Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
Not a member yet
168 research outputs found
Sort by
Anti-interleukin and associated receptors monoclonal antibodies therapy in autoimmune diseases
Get PDFThere are nearly 40 approved monoclonal antibodies (mABs) in the U.S. for different diseases. These drugs are increasingly using in different autoimmune diseases, including rheumatoid arthritis (RA), asthma, psoriasis, systemic lupus erythematosus (SLE), atopic dermatitis (AD), multiple sclerosis (MS), and type 1 diabetes (T1D). Several phase 2 and 3 studies reported the clinical improvement due to treating with mABs. However, some adverse events (AEs) such as infections, injection-site reactions are frequently reported. In addition to approved diseases, off-label uses also led to some new results, which may cause reviewing the drug for other diseases. In this review, it was tried to discuss on the role of mABs that target interleukins or their associated receptors in treatment of autoimmune diseases. Moreover, approval statues, efficiency, safety and the possible associated AEs of the mABs on the market, based on the least clinical trials were also discussed
Physiological role of receptor activator nuclear factor-kB (RANK) in denervation-induced muscle atrophy and dysfunction
Get PDFThe bone remodeling and homeostasis are mainly controlled by the receptor-activator of nuclear factor kB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin (OPG) pathway. While there is a strong association between osteoporosis and skeletal muscle dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology remains elusive. Our recent article published in the American Journal of Physiology (Cell Physiology) showed that RANK is also expressed in fully differentiated C2C12 myotubes and skeletal muscles. We used the Cre-Lox approach to inactivate muscle RANK (RANKmko) and showed that RANK deletion preserves the force of denervated fast-twitch EDL muscles. However, RANK deletion had no positive impact on slow-twitch Sol muscles. In addition, denervating RANKmko EDL muscles induced an increase in the total calcium concentration ([CaT]), which was associated with a surprising decrease in SERCA activity. Interestingly, the levels of STIM-1, which mediates Ca2+ influx following the depletion of SR Ca2+ stores, were markedly higher in denervated RANKmko EDL muscles. We speculated that extracellular Ca2+ influx mediated by STIM-1 may be important for the increase in [CaT] and the gain of force in denervated RANKmko EDL muscles. Overall, these findings showed for the first time that the RANKL/RANK interaction plays a role in denervation-induced muscle atrophy and dysfunction
Blocking the receptor EP3 to PGE2 as a way to safely prevent atherothrombosis
Get PDFAspirin inhibits the platelet production of thromboxane A2 and its beneficial effect on myocardial infarction was demonstrated more than two decades ago. This result validated the strategy aimed at targeting platelet function to prevent myocardial infarction. Since then, numerous drugs targeting various activators of platelets have been developed to further improve prevention. However, the beneficial effect of all these drugs on atherothrombosis is limited by an increased risk of bleeding, because they target thrombosis effectors which are also key players in hemostasis. Since aspirin blocks the generation of numerous prostanoids, including inhibitors of platelet activation, targeting one of them might allow the antithrombotic activity to be maintained without promoting bleeding. In examining the roles of various arachidonic acid metabolites on atherothrombosis, we studied the prostaglandin E2 (PGE2). In vivo, PGE2 facilitates the responses of platelets to all their various activators through its receptor EP3. PGE2 is produced in relatively high amounts in the context of chronic inflammation such as atherosclerosis, and aggravates murine atherothrombosis. Conversely, PGE2 is not involved in hemostasis. As expected, blocking EP3 strikingly reduced atherothrombosis in mice without impacting bleeding tests. In a recent paper published in Prostaglandins & Other Lipid Mediators, we reviewed literature data about the effect of PGE2 and its receptor EP3 on platelet thrombosis and hemostasis in mice and humans. We concluded that cumulated data now justifies validating the role of EP3 blockers with phase III trials to safely improve the prevention of myocardial infarction
Chronic exposure to Bisphenol A impairs progesterone receptor-mediated signaling in the uterus during early pregnancy
Get PDFEnvironmental and occupational exposure to endocrine disrupting chemicals (EDCs) is a major threat to female reproductive health. Bisphenol A (BPA), an environmental toxicant that is commonly found in polycarbonate plastics and epoxy resins, has received much attention due to its estrogenic activity and high risk of chronic exposure in human. Whereas BPA has been linked to infertility and recurrent miscarriage in women, the impact of its exposure on uterine function during early pregnancy remains unclear. In a recent publication in Endocrinology, we demonstrated that prolonged exposure to an environmental relevant dose of BPA disrupts progesterone receptor-regulated uterine functions, thus affecting uterine receptivity for embryo implantation and decidua morphogenesis, two critical events for establishment and maintenance of early pregnancy. In particular we reported a marked impairment of progesterone receptor (PGR) expression and its downstream effector HAND2 in the uterine stromal cells in response to chronic BPA exposure. In an earlier study we have shown that HAND2 controls embryo implantation by repressing fibroblast growth factor (FGF) expression and the MAP kinase signaling pathway, thus inhibiting epithelial proliferation. Interestingly we observed that downregulation of PGR and HAND2 expression in uterine stroma upon BPA exposure was associated with an enhanced activation of FGFR and MAPK signaling, aberrant proliferation, and lack of uterine receptivity in the epithelium. In addition, the proliferation and differentiation of endometrial stromal cells to decidual cells, an event critical for the maintenance of early pregnancy, was severely compromised in response to BPA. This research highlight will provide an overview of our findings and discuss the potential mechanisms by which chronic BPA impairs PGR-HAND2 pathway and adversely affects implantation and the establishment of pregnancy
Down regulation of acrolein on corticosterone secretion in male rats
Get PDFAcrolein is a small unsaturated aldehyde and can be found in a wide range of resources including all types of smoke and exhaust gases from gasoline engines. Although the toxicity and damage of acrolein have been recognized, the action mechanisms of acrolein, especially that of acrolein on the response of stresshormones are still unclear. The present study hypothesized that administration of acrolein altered the secretion of both adrenocorticotropin (ACTH) and corticosterone via the regulation of steroid biosynthetic pathway in rat zona fasciculata-reticularis (ZFR) cells. Both in vivo and in vitro approaches were uased. In the in vivo study, intraperitonal injection of acrolein (2 mg/ml/kg) once daily for 1 or 3 days resulted in a reduction of plasma levels of ACTH and corticosterone as well as the intracellular cAMP and ACTH-induced secretion of corticosterone. The protein expression of ACTH receptor (ACTHR) in rat ZFR cells was also reduced by 40-60% after treatment of acrolein for 1 day and 3 days, respectively. In the in vitro study, rat ZFR cells were prepared and chanllenged with ACTH (10-9 M), forskolin (an adenylyl cyclase activitior, 10-5 M), 8-Br-cAMP (a permeable synthetic cAMP, 5x10-5 M), 25-OH-cholesterol (10-5 M) ± trilostane (an inhibitor of 3?-hydroxysteroid dehydrogenase, 3?-HSD, 10-5 M). The evoked release of corticosterone by ACTH, forskolin, 8-Br-cAMP and the induced release of pregnenolone in response to 25-OH-cholesterol plus triolostane were decreased. Since the accumulation of pregnenolone after blocking 3?-HSD by trilostane represents the activity of P450scc, therate-limiting step of steroid biosynthesis, we suggest that not only the cAMP pathway was inhibited, but also the enzyme activity of P450scc was attenuated following administration of acrolein. Although insignificant, the protein expression of steroidogenic acute regulatory protein (StAR) was decreased by 40% in ZFR cells after treatment of acrolein in vivo. Incubation of ZFR cells with acrolein (10-9~10-7 M) also decreased the in vitro release of corticosterone. These results suggest that administration of acrolein inhibited corticosterone production via the attenuation of cAMP pathway, StAR protein expression, and the enzyme activity of P450scc. The attenuation of protein expression of ACTHR (also named melanocortin 2 receptor, MC2R) and reduced secrection of ACTH indicated that the hypothalamus-pituitary-adrenal (H-P-A) axis was also down- regulated by the administration of acrolein
(An) orexigenic hypothalamic neuropeptides are differentially expressed in high and low feed efficient quail lines
Get PDFThe livestock and poultry industry is facing numerous challenges to keep up with the increasing demand for high quality animal protein due to the continuously increasing global human population, severe drought conditions around the world, and grains being used for ethanol production. Since feed costs are the majority of the total cost required to produce a live bird, feed efficiency (FE) is a trait of importance. It is beneficial to develop a more deep molecular understanding of the mechanisms that determine feed efficiency. Recently, this study used Japanese quail that were divergently selected for high and low feed efficiency as a model to determine the differential expression of several feeding-related hypothalamic neuropeptides
Structural and functional insights into a quorum-sensing signal peptide receptor, the ComD histidine protein kinase of streptococcus mutans
Get PDFQuorum sensing activation by signal peptide pheromones (SP) in Gram-positive bacteria depends on a membrane-associated histidine kinase receptor, which senses the signal and triggers the signaling cascade for various cell density-dependent activities. However, relatively little is known of peptide pheromone-receptor interactions in these bacteria, largely because of technical challenges in working with membrane-associated proteins in these bacteria. Recently, we have described a genetic approach and several analysis methods to studying membrane topology and structure-function interaction of a quorum sensing pheromone receptor ComD in a Gram-positive bacterium Streptococcus mutans. Using these methods, we confirm that the membrane-spanning domain of the ComD protein forms six transmembrane segments and three extracellular loops, loopA, loopB and loopC. By mutational analyses of these three extracellular loops, we demonstrate that both loopC and loopB are required for signal recognition and quorum sensing activation, while loopA plays little role in signal detection. In particular, a deletion or substitution mutation of four residues NVIP within loopC abolishes signal recognition for quorum sensing activation. Consistent with these findings, the loopC and loopB mutants are completely or partially defective in bacteriocin production. We conclude that both loopC and loopB are required to form the signal peptide receptor and the residues NVIP of loopC are essential for signal recognition and quorum sensing activation in S. mutans
Myristic acid hitchhiking on sigma-1 receptor to fend off neurodegeneration
Get PDFNeurodegenerative diseases are linked to tauopathy as a result of cyclin dependent kinase 5 (cdk5) binding to its p25 activator instead of its p35 activator and becoming over-activated. The overactive complex stimulates the hyperphosphorylation of tau proteins, leading to neurofibrillary tangles (NFTs) and stunting axon growth and development. It is known that the sigma-1 receptor (Sig-1R), an endoplasmic reticulum chaperone, can be involved in axon growth by promoting neurite sprouting through nerve growth factor (NGF) and tropomyosin receptor kinase B (TrkB) [1, 2]. It has also been previously demonstrated that a Sig-1R deficiency impairs the process of neurogenesis by causing a down-regulation of N-methyl-D-aspartate receptors (NMDARs) [3]. The recent study by Tsai et al. sought to understand the relationship between Sig-1R and tauopathy [4]. It was discovered that the Sig-1R helps maintain proper tau phosphorylation and axon development by facilitating p35 myristoylation and promoting p35 turnover. Neurons that had the Sig-1R knocked down exhibited shortened axons and higher levels of phosphorylated tau proteins compared to control neurons. Here we discuss these recent findings on the role of Sig-1R in tauopathy and highlight the newly presented physiological consequences of the Sig-1R-lipid interaction, helping to understand the close relationship between lipids and neurodegeneration
Calcium signaling and transcription: elongation, DoGs, and eRNAs
Get PDFThe calcium ion (Ca2+) is a key intracellular signaling molecule with far-reaching effects on many cellular processes. One of the most important Ca2+ regulated processes is transcription. A body of literature describes the effect of Ca2+ signaling on transcription initiation as occurring mainly through activation of gene-specific transcription factors by Ca2+-induced signaling cascades. However, the reach of Ca2+ extends far beyond the first step of transcription. In fact, Ca2+ can regulate all phases of transcription, with additional effects on transcription-associated events such as alternative splicing. Importantly, Ca2+ signaling mediates reduced transcription termination in response to certain stress conditions. This reduction allows readthrough transcription, generating a highly inducible and diverse class of downstream of gene containing transcripts (DoGs) that we have recently described
GRK2: putting the brakes on the circadian clock
Get PDFG protein-coupled receptor kinases (GRKs) are a family of serine/threonine protein kinases that terminate G protein-coupled receptor (GPCR) signaling by phosphorylating the receptor and inducing its internalization. In addition to their canonical function, some GRKs can phosphorylate non-GPCR substrates and regulate GPCR signaling in a kinase-independent manner. GPCRs are abundantly expressed in the suprachiasmatic nucleus (SCN), a structure in the mammalian brain that serves as the central circadian pacemaker. Various facets of circadian timekeeping are under the influence of GPCR signaling, and thus are potential targets for GRK regulation. Despite this, little attention has been given to the role of GRKs in circadian rhythms. In this research highlight, we discuss our latest findings on the functional involvement of GRK2 in mammalian circadian timekeeping in the SCN. Using grk2 knockout mice, we demonstrate that GRK2 is critical for maintaining proper clock speed and ensuring that the clock is appropriately synchronized to environmental light cycles. Although grk2 deficiency expectedly alters the expression of a key GPCR in the SCN, our study also reveals that GRK2 has a more direct function that touches the heart of the circadian clock