Low-density lipoprotein receptor-related protein-1 (LRP1) is the main cell surface receptor involved in brain and systemic clearance of the Alzheimer's disease (AD) toxin amyloid-beta (Aβ). In plasma, a soluble form of LRP1 (sLRP1) is the major transport protein for peripheral Aβ. LRP1 in brain endothelium and mural cells mediates Aβ efflux from brain by providing a transport mechanism for A across the blood-brain barrier (BBB). sLRP1 maintains a plasma ‘sink’ activity for Aβ through binding of peripheral Aβ which in turn inhibits re-entry of free plasma Aβ into the brain. LRP1 in the liver mediates systemic clearance of Aβ. In AD, LRP1 expression at the BBB is reduced and Aβ binding to circulating sLRP1 is compromised by oxidation. Cell surface LRP1 and circulating sLRP1 represent druggable targets which can be therapeutically modified to restore the physiological mechanisms of brain Aβ homeostasis. In this review, we discuss how increasing LRP1 expression at the BBB and liver with lifestyle changes, statins, plant-based active principles and/or gene therapy on one hand, and how replacing dysfunctional plasma sLRP1 on the other regulate Aβ clearance from brain ultimately controlling the onset and/or progression of AD.
Alzheimer's disease; Amyloid β-peptide; LRP1; soluble LRP1 (sLRP1); sLRP1 fragments
Expression of the sodium iodide symporter (NIS) is required for efficient iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, β-emitting radioactive iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioiodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of iodide uptake is required to target tumors with radioiodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioiodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioiodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS.
Sodium iodide symporter; thyroid cancer; breast cancer; Transcriptional regulation; Posttranslational regulation
Pathological cardiac hypertrophy is a key risk factor for heart failure. It is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. The progression of pathological cardiac hypertrophy has long been considered as irreversible. However, recent clinical observations and experimental studies have produced evidence showing the reversal of pathological cardiac hypertrophy. Left ventricle assist devices used in heart failure patients for bridging to transplantation not only improve peripheral circulation but also often cause reverse remodeling of the geometry and recovery of the function of the heart. Dietary supplementation with physiologically relevant levels of copper can reverse pathological cardiac hypertrophy in mice. Angiogenesis is essential and vascular endothelial growth factor (VEGF) is a constitutive factor for the regression. The action of VEGF is mediated by VEGF receptor-1, whose activation is linked to cyclic GMP-dependent protein kinase-1 (PKG-1) signaling pathways, and inhibition of cyclic GMP degradation leads to regression of pathological cardiac hypertrophy. Most of these pathways are regulated by hypoxia-inducible factor. Potential therapeutic targets for promoting the regression include: promotion of angiogenesis, selective enhancement of VEGF receptor-1 signaling pathways, stimulation of PKG-1 pathways, and sustention of hypoxia-inducible factor transcriptional activity. More exciting insights into the regression of pathological cardiac hypertrophy are emerging. The time of translating the concept of regression of pathological cardiac hypertrophy to clinical practice is coming.
Angiogenesis; HIF-1; hypertrophy; LVADs; PKG-1; regression; VEGF; VEGF Receptors
Siglecs (sialic acid immunoglobulin-like lectins) are members of the immunoglobulin gene family that contain sialoside binding N-terminal domains. They are cell surface proteins found predominantly on cells of the immune system. Among them, Siglec-8 is uniquely expressed by human eosinophils and mast cells, as well as basophils. Engaging this structure with antibodies or glycan ligands results in apoptosis in human eosinophils and inhibition of release of preformed and newly generated mediators from human mast cells without affecting their survival. Pro-apoptotic effects are also seen when its closest functional paralog, Siglec-F, on mouse eosinophils is similarly engaged in vitro, and beneficial effects are observed after administration of Siglec-F antibody using models of eosinophilic pulmonary and gastrointestinal inflammation in vivo. Siglec-8 targeting may thus provide a means to specifically inhibit or deplete these cell types. Cell-directed therapies are increasingly sought after by the pharmaceutical industry for their potential to reduce side effects and increase safety. The challenge is to identify suitable targets on the cell type of interest, and selectively deliver a therapeutic agent. By targeting Siglec-8, monoclonal antibodies and glycan ligand-conjugated nanoparticles may be ideally suited for treatment of eosinophil and mast cell-related diseases, such as asthma, chronic rhinosinusitis, chronic urticaria, hypereosinophilic syndromes, mast cell and eosinophil malignancies and eosinophilic gastrointestinal disorders.
Siglec-8; Siglec-F; Glycan ligands; Allergic diseases; Apoptosis; Liposomes
Although reversible airway obstruction in part defines asthma, lung function as measured by spirometry alone inadequately predicts the value of new therapeutic agents in the treatment of severe asthma.
Our objectives are 1) to review whether pulmonary function and bronchodilator reversibility are endpoints for drug discovery and 2) to identify parameters that predict efficacy in drug development in severe asthma.
An English language literature search using MedLine and PubMed was conducted from 1997 to present concerning pathophysiology, diagnosis and therapy of severe asthma using the terms “severe asthma,” “irreversible asthma,” “difficult asthma,” “airway remodeling,” “fixed airway obstruction,” “reversibility” and “bronchodilator reversibility” as index terms. Eight studies were characterized that encompass 1,424 subjects with asthma.
Our review identified the limitations of using bronchodilator reversibility as a predictor in drug development for severe asthma. Neither improvement in lung function nor bronchodilator reversibility characterized the benefit of new drugs in the treatment of severe asthma. Newly approved drugs in the treatment of severe asthma show decreased asthma exacerbations and improved quality of life associated with steroid-sparing benefits without altering bronchodilator responsiveness or improving lung function.
Although changes in lung function predict asthma control in mild/moderate asthma, lung function alone is inadequate to assess improvement in asthma control in severe asthma manifested by fixed airway obstruction. Endpoints that focus on asthma control, as defined by the Expert Panel Report 3 and GINA guidelines, may predict the value of new therapeutics in the management of severe asthma.
Airway remodeling; fixed airway obstruction; irreversible asthma; drug discovery
Cholesterol (CLR) is an essential component of eukaryotic plasma membranes. CLR regulates the membrane physical state, microdomain formation and the activity of membrane-spanning proteins, including ion channels. Large conductance, voltage- and Ca2+-gated K+ (BK) channels link membrane potential to cell Ca2+ homeostasis. Thus, they control many physiological processes and participate in pathophysiological mechanisms leading to human disease. Because plasmalemma BK channels cluster in CLR-rich membrane microdomains, a major driving force for studying BK channel-CLR interactions is determining how membrane CLR controls the BK current phenotype, including its pharmacology, channel sorting, distribution, and role in cell physiology. Since both BK channels and CLR tissue levels play a pathophysiological role in human disease, identifying functional and structural aspects of the CLR-BK channel interaction may open new avenues for therapeutic intervention. Here, we review the studies documenting membrane CLR-BK channel interactions, dissecting out the many factors that determine the final BK current response to changes in membrane CLR content. We also summarize work in reductionist systems where recombinant BK protein is studied in artificial lipid bilayers, which documents a direct inhibition of BK channel activity by CLR and builds a strong case for a direct interaction between CLR and the BK channel-forming protein. Bilayer lipid-mediated mechanisms in CLR action are also discussed. Finally, we review studies of BK channel function during hypercholesterolemia, and underscore the many consequences that the CLR-BK channel interaction brings to cell physiology and human disease.
MaxiK channel; cholesterol; membrane lipids; lipid raft; hypercholesterolemia; alcohol
Tau is a microtubule-associated protein thought to help modulate the stability of neuronal microtubules. In tauopathies, including Alzheimer’s disease and several frontotemporal dementias, tau is abnormally modified and misfolded resulting in its disassociation from microtubules and the generation of pathological lesions characteristic for each disease. A recent surge in the population of people with neurodegenerative tauopathies has highlighted the immense need for disease-modifying therapies for these conditions, and new attention has focused on tau as a potential target for intervention. In the current work we summarize evidence linking tau to disease pathogenesis and review recent therapeutic approaches aimed at ameliorating tau dysfunction. The primary therapeutic tactics considered include kinase inhibitors and phosphatase activators, immunotherapies, small molecule inhibitors of protein aggregation, and microtubule-stabilizing agents. Although the evidence for tau-based treatments is encouraging, additional work is undoubtedly needed to optimize each treatment strategy for the successful development of safe and effective therapeutics.
Tau; Alzheimer’s disease; Tauopathy; Kinase inhibitors; Phosphatase activators; Immunotherapy; Aggregation inhibitors; Microtubule stabilization
Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB1 receptors and of immune responses through the activation of CB2 receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB1 and/or CB2 receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB1 and/or CB2 receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.
cannabinoid; CB1; CB2; non-CB1/CB2
The glial cell line-derived neurotrophic factor (GDNF) is a secreted protein, best known for its role in the development of the central and peripheral nervous systems and the survival of adult dopaminergic neurons. More recently, accumulating evidence suggests that GDNF plays a unique role in negatively regulating the actions of drugs of abuse. In this article, we review these data and highlight the possibility that the GDNF pathway may be a promising target for the treatment of addiction.
GDNF; Growth factor; Addiction; Alcohol; Psychostimulants; Opioids
Delay discounting describes the devaluation of a reinforcer as a function of the delay until its receipt. Although all people discount delayed reinforcers, one consistent finding is that substance-dependent individuals tend to discount delayed reinforcers more rapidly than do healthy controls. Moreover, these higher-than-normal discounting rates have been observed in individuals with other behavioral maladies such as pathological gambling, poor health behavior, and overeating. This suggests that high rates of delay discounting may be a trans-disease process (i.e., a process that occurs across a range of disorders, making findings from one disorder relevant to other disorders). In this paper, we argue that delay discounting is a trans-disease process, undergirded by an imbalance between two competing neurobehavioral decision systems. Implications for our understanding of, and treatment for, this trans-disease process are discussed.
Delay discounting; trans-disease process; neuroscience; addiction; gambling; obesity; health behaviors
The clinical picture of autonomic failure is characterized by severe and disabling orthostatic hypotension. These disorders can develop as a result of damage of central neural pathways or peripheral autonomic nerves, caused either by a primary autonomic neurodegenerative disorder or secondary to systemic illness. Treatment should be focused on decreasing presyncopal symptoms instead of achieving blood pressure goals. Non-pharmacologic strategies such as physical counter-maneuvers, dietary changes (i.e. high salt diet, rapid water drinking or compression garments) are the first line therapy. Affected patients should be screened for co-morbid conditions such as post-prandial hypotension and supine hypertension that can worsen orthostatic hypotension if not treated. If symptoms are not controlled with these conservative measures the next step is to start pharmacological agents; these interventions should be aimed at increasing intravascular volume either by promoting water and salt retention (fludrocortisone) or by increasing red blood cell mass when anemia is present (recombinant erythropoietin). When pressor agents are needed, direct pressor agents (midodrine) or agents that potentiate sympathetic activity (atomoxetine, yohimbine, pyridostigmine) can be used. It is preferable to use short-acting pressor agents that can be taken on as needed basis in preparation for upright activities.
Autonomic failure; Treatment; Multiple system atrophy; Pure autonomic failure; Autonomic agents; Pharmacology
The class of chemicals known as the “organophosphates” (OPs) comprises many of the most common agricultural and commercial pesticides that are used worldwide as well as the highly toxic chemical warfare agents. The mechanism of the acute toxicity of OPs in both target and non-target organisms is primarily attributed to inhibitory actions on various forms of cholinesterase leading to excessive peripheral and central cholinergic activity. However, there is now substantial evidence that this canonical (cholinesterase-based) mechanism cannot alone account for the wide-variety of adverse consequences of OP exposure that have been described, especially those associated with repeated exposures to levels that produce no overt signs of acute toxicity. This type of exposure has been associated with prolonged impairments in attention, memory, and other domains of cognition, as well as chronic illnesses where these symptoms are manifested (e.g., Gulf War Illness, Alzheimer’s disease). Due to their highly reactive nature, it is not surprising that OPs might alter the function of a number of enzymes and proteins (in addition to cholinesterase). However, the wide variety of long-term neuropsychiatric symptoms that have been associated with OPs suggests that some basic or fundamental neuronal process was adversely affected during the exposure period. The purpose of this review is to discuss several non-cholinesterase targets of OPs that might affect such fundamental processes and includes cytoskeletal and motor proteins involved in axonal transport, neurotrophins and their receptors, and mitochondria (especially their morphology and movement in axons). Potential therapeutic implications of these OP interactions are also discussed.
Pesticide; Cholinesterase inhibitor; Chronic; Memory; Cognition
The large variety of biological functions governed by prostaglandin (PG) E2 is mediated by signaling through four distinct E-type prostanoid (EP) receptors. The availability of mouse strains with genetic ablation of each EP receptor subtype and the development of selective EP agonists and antagonists have tremendously advanced our understanding of PGE2 as a physiologically and clinically relevant mediator. Moreover, studies using disease models revealed numerous conditions in which distinct EP receptors might be exploited therapeutically. In this context, the EP4 receptor is currently emerging as most versatile and promising among PGE2 receptors. Anti-inflammatory, anti-thrombotic and vasoprotective effects have been proposed for the EP4 receptor, along with its recently described unfavorable tumor-promoting and pro-angiogenic roles. A possible explanation for the diverse biological functions of EP4 might be the multiple signaling pathways switched on upon EP4 activation. The present review attempts to summarize the EP4 receptor-triggered signaling modules and the possible therapeutic applications of EP4-selective agonists and antagonists.
AMPK, AMP-activated protein kinase; cAMP, cyclic adenylyl monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; ClC, chloride channel; COX, cyclooxygenase; CREB, cAMP-response element-binding protein; DP, D-type prostanoid receptor; DSS, dextran sodium sulfate; EGFR, epidermal growth factor receptor; eNOS, endothelial nitric oxide synthase; EP, E-type prostanoid receptor; Epac, exchange protein activated by cAMP; EPRAP, EP4 receptor-associated protein; ERK, extracellular signal-regulated kinase; FEM1a, feminization 1 homolog a; FP, F-type prostanoid receptor; GRK, G protein-coupled receptor kinase; 5-HETE, 5-hydroxyeicosatetraenoic acid; ICER, inducible cAMP early repressor; ICAM-1, intercellular adhesion molecule-1; Ig, immunoglobulin; IL, interleukin; IFN, interferon; IP, I-type prostanoid receptor; LPS, lipopolysaccharide; MAP, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; MEK, MAP kinase kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; PI3K, phosphatidyl insositol 3-kinase; PK, protein kinase; TP, T-type prostanoid receptor; TX, thromboxane receptor; Prostaglandins; Inflammation; Vascular disease; Cancerogenesis; Renal function; Osteoporosis
The glycine deportation system is an essential component of glycine catabolism in man whereby 400 to 800 mg glycine per day are deported into urine as hippuric acid. The molecular escort for this deportation is benzoic acid, which derives from the diet and from gut microbiota metabolism of dietary precursors. Three components of this system, involving hepatic and renal metabolism, and renal active tubular secretion help regulate systemic and central nervous system levels of glycine. When glycine levels are pathologically high, as in congenital nonketotic hyperglycinemia, the glycine deportation system can be upregulated with pharmacological doses of benzoic acid to assist in normalization of glycine homeostasis. In congenital urea cycle enzymopathies, similar activation of the glycine deportation system with benzoic acid is useful for the excretion of excess nitrogen in the form of glycine. Drugs which can substitute for benzoic acid as substrates for the glycine deportation system have adverse reactions that may involve perturbations of glycine homeostasis. The cancer chemotherapeutic agent ifosfamide has an unacceptably high incidence of encephalopathy. This would appear to arise as a result of the production of toxic aldehyde metabolites which deplete ATP production and sequester NADH in the mitochondrial matrix, thereby inhibiting the glycine deportation system and causing de novo glycine synthesis by the glycine cleavage system. We hypothesize that this would result in hyperglycinemia and encephalopathy. This understanding may lead to novel prophylactic strategies for ifosfamide encephalopathy. Thus, the glycine deportation system plays multiple key roles in physiological and neurotoxicological processes involving glycine.
Glycine; Deportation; Catabolism; Homeostasis; Neuroregulation; Benzoic acid; Hippuric acid; Ifosfamide encephalopathy
One of the most frequent and serious complications to develop in septic patients is acute kidney injury (AKI), a disorder characterized by a rapid failure of the kidneys to adequately filter the blood, regulate ion and water balance, and generate urine. AKI greatly worsens the already poor prognosis of sepsis and increases cost of care. To date, therapies have been mostly supportive; consequently there has been little change in the mortality rates over the last decade. This is due, at least in part, to the delay in establishing clinical evidence of an infection and the associated presence of the systemic inflammatory response syndrome and thus, a delay in initiating therapy. A second reason is a lack of understanding regarding the mechanisms leading to renal injury, which has hindered the development of more targeted therapies. In this review, we summarize recent studies, which have examined the development of renal injury during sepsis and propose how changes in the peritubular capillary microenvironment lead to and then perpetuate microcirculatory failure and tubular epithelial cell injury. We also discuss a number of potential therapeutic targets in the renal peritubular microenvironment, which may prevent or lessen injury and/or promote recovery.
sepsis; acute kidney injury; microcirculation; oxidative stress; peritubular capillary; tubular epithelium
This review focuses on the neurobiology of integrins, pathophysiological roles of integrins in neuroplasticity and nervous system disorders, and therapeutic implications of integrins as potential drug targets and possible delivery pathways. Neuroplasticity is a central phenomenon in many neurological conditions such as seizures, trauma, and traumatic brain injury. During the course of many brain diseases, in addition to intracellular compartment changes, alterations in non-cell compartments such as extracellular matrix (ECM) are recognized as an essential process in forming and reorganizing neural connections. Integrins are heterodimeric transmembrane receptors that mediate cell–ECM and cell–cell adhesion events. Although the mechanisms of neuroplasticity remain unclear, it has been suggested that integrins undergo plasticity including clustering through interactions with ECM proteins, modulating ion channels, intracellular Ca2+ and protein kinases signaling, and reorganization of cytoskeletal filaments. As cell surface receptors, integrins are central to the pathophysiology of many brain diseases, such as epilepsy, and are potential targets for the development of new drugs for neurological disorders.
Extracellular matrix protein; integrin; neuroplasticity; nervous diseases; drug development
Heart failure (HF) is a global epidemic that continues to cause significant morbidity and mortality despite advances in medical therapy. Ventricular assist device technology has emerged as a therapeutic option to bridge patients with end-stage HF to heart transplantation or as an alternative to transplantation in selected patients. In some patients, mechanical unloading induced by ventricular assist devices leads to improvement of myocardial function and a possibility of device removal. The implementation of this advanced technology requires multiple pharmacological interventions, both in the perioperative and long-term periods, in order to minimize potential complications and improve patient outcomes. We herein review the latest available evidence supporting the use of specific pharmacological interventions and current practices in the care of these patients: anticoagulation, bleeding management, pump thrombosis, infections, arrhythmias, right ventricular failure, hypertension, desensitization protocols, among others. Areas of uncertainty and ground for future research are also highlighted.
Ventricular assist device; Chronic mechanical circulatory support; Pharmacology; Anticoagulation; Bleeding; Infection; Right ventricular failure; HLA sensitization; Arrhythmias; Harefield protocol
Cytochromes P450 (P450) are membrane-bound enzymes that catalyze the monooxygenation of a diverse array of xenobiotic and endogenous compounds. The P450s responsible for foreign compound metabolism generally are localized in the endoplasmic reticulum of the liver, lung and small intestine. P450 enzymes do not act alone but require an interaction with other electron transfer proteins such as NADPH-cytochrome P450 reductase (CPR) and cytochrome b5. Because P450s are localized in the endoplasmic reticulum with these and other ER-resident proteins, there is a potential for protein-protein interactions to influence P450 function. There has been increasing evidence that P450 enzymes form complexes in the ER, with compelling support that formation of P450•P450 complexes can significantly influence their function. Our goal is to review the research supporting the formation of P450•P450 complexes, their specificity, and how drug metabolism may be affected. This review describes the potential mechanisms by which P450s may interact, and provides evidence to support each of the possible mechanisms. Additionally, evidence for the formation of both heteromeric and homomeric P450 complexes are reviewed. Finally, direct physical evidence for P450 complex formation in solution and in membranes is summarized, and questions directing the future research of functional P450 interactions are discussed with respect to their potential impact on drug metabolism.
Cytochrome P450; Protein-protein interactions; P450 function; P450•P450 complex formation
Advances in analytical methodologies, principally nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS), during the last decade have made large-scale analysis of the human metabolome a reality. This is leading to the reawakening of the importance of metabolism in human diseases, particularly cancer. The metabolome is the functional readout of the genome, functional genome, and proteome; it is also an integral partner in molecular regulations for homeostasis. The interrogation of the metabolome, or metabolomics, is now being applied to numerous diseases, largely by metabolite profiling for biomarker discovery, but also in pharmacology and therapeutics. Recent advances in stable isotope tracer-based metabolomic approaches enable unambiguous tracking of individual atoms through compartmentalized metabolic networks directly in human subjects, which promises to decipher the complexity of the human metabolome at an unprecedented pace. This knowledge will revolutionize our understanding of complex human diseases, clinical diagnostics, as well as individualized therapeutics and drug response.
In this review, we focus on the use of stable isotope tracers with metabolomics technologies for understanding metabolic network dynamics in both model systems and in clinical applications. Atom-resolved isotope tracing via the two major analytical platforms, NMR and MS, has the power to determine novel metabolic reprogramming in diseases, discover new drug targets, and facilitates ADME studies. We also illustrate new metabolic tracer-based imaging technologies, which enable direct visualization of metabolic processes in vivo. We further outline current practices and future requirements for biochemoinformatics development, which is an integral part of translating stable isotope-resolved metabolomics into clinical reality.
Metabolomics; systems biochemistry; stable isotope tracing; drug discovery; metabolic compartmentation and regulation; pathway reconstruction
Iron (Fe) and copper (Cu) are essential to neuronal function; excess or deficiency of either is known to underlie the pathoetiology of several commonly known neurodegenerative disorders. This delicate balance of Fe and Cu in the central milieu is maintained by the brain barrier systems, i.e., the blood-brain barrier (BBB) between the blood and brain interstitial fluid and the blood- cerebrospinal fluid barrier (BCB) between the blood and cerebrospinal fluid (CSF). This review provides a concise description on the structural and functional characteristics of the brain barrier systems. Current understanding of Fe and Cu transport across the brain barriers is thoroughly examined, with major focuses on whether the BBB and BCB coordinate the direction of Fe and Cu fluxes between the blood and brain/CSF. In particular, the mechanism by which pertinent metal transporters in the barriers, such as the transferrin receptor (TfR), divalent metal transporter (DMT1), copper transporter (CTR1), ATP7A/B, and ferroportin (FPN), regulate metal movement across the barriers is explored. Finally, the detrimental consequences of dysfunctional metal transport by brain barriers, as a result of endogenous disorders or exogenous insults, are discussed. Understanding the regulation of Fe and Cu homeostasis in the central nervous system aids in the design of new drugs targeted on the regulatory proteins at the brain barriers for the treatment of metal’s deficiency or overload-related neurological diseases.
iron; copper; blood-brain barrier; blood-CSF barrier; choroid plexus; transferrin receptor or TfR; divalent metal transporter or DMT1; copper transporter or CTR1
GPCRs are a major family of homologous proteins and are key mediators of the effects of numerous endogenous neurotransmitters, hormones, cytokines, therapeutic drugs, and drugs-of-abuse. Despite the enormous amount of research on the pharmacological and biochemical properties of GPCRs, the question as to whether they exist as monomers, dimers, or higher order structures in the body is unanswered. The GPCR dimer field has been dominated by techniques involving recombinant cell lines expressing mutant receptors, often involving the solubilization of the receptors. These techniques cannot be applied in vivo or even to primary cell cultures. This review will focus on a novel approach to exploring the functional properties of homodimers. Studies of the 5-HT7 and 5-HT2A serotonin receptors have revealed that binding of a pseudo-irreversible antagonist (“inactivator”) to one of the orthosteric sites of a homodimer abolishes all receptor activity, and subsequent binding of a competitive antagonist to the orthosteric site of the second protomer releases the inactivator, allowing the receptor to return to an active state. This approach demonstrates allosteric crosstalk between protomers of native GPCR homodimers, indicating that GPCRs do exist and function as homodimers in both recombinant cells and rat primary astrocytes. This technique can be applied universally using intact recombinant or primary cells in culture, membrane homogenate preparations and, potentially, in vivo. The data obtained using the 5-HT7 and 5-HT2A receptors are strongly supportive of a GPCR homodimer structure, with little evidence of monomer involvement in the function of these receptors.
GPCR; homodimer; heterodimers; 5-HT7; 5-HT2A; allosterism
MicroRNAs (miRNAs) are abundant, endogenous, short, noncoding RNAs that act as important post-transcriptional regulators of gene expression by base-pairing with their target mRNA. During the last decade, substantial knowledge has accumulated regarding the biogenesis of miRNAs, their molecular mechanisms and functional roles in a variety of cellular contexts. Altered expression of certain miRNA molecules in the brains of patients with neurodegenerative diseases such as Alzheimer and Parkinson suggests that miRNAs could have a crucial regulatory role in these disorders. Polymorphisms in miRNA target sites may also constitute an important determinant of disease risk. Additionally, emerging evidence points to specific miRNAs targeting and regulating the expression of particular proteins that are key to disease pathogenesis. Considering that the amount of these proteins in susceptible neuronal populations appears to be critical to neurodegeneration, miRNA-mediated regulation represents a new target of significant therapeutic prospects. In this review, the implications of miRNAs in several neurodegenerative disorders and their potential as therapeutic interventions are discussed.
microRNA; neurodegenerative disease; polymorphism; therapeutic
Autophagy is a catabolic process that turns over long-lived proteins and organelles and contributes to cell and organism survival in times of stress. Current cancer therapies including chemotherapy and radiation are known to induce autophagy within tumor cells. This is therefore an attractive process to target during cancer therapy as there are safe, clinically available drugs known to both inhibit and stimulate autophagy. However, there are conflicting positive and negative effects of autophagy and no current consensus on how to manipulate autophagy to improve clinical outcomes. Careful and rigorous evaluation of autophagy with a focus on how to translate laboratory findings into relevant clinical therapies remains an important aspect of improving clinical outcomes in patients with malignant disease.
Autophagy; Cancer; Cancer therapy; Cell death; Clinical trial; Chloroquine
Since its commercial advent in 1985, transcranial magnetic stimulation (TMS), a technique for stimulating neurons in the cerebral cortex through the scalp, safely and with minimal discomfort, has captured the imaginations of scientists, clinicians and lay observers. Initially a laboratory tool for neurophysiologists studying the human motor system, TMS now has a growing list of applications in clinical and basic neuroscience. Although we understand many of its effects at the system level, detailed knowledge of its actions, particularly as a modulator of neural activity, has lagged, due mainly to the lack of suitable non-human models. Nevertheless, these gaps have not blocked the therapeutic application of TMS in brain disorders. Moderate success has been achieved in treating disorders such as depression, where the U.S. Food and Drug Administration has cleared a TMS system for therapeutic use. In addition, there are small, but promising, bodies of data on the treatment of schizophrenic auditory hallucinations, tinnitus, anxiety disorders, neurodegenerative diseases, hemiparesis, and pain syndromes. Some other nascent areas of study also exist. While the fate of TMS as a therapeutic modality depends on continued innovation and experimentation, economic and other factors may be decisive.
Brain stimulation; neuromodulation; neurology; psychiatry; depression
G protein-coupled receptor (GPCR) kinases (GRKs) are best known for their role in homologous desensitization of GPCRs. GRKs phosphorylate activated receptors and promote high affinity binding of arrestins, which precludes G protein coupling. GRKs have a multidomain structure, with the kinase domain inserted into a loop of a regulator of G protein signaling homology domain. Unlike many other kinases, GRKs do not need to be phosphorylated in their activation loop to achieve an activated state. Instead, they are directly activated by docking with active GPCRs. In this manner they are able to selectively phosphorylate Ser/Thr residues on only the activated form of the receptor, unlike related kinases such as protein kinase A. GRKs also phosphorylate a variety of non-GPCR substrates and regulate several signaling pathways via direct interactions with other proteins in a phosphorylation-independent manner. Multiple GRK subtypes are present in virtually every animal cell, with the highest expression levels found in neurons, with their extensive and complex signal regulation. Insufficient or excessive GRK activity was implicated in a variety of human disorders, ranging from heart failure to depression to Parkinson’s disease. As key regulators of GPCR-dependent and -independent signaling pathways, GRKs are emerging drug targets and promising molecular tools for therapy. Targeted modulation of expression and/or of activity of several GRK isoforms for therapeutic purposes was recently validated in cardiac disorders and Parkinson’s disease.
G protein-coupled receptors; G protein-coupled receptor kinases; signaling; regulation; phosphorylation; G proteins; regulator of G protein signaling