Receptor-binding specificity is a major determinant of host range, pathogenesis, and interspecies transmission in influenza virus. Recognition of different conformations of sialic acid by the influenza virus hemagglutinin has driven influenza intra- and interspecies transmission for nearly 100 years since the first human pandemic was recorded in 1918. Key amino acid residues near or at the receptor-binding site of the hemagglutinin of different influenza A subtypes correlate with the ability of the virus to infect and replicate in the upper or lower respiratory tract of the host and transmit efficiently. A global concern exists for those highly pathogenic avian viruses that have emerged with the potential to cause a novel pandemic in humans. Studying the receptor-binding affinity to sialic acid receptors as a marker of pandemic risk could provide reliable measures to aid in timely pandemic planning and surveillance worldwide.
Disruption of energy metabolism, resulting in metabolic illnesses including diabetes, hyperlipidemia, fatty liver, hypertension and atherosclerosis, will likely shorten human life expectancy over the next several decades. Past work focusing on diet and exercise needs to be continued, but new environmental factors such as exposure to pollutants and the disruption of circadian rhythms in modern life urgently need more attention and understanding. This review focuses on how environmental pollutants acting through the aryl hydrocarbon receptor (AhR) to cause circadian disruption lead to metabolic derangements. AhR-mediated metabolic dysregulation in the whole organism, and dysregulation specific to the liver and adipose tissue, will be explored. Finally, the role of AhR in circadian desynchrony and resultant effects on energy metabolism will be discussed. This review summarizes information vital to future developments that can combat metabolic illnesses.
The Duffy antigen receptor for chemokine (DARC) is a nonspecific receptor for several proinflammatory cytokines. It is homologous to the G-protein chemokine receptor superfamily, which is suggested to function as a scavenger in many inflammatory-and proinflammatory- related diseases. G-protein chemokine receptors are also known to play a critical role in infectious diseases; they are commonly used as entry vehicles by infectious agents. A typical example is the chemokine receptor CCR5 or CXCR4 used by HIV for infecting target cells. In malaria, DARC is considered an essential receptor that mediates the entry of the human and zoonotic malaria parasites Plasmodium vivax and Plasmodium knowlesi into human reticulocytes and erythrocytes, respectively. This process is mediated through interaction with the parasite ligand known as the Duffy binding protein (DBP). Most therapeutic strategies have been focused on blocking the interaction between DBP and DARC by targeting the parasite ligand, while strategies targeting the receptor, DARC, have not been intensively investigated. The rapid increase in drug resistance and the lack of new effective drugs or a vaccine for malaria constitute a major threat and a need for novel therapeutics to combat disease. This review explores strategies that can be used to target the receptor. Inhibitors of DARC, which block DBP-DARC interaction, can potentially provide an effective strategy for preventing malaria caused by P. vivax.
: A family of small polypeptides in many virus types associate to form oligomers and have channel activity. These proteins have been referred to as viroporins or virochannels and are increasingly recognized as important virulence factors and potential drug targets. In this review, we focus on two of the viroporins that have been studied in more detail from a structural and functional point of view. One is the 76-residue envelope (E) protein found in coronaviruses (CoVs) that causes the severe acute respiratory syndrome (SARS). The other is the 65-residue small hydrophobic (SH) protein found in a paramyxovirus, the respiratory syncytial virus (RSV). RSV SH and SARS-CoV E proteins are short polypeptides with a single transmembrane domain. In both cases, the presence of the viroporin has a protective effect on cells, preventing early apoptosis, but it leads to increased virulence in infected animal models. Both viroporins form homopentameric oligomers that show channel activity with no or low selectivity. The role of channel activity is still unclear, but associations have been made to facilitation of the egress of the virus by modification of the secretory pathway, and contributions to inflammation. SARS-CoV E protein has a cytoplasmically oriented C-terminus and a lumenal N-terminus, whereas the opposite orientation is found in RSV SH protein. Despite this opposite topology, nuclear magnetic resonance (NMR)-based structural models of these two channels show a similar champagne flute shape, with the wider opening facing the cytoplasmic side. Good channel inhibitors are lacking, but those found seem to have a preference for the narrow end of the channel. Availability of good inhibitors will help reveal the specific role of these channels in the life cycle of these viruses.
Hyperactivity of trigeminal sensory neurons is a major process to generate recurrent headache, typical of migraine attacks. How physiological nociception is converted into strong pathological pain remains, however, poorly understood. In recent years, certain neuropeptides and their receptors have been shown to modulate sensory neuron nociception and to contribute to the persistent hyperalgesia due to the sensory stimulus sensitization that defines the clinical experience of chronic pain syndromes, including migraine. Using calcitonin gene-related peptide (CGRP) and brain natriuretic peptide (BNP) as examples, this review addresses the mechanisms through which neuropeptides might modulate nociceptor activity. One attractive notion is that pain signaling by trigeminal sensory neurons is potently regulated by the ambient levels of these peptides: CGRP is thought to facilitate neuronal firing responsible for trigeminal sensitization necessary to trigger headache, whereas BNP is proposed to act as a negative regulator of trigeminal neuron activity. For either peptide, the key target appears to be the ATP-gated P2X3 receptor that, widely expressed by trigeminal sensory neurons, generates fast, large excitation to release glutamate onto second-order brain neurons. The fine balance between the activities of these peptides is suggested to ultimately determine whether nociception is perceived at higher center as a physiological or pathological response. Hence, the clinical goal of CGRP antagonism using either pharmacological receptor blockers or monoclonal antibodies (to sequester this peptide or to directly inhibit its receptor) is currently considered a novel approach for migraine prophylaxis and to treat acute headache attacks.
Neuronal excitability is mediated mainly by voltage-gated ion channels (VGICs), which include voltage-gated Na+, K+, and Cl-channels located along the axon and at neuronal synapses. Voltage-gated channels play pivotal roles in the proper functioning of the nervous system because they set the resting membrane potential, initiate and propagate action potentials, and regulate neurotransmitter release. The abnormal activity or misregulation of VGICs caused by mutations has been directly linked to neurological and cardiac diseases. Among other posttranslational modifications, the ubiquitination of VGICs is a key to the regulation of the number of channels in the cell surface, and hence, neuronal excitability. Nedd4-2 is an E3 ubiquitin ligase that ubiquitinates several proteins, including different VGICs. Accordingly, understanding the molecular mechanisms underlying channel regulation will provide insights to design drugs to treat illnesses. The focus of the present review is to provide an update about the regulation of VGICs upon ubiquitination by Nedd4-2 and the relevance of such regulation in the pathophysiological consequences of dysfunction.
Simultaneous substitution of three amino acid residues in the calmodulin binding domain (W3587A/L3591D/F3603A, ADA) of the cardiac ryanodine receptor ion channel (RyR2) impairs calmodulin inhibition of RyR2 and causes cardiac hypertrophy and early death of Ryr2ADA/ADA mice. To determine the physiological significance of growth promoting signaling molecules, the protein and phosphorylation levels of Ser/Thr kinase mTOR and upstream and downstream signaling molecules were determined in hearts of wild-type and Ryr2ADA/ADA mice. Phosphorylation of mTOR at Ser-2448, and mTOR downstream targets p70S6 kinase at Thr-389, S6 ribosomal protein at Ser-240/244, and 4E-BP1 at Ser-65 were increased. However, there was no increased phosphorylation of mTOR upstream kinases PDK1 at Ser-241, AKT at Thr-308, AMPK at Thr-172, and ERK1/2 at Thr-202/Tyr204. To confirm a role for mTOR signaling in the development of cardiac hypertrophy, rapamycin, an inhibitor of mTOR, was injected into wild-type and mutant mice. Rapamycin decreased mouse heart-to-body weight ratio, improved cardiac performance, and decreased phosphorylation of mTOR and downstream targets p70S6K and S6 in 10-day-old Ryr2ADA/ADA mice but did not extend longevity. Taken together, the results link a dysfunctional RyR2 to an altered activity of signaling molecules that regulate cardiac growth and function.
Cyclic nucleotide second messengers adenosine-3',5'-cyclic monophosphate (cAMP) and guanosine-3', 5'-cyclic monophosphate (cGMP) influence numerous cellular functions, including inflammatory and immune responses. Intracellular levels of these nucleotides are regulated by a diverse group of phosphodiesterase enzymes. Inhibition of the various types of phosphodiesterase enzymes may offer a novel means to manage both inflammatory and autoimmune disorders. Recently, progress has been made in the development of phosphodiesterase inhibitors for a variety of conditions. This article reviews recent developments in the search for phosphodiesterase inhibitors as novel therapeutic agents for inflammatory and autoimmune conditions.
Over the past few years, the functional modulation of immune-checkpoint pathways using monoclonal antibodies has emerged as a promising anticancer therapeutic strategy. A key mechanism utilized by tumor cells to induce immune tolerance is upregulation of the programmed death-1 (PD-1) pathway. PD-1 is a negative coregulatory receptor on T-cells and antigen-presenting cells. The PD-1 ligand (PD-L1) is expressed by several tumor types, and appears to be dynamically regulated by the immune microenvironment. Several investigational agents targeting either PD-1 or PD-L1 are under clinical development and show durable antitumor activity across several tumor types. This review summarizes the conceptual basis, safety, and clinical activity of currently available PD-1 pathway therapeutic antibodies.
Despite significant progress in major depressive disorder (MDD) research over the past decades, the mechanisms underlying its pathophysiology and treatment remain to be established. The complexity and heterogeneity of MDD involves multiple causes, such as inflammation, genetic, and environmental factors that could be related to poor effectiveness, variability of response to antidepressant drugs, delay in clinical response, and side effects. Ketamine, an N-methyl-d-aspartate receptor antagonist, has been proposed as a revolutionary antidepressant that acts rapidly and is effective for treatment-resistant MDD. Ketamine stimulates mammalian target of rapamycin (mTOR), which is involved in transcription, survival, and cell proliferation. mTOR is an emerging signaling pathway of interest in MDD pathophysiology and treatment. Thus, this review describes the role of mTOR in the pathophysiology of MDD as well as highlights therapeutic targets that modulate mTOR signaling.
Appropriate supply of blood to organs and tissues is highly dependent on arterial blood pressure and therein of the peripheral blood vessel resistance. Of the two main components of vessel resistance, the active resistance results from the modulation of the contractility level of vascular smooth muscle cells (VSMCs). The intracellular level of Ca2+ in VSMCs is an essential component of muscle contraction and is tightly regulated through modulation of the membrane potential. Since resting membrane potential of vascular cells is mainly dependent on K+ ions, ion channels permeable to K+ ions have a significant impact on contractility of smooth muscle cells and therefore on vascular diameter and blood pressure. Activation of K+ channels on both endothelial cells and VSMCs is generally associated to hyperpolarization and relaxation of vascular smooth muscle. Several types of K+ channels are expressed in VSMCs and endothelial cells, and they are classified based on their pharmacological and biophysical properties. Voltage-dependent K+ channels are activated by depolarization and are mainly involved in negative-feedback mechanisms. Ca2+-activated K+ channels can be divided into three groups, with BKCa being activated by both intracellular Ca2+ and depolarization. On the other hand, K(Ca)2.x and K(Ca)3.1 channels (small and intermediate Ca2+-activated K+ channels, respectively) are almost strictly dependent on rises in intracellular Ca2+ levels to increase their open probability. K-ir and adenosine triphosphate (ATP)-sensitive K+ (K-ATP) channels, members of the same family, have a significant impact on VSMC membrane potential. The more recently studied two-pore K+ channels are thought to be metabolic sensors (like K-ATP channels) and would be involved in acute regulation of local blood flow. This review will summarize the main K+ channels expressed in vascular cells and their relevance in the control of vascular tone and blood pressure. Keywords: membrane potential, Ca2+, vascular tone and blood pressure.
Adipose tissue is an extremely active organ, and plays a fundamental role in the genesis of comorbidities associated with obesity. Since the discovery of leptin, an important focus has been assigned to adipose tissue as a key organ in the pathogenesis of metabolic disorders. The influence on the genesis of comorbidities associated with obesity is directly related to the pattern of adipokine secretion, the bioactive molecules produced on adipose tissue. The imbalance of adipokines consequent to the expansion of adipose tissue has been implicated in the development of the low-grade chronic inflammation seen in obesity. Adipokines act in a paracrine, autocrine, and endocrine fashion, influencing cytokine and chemokine secretions and hormonal and growth factors, as well as interfering with actions of insulin and lipid and glucose metabolism. The main adipokines include leptin, adiponectin, resistin, tumor-necrosis factor, interleukin 6, chemokine (C-C motif) ligand 2, interleukin 10, and transforming growth factor-beta. The imbalance between pro- and anti-inflammatory adipokines on adipose tissue results in insulin resistance and the development of metabolic syndrome, type 2 diabetes, and cardiovascular disease. However, not all obese individuals develop these comorbidities or metabolic changes. Metabolically normal obese or metabolically healthy obese individuals have been the focus of research because of their absence of comorbidities. The profile of adipokines in adipose tissue of these individuals can be protective for the development of insulin resistance and metabolic disorders. This review emphasizes the roles of adipokines, the signaling pathways involved in the pathogenesis of inflammation and insulin resistance, and the profile found in metabolically healthy obese individuals.
: Large-conductance Ca 2 + - and voltage-gated big K + (BK Ca , MaxiK, or Slo1) channels are expressed in almost every cell of mammalian tissues and participate in a multitude of physiological processes such as vascular tone regulation, neuronal excitability, neurotransmitter release, neurovascular coupling, bladder tone regulation, urinary K + excretion, and retinal circulation. BK Ca channel is a tetramer of the pore-forming α -subunit encoded by a single gene, Slo . The BK Ca - α -subunits are associated with the modulatory β -subunits, which contribute to the functional diversity of the channel. BK Ca channels sense and regulate membrane voltage and intracellular Ca 2 + , which then modulates several cell signaling and metabolic pathways. This review focuses on the main physiologic roles of BK Ca channels and the pathogenesis of diseases associated with their loss or malfunction. The mechanistic information highlighted in this review is aimed to enhance the understanding of the unique and diverse roles of BK Ca channels in various physiological and pathophysiological phenomena.
Pharmacophore modeling is a successful yet very diverse subfield of computer-aided drug design. The concept of the pharmacophore has been widely applied to the rational design of novel drugs. In this paper, we review the computational implementation of this concept and its common usage in the drug discovery process. Pharmacophores can be used to represent and identify molecules on a 2D or 3D level by schematically depicting the key elements of molecular recognition. The most common application of pharmacophores is virtual screening, and different strategies are possible depending on the prior knowledge. However, the pharmacophore concept is also useful for ADME-tox modeling, side effect, and off-target prediction as well as target identification. Furthermore, pharmacophores are often combined with molecular docking simulations to improve virtual screening. We conclude this review by summarizing the new areas where significant progress may be expected through the application of pharmacophore modeling; these include protein-protein interaction inhibitors and protein design.
: Epilepsy affects around 0.5%–1% of the general population. The most established hypothesis for its underlying pathophysiology is the imbalance of excitatory and inhibitory neuronal activity. The α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor has significant roles in fast excitatory neuronal transmission in the central nervous system (CNS) and the plasticity of synaptic strength. Based on this, AMPA-receptor modulation could be a way of adjusting the excitatory–inhibitory balance. The role of the AMPA receptor in epilepsy and epileptogenesis, and its potential as a target for antiepileptic drugs, has been supported by studies in a range of animal models, as well as clinical investigation in humans. However, it has been difficult to develop drugs that target AMPA-receptor activity, especially without considerable CNS-related side effects. In the case of AMPA-receptor antagonists, CNS-depressant side effects had to be overcome before they could be considered viable drugs. Recently, the first selective AMPA receptor antagonist on the market, perampanel, was approved as an adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older. Further research into the role of AMPA receptors, particularly in the process of epileptogenesis, and the development of AMPA-targeted drugs is warranted.
Structure-based pharmacophore approaches have become widely used in drug discovery and design. This can be attributed to the development of new tools and methods over the past decade. Various tools based on different premises have been developed, including active site information in traditional pharmacophores. These tools have been widely used in virtual screening, de novo design, and lead optimization and been proven to be highly successful. Studies based on simultaneous use of structure-based pharmacophores, ligand-based phar- macophores, and docking have also come into the picture recently. Here, the development of structure-based pharmacophores as an alternative to traditional drug discovery approaches is discussed, with emphasis on the advances and latest developments in tools and success stories
Research evidence points to abnormal brain-derived neurotrophic factor (BDNF) signaling being a common and vital participant in the etiology and pathophysiology of many psychiatric disorders, including depression, schizophrenia, and bipolar disorder. To increase BDNF levels in patients is therefore a necessary goal of any treatment. This review explores the various therapeutic strategies that can increase BDNF brain expression and recover mental health disturbances. From environmental enrichment and exercise to dietary intake, it is apparent that a healthy lifestyle significantly influences BDNF signaling and mental health. We conclude that in order to combat the inefficiency of current treatment methods, more attention should be focused on holistic approaches to achieve this goal, as BDNF is proven to have dynamic responses to environmental influences.
Living organisms require a host of regulatory circuits in order to survive optimally in a given environment. Gene regulation is one of the most important mechanisms for achieving normal cellular activities and overall homeostasis. The orphan nuclear receptors (ONRs) belonging to the nuclear receptors (NR) superfamily are mediators of pleiotropic effects in multiple cell types via control of gene expression. A huge volume of studies, especially in the past two decades, has revealed the detailed structures and many functions of the ONRs. However, many biological functions governed by the ONRs through gene control remain elusive. Moreover, gene regulatory mechanisms of the ONRs are still being dissected. The ONRs can interact with other members of the NR superfamily, forming heteromeric complexes at the DNA binding sites to modulate gene transcription. Additionally, the ONRs' gene regulatory abilities are further controlled via interactions with a host of coregulators. Data from several studies have unequivocally shown that the ONRs are unique regulators of biological processes, including energy and general metabolism, immunity, growth and reproduction, cell proliferation and specialization, sensory control, and many others. Furthermore, the evidence has suggested the modulatory role played by the ONRs in the onset and progression of diseases and that targeting their activities might provide a vital tool in the treatment of various diseases. Here, the current perspective on the ONRs is being reviewed.
