knowledge on the relevance of BMPs in liver physiology and pathophysiology, from the well-recognized role in liver development to the emerging contribution to the function and dysfunction of the adult liver. While no doubts seem to rise about the regulatory activities of BMPs on metabolic pathways in the liver, potential pro- and anti-fibrogenic and tumorigenic actions will likely be a matter of debate during coming years. Collectively, the work here presented provides the basis to consider BMPs as potential targets of intervention in liver diseases.
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TGF-Beta: a Master Switch in Tumor Immunity
Authors: Margherita Gigante, Loreto Gesualdo and Elena RanieriThe capacity of the immune system to distinguish foreign from self-antigen, and to subsequently eliminate the threat of disease without injuring the host is crucial for survival. It also serves to defend against tumor formation and progression via a process termed cancer immunosurveillance. Innate and adaptive immune cell types and effector molecules collectively function as extrinsic tumorsuppressor mechanisms. However, tumors may escape immunesurveillance through a variety of mechanisms that create a local microenvironment that is unfavorable for effective tumor immunity. Transforming growth factor β (TGF-β) has pleiotropic effects on the immune system, and is recognized as one of the most potent immunosuppressive agents in facilitating oncogenesis. The TGF-β pathway promotes cancer progression by concomitantly enhancing tumor metastases while inhibiting the protective host immunity. In this review, we discuss mechanisms through which TGF-β interferes with the development of an anti-tumor immunity and potential means through which to circumvent its activity in order to define more effective cancer immunotherapies.
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TGF-β in Epithelial to Mesenchymal Transition and Metastasis of Liver Carcinoma
Authors: Patrick Reichl, Christine Haider, Markus Grubinger and Wolfgang MikulitsHepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) represent the majority of hepatic malignancies and are among the most frequent causes of cancer deaths worldwide with a rising incidence in western countries. Upon progression of liver cancer, the epithelial to mesenchymal transition (EMT) is considered a key process that drives intrahepatic metastasis. EMT is the transformation of epithelial cells to a mesenchymal phenotype exacerbating motility and invasiveness of various epithelial cell types. In this review we focus on EMT in hepatic fibrosis, HCC and CCC that is governed by the transforming growth factor (TGF)-β signaling. This cytokine has been shown to play diverse and conflicting roles in malignant development, acting as a tumor-suppressor in early cancerogenesis but enhancing tumor dissemination in later stages of tumor progression. Importantly, TGF-β can induce EMT in a variety of cancers including HCC and CCC, even though the complex molecular mechanisms underlying this process are not yet fully understood. We aim at collecting recent findings on the impact of TGF-β-induced EMT in liver carcinoma progression and at discussing new insights on promising drugable targets for future therapeutic approaches against CCC and HCC.
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The TGF-β Signaling Pathway as a Pharmacological Target in a Hepatocellular Carcinoma
Authors: Antonio Mazzocca, Salvatore Antonaci and Gianluigi GiannelliHepatocellular carcinoma (HCC) is a cancer that usually develops on a liver already compromised by cirrhosis. Study of the underlying molecular mechanisms is essential so as to improve therapeutic strategies and to develop new pharmacological agents that may prevent or improve the course of this malignancy. Transforming growth factor-beta (TGF-β) intervenes in the process of hepatic fibrogenesis and cirrhosis, two pathogenic preconditions for the formation and progression of HCC [1] [2]. In addition, TGF-β plays a crucial role in the molecular pathogenesis of HCC and may, therefore, prove to be a promising drug target. We and other authors have recently demonstrated that inhibition of the TGF-β signaling pathway results in a synergistic downstream action with an inhibitory effect on the progression of HCC. Several TGF-β inhibitors have recently been developed, most of which are still in a preclinical phase, but they may soon be available for testing in patients with HCC. However, well-designed clinical trials will be needed to evaluate the effectiveness of these new agents prior to routine use in the clinic. Aim of this article is to make a brief review of the benefits and limitations of targeting the TGF-β signaling pathway in HCC.
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TGF-Beta Inihibitor-loaded Polyelectrolyte Multilayers Capsules for Sustained Targeting of Hepatocarcinoma Cells
In this review we will report on recent advanced in polyelectrolyte capsules for targeted drug delivery (eg of growth factor inhibitor) against epatocarcinoma. Degradable polyelectrolyte multilayers capsules (PMCs) are of particular interest for cancer therapy since under physiological conditions they can be enzymatically degraded upon cell interaction. Small bioactive molecules such as TGFBeta inhibitors can be incorporated inside them. Nano-to-microscale delivery systems can enhance efficacy at single cell level for targeted therapy. Layer-by-layer (LbL) self-assembled capsules are novel carriers maximizing drug administration and improving antimetastatic activity of TGF-Beta inhibitors in Hepatocellular Carcinoma (HCC).
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The Development of HEPT-Type HIV Non-Nucleoside Reverse Transcriptase Inhibitors and Its Implications for DABO Family
Authors: Wenmin Chen, Peng Zhan, Jingde Wu, Zhenyu Li and Xinyong Liu1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) was discovered as the first HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) in 1989. The research on HEPT derivatives (HEPTs) has been lasted for more than 20 years and HEPT family is probably the most investigated NNRTI. Extensive molecular modifications on HEPT have led to many highly potent compounds with broad-resistance spectrum and optimal pharmacokinetic profiles. Moreover, X-crystallographic studies of HEPTs/RT complexes revealed the binding mode of HEPTs and the action mechanism of NNRTI, which has greatly facilitated the design of novel NNRTIs. Recently, the development of HEPTs was accelerated by the application of the “follow-on”-based chemical evolution strategies, such as designed multiple ligands (DMLs) and molecular hybridization (MH). Herein, this article will provide an insight into the development of HEPTs, including structural modifications, crystal structure of RT complexed with HEPTs and its structure-activity relationship (SAR). Additionally, this review also covers the emerging HEPT related dual inhibitors and HEPT-pyridinone hybrids, as well as the contributions of HEPTs to the development of dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family, thus highlighting the importance of HEPTs on the development of NNRTIs.
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Removal of the Tag from His-tagged ILYd4, a Human CD59 Inhibitor, Significantly Improves its Physical Properties and its Activity
Authors: Lin Wu, Sanbao Su, Fengming Liu, Tao Xu, Xiaoxiao Wang, Yan Huang, Xinlu Sun, Xiaowen Ge, Ting Chen, Huixia Liu, Chun Wang, Michael Chorev, Ting Xu and Xuebin QinComplement dependent cytotoxicity (CDC) significantly contributes to Rituximab (RTX) and Ofatumumab (OFA) efficacies in the treatment of B-cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex and thereby inhibits CDC. hCD59 is an important determinant of the sensitivity of NHL and CLL to RTX and OFA treatment. Recently, we developed a specific and potent hCD59 inhibitor, His-tagged ILYd4, which consists of 30 amino acid sequences extending from the N-terminus of ILYd4. Our previously published results indicate that His-tagged ILYd4 can be used as a lead candidate to further develop a potential therapeutic adjuvant for RTX and OFA treatment of RTX-resistant NHL and CLL. However, these studies were conducted using ILYd4 tagged on the N-terminus with 30 additional amino acids (AA) containing 6 X His used for immobilized metal affinity chromatograph. As a further step towards the development of ILYd4-based therapeutics, we investigated the impact of the removal of this extraneous sequence on the anti-hCD59 activity. In this paper, we report the generation and characterization of tag-free ILYd4. We demonstrate that tag-free ILYd4 has over threefold higher anti-hCD59 activities than the His-tagged ILYd4. The enhanced RTX-mediated CDC effect on B-cell malignant cells comes from tag-free ILYd4's improved functionality and physical properties including better solubility, reduced tendency to aggregation, and greater thermal stability. Therefore, tag-free ILYd4 is a better candidate for the further development for the clinical application.
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Structure and Ligand-based Design of P-glycoprotein Inhibitors: A Historical Perspective
Computer-assisted drug design (CADD) is a valuable approach for the discovery of new chemical entities in the field of cancer therapy. There is a pressing need to design and develop new, selective, and safe drugs for the treatment of multidrug resistance (MDR) cancer forms, specifically active against P-glycoprotein (P-gp). Recently, a crystallographic structure for mouse P-gp was obtained. However, for decades the design of new P-gp inhibitors employed mainly ligand-based approaches (SAR, QSAR, 3D-QSAR and pharmacophore studies), and structure-based studies used P-gp homology models. However, some of those results are still the pillars used as a starting point for the design of potential P-gp inhibitors. Here, pharmacophore mapping, (Q)SAR, 3D-QSAR and homology modeling, for the discovery of P-gp inhibitors are reviewed. The importance of these methods for understanding mechanisms of drug resistance at a molecular level, and design P-gp inhibitors drug candidates are discussed. The examples mentioned in the review could provide insights into the wide range of possibilities of using CADD methodologies for the discovery of efficient P-gp inhibitors.
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Preclinical Safety and Pharmacokinetic Profile of 3K3A-APC, a Novel, Modified Activated Protein C for Ischemic Stroke
Activated protein C (APC), a protease with anticoagulant and cytoprotective activities, protects neurons and cerebrovascular endothelium from ischemic injury. A recombinant APC, drotrecogin alfa (activated) (DrotAA) (Xigris®), was approved by the Food and Drug Administration for the treatment of sepsis; however, serious bleeding was a dose-limiting side effect. A modified APC, containing 405 amino acid residues, 3K3A-APC, was designed to possess significantly reduced anticoagulant activity (< 10 %) while maintaining full cytoprotective properties. The preclinical safety assessment of 3K3A-APC was conducted to support initiation of ischemic stroke clinical trials.The safety and toxicokinetics of 3K3A-APC were studied in CD-1 mice and cynomolgus monkeys. Multiple-dose (14-day), intravenous GLP toxicology assessed toxicity, histopathology, immunogenicity, and toxicokinetics.Dose-related increases in plasma total 3K3A-APC were observed in mice and monkeys with no evidence of accumulation over 14 days. The elimination T1/2 in monkeys was 1 hour. 3K3A-APC was well tolerated in mice and monkeys, and no signs of 3K3A-APC toxicity were identified in mice or monkeys at any time. Additionally,wild-type APC (DrotAA) was studied to obtain comparative anticoagulant data using clotting assays. Anticoagulant activity of 3K3A-APC was observed in monkeys at doses of 1 and 5 mg/kg/day .In contrast, DrotAA showed prolongation of clotting assays in monkeys at doses 1/10thof those showing effects with 3K3A-APC. Based upon the anticoagulant profiles, the risk for APCinduced bleeding in clinical trials of 3K3A-APC is greatly reduced relative to wild type APC which makes this new drug a feasible therapy for ischemic stroke patients.
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New Therapeutic Strategies for Cancer and Neurodegeneration Emerging from Yeast Cell-based Systems
Authors: Clara Pereira, Mariana Leao, Joana Soares, Claudia Bessa and Lucilia SaraivaDespite great advances in understanding the molecular etiology of cancer and neurodegeneration, therapeutic strategies against these diseases are still largely lacking. Hence, acceleration of the discovery of new therapeutic agents against these pathologies is of enormous interest. This review is focused on the role of multi-faceted and expanding yeast cell-based systems in the search for new drugs and therapeutic targets in cancer and neurodegeneration. Though the obvious limitations of using a microorganism to address human diseases, when used in the early phase and with complementary mammalian systems, it can have a tremendous impact in the discovery of new therapeutic opportunities. In this review, many evidence are provided demonstrating the valuable contribution of yeast in this area. Additionally, several yeast target-based drug screening approaches based on a readily screenable phenotype on genomic technologies increasingly oriented towards genetic and chemical high-throughput analysis are addressed. Altogether, with this review, we intend not only to recognize previous successes and ongoing work in this area, but also to point out new opportunities that may be of interest for yeast as a model organism and as a powerful system in the discovery of new lead compounds that have the potential to become novel drugs in cancer and neurodegeneration.
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A Computational Study of the Oligosaccharide Binding Sites in the Lectin-Like Domain of Tumor Necrosis Factor and the TNF-derived TIP Peptide
Authors: Alexander Dulebo, Rudiger Ettrich, Rudolf Lucas and David KaftanThe lectin-like domain of Tumor Necrosis Factor (TNF), mimicked by the TIP peptide, activates amiloride-sensitive sodium uptake in type II alveolar epithelial cells and as such increases alveolar liquid clearance in dysfunctional lungs. This protective effect is blunted upon mutation of residues T105, E107 and E110 in human TNF into alanine or upon pre-incubation of the cytokine with the disaccharide N,N’-diacetylchitobiose. In this study, we used molecular docking and molecular dynamics simulation to predict the binding sites for N,N'-diacetylchitobiose and trimannose-O-ethyl in the lectin-like domain of TNF and in the TIP peptide. Specific sites (K98, S99, P100, Q102 and E116) in the three loops of the lectin-like domain provide specific binding for both oligosaccharides, but none of the residues crucial for anti-edema activity are involved in hydrogen bonding with oligosaccharides or are subjected to steric hindrance by them. These results thus suggest that neither chitobiose nor trimannose affect crucial amino acids, while they occupy the cavity in the lectin-like domain. Consequently, both crucial amino acids and the emptiness of the cavity in the lectin-like domain may be critical for TNF's lectin-like activity. Analogously, the R4, E5, P7, Y16 amino acids of the TIP peptide are involved in forming hydrogen bonds with both oligosaccharides, whereas residues T6, E8 and E11 (corresponding to T105, E107 and E110 in hTNF) play an important role in stabilizing the peptide-oligosaccharide complex, supporting the hypothesis that amino acids in the polar region (TPEGAE) of the TIP peptide represent only a partial binding motif for sugars.
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Target-based Anti-angiogenic Therapy in Breast Cancer
Authors: Markus Wehland, Johann Bauer, Manfred Infanger and Daniela GrimmBreast cancer is the most common female cancer. Despite advances in prevention, early diagnosis, and surgical treatment, its prognosis is still poor. Therefore, immunological and pharmacological methods of treatment have been emphasized recently. Prominent targets of drugs or antibodies are proteins, which are predominantly expressed on breast cancer cells and are simultaneously involved in promoting cell growth or apoptosis. However, breast cancer is a heterogeneous disease, because breast cancer cells may show a variety of malignant gene expression patterns. Therefore, it is difficult at the current state of technology, to apply the optimal cocktail of drugs to hit all cancer cells of any given patient. Under these circumstances, the option of targeting more tractable, normal cells surrounding the tumor instead of the less heterogeneous ones, preventing them from supporting tumor cell growth, became particularly interesting. Endothelial cells are important supporters of cancer cell growth. As a rule, tumors induce them to grow out and to develop a tumor vasculature, which enables the cancer cells to survive and to spread. The introduction of inhibitors of neovascularization was therefore an important milestone on the way toward treating breast cancer more successfully. It has already been demonstrated that the blockade of vascular endothelial growth results in regression of the disease and first clinical studies seemed to hint toward a beneficial effect on prolongation of survival. Nevertheless, more clinical and basic research is necessary to improve this therapy approach. This review will compile the knowledge about recently developed anti-angiogenic drugs in the treatment of breast cancer and will provide an overview on currently relevant clinical trials.
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The Effect of First-in-Class Small Molecule RhoA Inhibitor, HL07, on the Phenylephrine-induced Artery Contraction
Authors: Yan Zhang, Jing Deng, Sheng Ma, Lin Xue, Jin Zhu, Wei-liang Zhu, Hua-liang Jiang, Jian Li and Li-yan MiaoThe RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. Recently, we first reported a series of first-in-class small molecular RhoA inhibitors and a chemical compound named HL07 showed high RhoA inhibition activities. In this study, we aimed to explore the pharmacological effect and possible mechanism of HL07 on agonists-induced vasoconstriction. Results showed that 1) in rat thoracic aorta (TA) rings, HL07(0∼180µmol/L) effectively inhibited phenylephrine (PE)-induced contraction in concentration-dependent manner , whereas the half maximal inhibitory concentration (IC50) being 156.93 µmol/L, while it produced weak inhibition on high-K+ -induced contraction. Furthermore, in the presence of nifedipine and thapsigargin (Nif/TSG), HL07 had a comparable degree of inhibition on PE-induced contraction with IC50=149.52 µmol/L; especially at the concentration (0∼150 µmol/L), the inhibition was greater than the inhibition in absence of Nif/TSG (P<0.01). In addition, HL07 displayed greater inhibition on pulmonary artery (PA) rings (IC50=134.97 µmol/L) than on TA rings. 2) HL07 potently blocked RhoA activation stimulated by PE in concentration-dependent manner in human cerebrovascular smooth muscle cells (HBVSMCs), when HL07 at 10, 2, 0.25 µmol/L, the corresponding inhibition rates were 64 ± 5%, 42 ± 7%, 31 ± 5%, respectively; and at the same concentrations, HL07 had no significant effect on RhoA mRNA level. 3) In HBVSMCs, RhoA activity was increased by pre-incubating with GNP, but HL07 showed inhibitory effect on this tendency. These results indicate that HL07 produces significant inhibitory effects on PE-induced vascular smooth muscle contraction. The inhibitory effects of HL07 were mainly contributed to its inhibition on RhoA/Rho-kinase pathway through blocking RhoA activation, and the binding affinities of HL07 for RhoA preference over the GNP might be responsible for the inhibition of HL07 on RhoA activity.
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Volumes & issues
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)