Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
Not a member yet
168 research outputs found
Sort by
Inhibition of VEGF/VEGFR1 interaction by a series of C-terminal modified cyclic peptides
Get PDFInhibition of the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) is a validated therapeutic strategy of anti-cancer treatment. This approach consists in indirect blockage of the kinase activity on VEGFR with inhibitors of protein-protein interactions, which showed great interests in oncology. The FDA approved anti-cancer agents bevacizumab (Avastin®) and ziv-aflibercept (Zaltrap®) bind specifically to VEGF are from anti-VEGF strategy. The very recently approved agent ramucirumab (Cyramza®), a recombinant humanized monoclonal antibody that specifically binds to VEGFR2 is from anti-VEGFR strategy. Based on a cyclic peptide antagonist of VEGFR1 designed from VEGF fragments, we developed, by a new synthesis process, a series of C-terminal modified cyclic peptides to improve their receptor binding ability. Three of such peptides with aromatic groups showed greatly increased VEGFR1 binding affinity in a competition ELISA-based test. This research highlight discusses the processing and findings of the recent study
Orexin regulates mitochondrial dynamics in avian muscle
Get PDFThe growing obesity epidemic has sparked numerous studies on the identification of molecular signatures that regulate energy homeostasis using different experimental animal models. Orexin, which acts via two G-protein coupled receptors, orexin receptor 1 and 2, has been originally identified as feeding-related hypothalamic neuropeptide that regulate energy balance in mammals. Recently, using chicken, non-mammalian species that are characteristically hyperglycemic and prone to obesity, we made a breakthrough by identifying the orexin system in avian muscle and unraveling its effect on mitochondrial dynamics and function. Therefore, understanding orexin signaling and function may help to identify novel therapeutic opportunities for treating metabolic disorders related to mitochondrial dysfunction
The perlecan LDL-binding receptor needs sugar: Implication of perlecan core protein interaction with LDL for atherosclerosis
Get PDFCardiovascular disease (CVD) is the deadliest disease in the US and finding cures for CVD has been a pressing and challenging problem in biomedical science. Atherosclerosis is a pathological condition caused by an elevated plasma LDL cholesterol level and its deposition in the arterial wall. Although cholesterol-lowering therapies are currently effective in reducing circulating LDL cholesterol level, clinical trials have shown limited impact on reducing CVD risk. Thus, a supplemental treatment is urgently needed. Subendothelial LDL retention in the arterial wall is an early step in the atherogenic process, and finding the regulators that can be targeted to block this retention offers an alternative approach for early prevention. This review first presents the current understanding about the mechanism of the atherosclerosis development, and then focus on perlecan and its role in atherosclerosis. Perlecan is a major arterial proteoglycan consisting of a core protein and three heparan sulfate (HS) side chains. Many studies have linked perlecan to atherosclerosis because its HS side chains interact with LDL. Recently, we reported that the perlecan core protein also interacts with LDL via its LDL receptor (LDLR)-like domain II. Critical to the interaction is the sialic acid modification on the domain. In this review, the recent findings and the potential role of the arterial sialic acid in the early subendothelial LDL retention are discussed
In Silico Study of Polypharmacology with Ligand-based Interaction Fingerprint
No full textThe past years have witnessed the versatile applications of interaction fingerprint method, including three-dimensional structure analysis, docking-pose clustering and filtering, scoring function improvement and enhancing enrichment of virtual screening. However, it’s still unclear whether it’s possible to study the polypharmacology with such a strategy. We have explored this important question by assessing the performance of ligand-based interaction fingerprint (LIFt), a new approach providing insights into the potential targets for the specific small-molecule drug. According to our results, it’s found that LIFt could recognize most of the native targets for the promiscuous kinase inhibitor staurosporine on the basis of experimental determined complex structures. In addition, with assistance of physics-based docking and sampling techniques, LIFt can predict the kinase-selectivity profile as well as the unexpected off-targets for the established drug or drug candidates with appreciated accuracy. More encouragingly, a prospective prediction of new kinase target for the anticancer drug candidate TN-16 was experimentally validated, which suggests the promise of LIFt in practical use of polypharmacology study
Plakophilin-2 induced EGFR phosphorylation: a focus on the intracellular activators of EGFR
Get PDFThe oncogenic role of EGFR in many tumors has attracted a great deal of attention in the recent years and initiated the development of several potent EGFR inhibitors, which are used clinically for cancer treatment. However, the current therapeutic inhibition of EGFR signaling is limited to monoclonal antibodies that bind to the EGFR extracellular domain or tyrosine kinase inhibitors that block EGFR kinase activation directly. Despite the great promise of these inhibitors, a certain percentage of patients develop resistance to these therapies, highlighting the necessity for alternative therapeutic strategies based on our most current knowledge of the mechanisms of EGFR signaling. We recently reported that Plakofilin-2 (PKP2) is a novel ligand-independent cytoplasmic activator of EGFR signaling. Here we focus on recent studies demonstrating important roles of intracellular EGFR activators, and propose targeted disruption of these activators as a novel avenue of therapeutic intervention to inhibit EGFR-mediated cancer development
Vascular protective effects of Angiotensin Receptor Blockers: Beyond Blood pressure
Get PDFAT1R blockers (ARBs) represent a major class of antihypertensive medications. They are considered first line treatment for essential hypertension. Moreover, ARBs are the cornerstone treatment for other cardiovascular diseases especially in patients with diabetic and renal comorbidities. Clinical and experimental evidence have documented the beneficial actions of ARBs beyond the blood pressure lowering effect. Ischemic diseases such as stroke and proliferative retinopathy are characterized by hypoxia-driven release of angiogenic growth factors [2]. However, revascularization of the ischemic areas is inadequate, resulting in impaired neuro-vascular function. ARBs have been shown to exhibit vascular protective and pro- or anti-angiogenic effects depending on the tissue/cell type and disease condition under study [3]. Our group has demonstrated the vascular protective effects of ARBs and candesartan, in particular, in models of ischemic stroke and retinopathy. The positive impact of candesartan was mainly via enhancing the proangiogenic state and stimulation of reparative angiogenesis. This commentary aims to highlight the recently identified pathways that took place as result of directly blocking AT1 receptor or indirectly by possible activation of AT2 receptor in the context of the published literature
Implications of Scavenger Receptors in the Safe Development of Nanotherapeutics
Get PDFNanomaterials (NMs) are being utilized in a variety of biomedical applications including drug delivery, diagnostics, and therapeutic targeting. These applications are made possible due to the unique physicochemical properties that are exhibited at the nanoscale. To ensure safe development of NMs for clinical use, it is necessary to understand their interactions with cells and specifically cell surface receptors, which will facilitate either their toxicity and/or clinical function. Recently our research and others have investigated the role of scavenger receptors in mediating NM-cell interactions and responses. Scavenger receptors are expressed by a variety of cell types that are first to encounter NMs during clinical use such as macrophages and endothelial cells. Scavenger receptors are recognized to facilitate uptake of a wide variety of ligands ranging from foreign substances to endogenous lipids/proteins. While interaction of NMs with scavenger receptors may allow therapeutic targeting in some instances, it also presents a challenge for the stealth delivery of NMs and avoidance of the scavenging capability of this class of receptors. Due to their role in facilitating immune responses, scavenger receptor-mediated inflammation is also of concern following NM delivery. The research highlight in this brief review intends to summarize our current understanding regarding the consequences of NM-scavenger receptor interactions
Physical activity controlled by estrogen signals in the medial amygdala
Get PDFEstrogen receptor ? (ER?) in the brain is known to regulate different aspects of energy homeostasis in both males and females. However, the essential brain ER? sites for the estrogenic control of body weight have not been fully illustrated. In a recent paper published in the Journal of Clinical Investigation, we demonstrated that the ER? expressing neurons in the medial amygdala (MeA), which is originally recognized as an important emotion and motivation control center, is required to stimulate physical activity. Our results from both selective deletion or overexpression mouse model and electrophysiology recording support a model that ER? signals activate MeA neurons to stimulate physical activity, which in return prevents body weight gain. These results indicate that MeA ER? is a potential therapeutic target for treatment of obesity not only in females, but also in males
The role of LMTK3 in chromatin remodeling and transcriptional regulation
Get PDFNuclear receptor tyrosine kinases such as EGFR have been shown to be associated with increased tumor grade and poorer patient survival. One explanation for this is that following nuclear transport, these RTKs are directly involved in the transcriptional regulation through chromatin binding. LMTK3 is a novel oncogenic RTK implicated in breast cancer, whose cytoplasmic and nuclear abundance are highly associated with poorer survival in breast cancer patient. So far the function of the cytoplasmic LMTK3 in breast cancer growth, invasion and endocrine resistance has been addressed, however little is known about the role of nuclear LMTK3. In our recent study, we discovered that LMTK3 binds chromatin via its interacting partners PP1? and KAP1. Moreover, LMTK3 induces the tethering of chromatin to the nuclear periphery. These events result in chromatin condensation and subsequent transcriptional repression of various tumor suppressor-like genes, leading to breast cancer progression. Overall, this research work provides an insight of the nuclear kinase function and suggests that targeting LMTK3 may have further clinical potentials in treating breast cancer
Role of the nuclear pregnane X receptor in drug metabolism and the clinical response
Get PDFThe pregnane X receptor (PXR) is an orphan nuclear receptor that regulates the expression of phase I and phase II drug metabolizing enzymes and transporters involved in the absorption, distribution, metabolism, and elimination of xenobiotics. PXR is expressed predominantly in the liver and intestine and resembles cytochrome P450s (CYPs), which is a phase I drug metabolizing enzyme. It is estimated that CYP 3As and CYP2Cs metabolize > 50% of all prescription drugs. PXR upregulates gene expression of these CYPs. Therefore, PXR plays a crucial role detoxifying xenobiotics and could potentially have effects on drug-drug interactions. PXR is reportedly responsible for activating a variety of target genes through cross-talk with other nuclear receptors and coactivators at transcriptional and translation levels. Recent findings have demonstrated the regulatory role of PXR and show the potential use of a PXR antagonist during drug therapy. In addition, genetic variations in the PXR gene are associated with the pharmacological effects of several drugs, and inter-individual differences in the clinical response are likely to be understood through these PXR polymorphisms. Many approaches have been used to explain the PXR regulatory mechanisms, such as microRNA-mediated PXR post-translational regulation and diverse PXR haplotype analysis. Understanding these PXR polymorphisms may lead to improving personalized therapeutic treatments