Eliminating cancer was once thought of as a war. This analogy is still apt today; however, we now realize that cancer is a much more formidable enemy than scientists originally perceived, and in some cases, it harbors a profound ability to thwart our best efforts to defeat it. However, before we were aware of the complexity of cancer, chemotherapy against childhood acute lymphoblastic leukemia (ALL)

Cancer and organ injury—such as that occurring in the perioperative period, including acute lung injury, myocardial infarction, and acute gut injury—are among the leading causes of death in the United States and impose a significant impact on quality of life. MicroRNAs (miRNAs) have been studied extensively during the last two decades for their role as regulators of gene expression, their translational

Tobacco use is a persistent public health issue. It kills up to half its users and is the cause of nearly 90% of all lung cancers. The main psychoactive component of tobacco is nicotine, primarily responsible for its abuse-related effects. Accordingly, most pharmacotherapies for smoking cessation target nicotinic acetylcholine receptors (nAChRs), nicotine's major site of action in the brain. The goal

The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1-4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a

The organic cation transporters (OCTs) OCT1, OCT2, OCT3, novel OCT (OCTN)1, OCTN2, multidrug and toxin exclusion (MATE)1, and MATE kidney-specific 2 are polyspecific transporters exhibiting broadly overlapping substrate selectivities. They transport organic cations, zwitterions, and some uncharged compounds and operate as facilitated diffusion systems and/or antiporters. OCTs are critically involved

Bronchodilators remain the cornerstone of the treatment of airway disorders such as asthma and chronic obstructive pulmonary disease (COPD). There is therefore considerable interest in understanding how to optimize the use of our existing classes of bronchodilator and in identifying novel classes of bronchodilator drugs. However, new classes of bronchodilator have proved challenging to develop because

It is widely accepted that molecular reductionist views of highly complex human physiologic activity, e.g., the aging process, as well as therapeutic drug efficacy are largely oversimplifications. Currently some of the most effective appreciation of biologic disease and drug response complexity is achieved using high-dimensionality (H-D) data streams from transcriptomic, proteomic, metabolomics, or

This review evaluates current knowledge about obsessive-compulsive disorder (OCD), with the goal of providing a roadmap for future directions in research on the psychopharmacology of the disorder. It first addresses issues in the description and diagnosis of OCD, including the structure, measurement, and appropriate description of the disorder and issues of differential diagnosis. Current pharmacotherapies

Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily

±3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic, psychoactive drug that is primarily used recreationally but also may have some therapeutic value. At low doses, MDMA produces feelings of relaxation, empathy, emotional closeness, and euphoria. Higher doses can produce unpleasant psychostimulant- and hallucinogen-like adverse effects and therefore are usually not taken intentionally. There is

Substance use disorder, especially in relation to opioids such as heroin and fentanyl, is a significant public health issue and has intensified in recent years. As a result, substantial interest exists in developing therapeutics to counteract the effects of abused drugs. A promising universal strategy for antagonizing the pharmacology of virtually any drug involves the development of a conjugate vaccine

The visual/β-arrestins, a small family of proteins originally described for their role in the desensitization and intracellular trafficking of G protein-coupled receptors (GPCRs), have emerged as key regulators of multiple signaling pathways. Evolutionarily related to a larger group of regulatory scaffolds that share a common arrestin fold, the visual/β-arrestins acquired the capacity to detect and

Memory consolidation involves the process by which newly acquired information becomes stored in a long-lasting fashion. Evidence acquired over the past several decades, especially from studies using post-training drug administration, indicates that emotional arousal during the consolidation period influences and enhances the strength of the memory and that multiple different chemical signaling systems

Catecholamine neurotransmission plays a key role in regulating a variety of behavioral and physiologic processes, and its dysregulation is implicated in both neurodegenerative and neuropsychiatric disorders. Over the last four decades, in vivo electrochemistry has enabled the discovery of contrasting catecholamine regulation in the brain. These rapid and spatially resolved measurements have been conducted

A subset of potassium channels is regulated primarily by changes in the cytoplasmic concentration of ions, including calcium, sodium, chloride, and protons. The eight members of this subfamily were originally all designated as calcium-activated channels. More recent studies have clarified the gating mechanisms for these channels and have documented that not all members are sensitive to calcium. This

Presynaptic nerve terminals are highly specialized vesicle-trafficking machines. Neurotransmitter release from these terminals is sustained by constant local recycling of synaptic vesicles independent from the neuronal cell body. This independence places significant constraints on maintenance of synaptic protein complexes and scaffolds. Key events during the synaptic vesicle cycle-such as exocytosis

Depression is caused by a change in neural activity resulting from an increase in glutamate that drives excitatory neurons and may be responsible for the decline in the activity and number of the GABAergic inhibitory neurons. This imbalance between the excitatory and inhibitory neurons may contribute to the onset of depression. At the cellular level there is an increase in the concentration of intracellular

More than 95% of genes in the human genome are alternatively spliced to form multiple transcripts, often encoding proteins with differing or opposing function. The control of alternative splicing is now being elucidated, and with this comes the opportunity to develop modulators of alternative splicing that can control cellular function. A number of approaches have been taken to develop compounds that

Primary neurodegenerative autonomic disorders are characterized clinically by loss of autonomic regulation of blood pressure. The clinical picture is dominated by orthostatic hypotension, but supine hypertension is also a significant problem. Autonomic failure can result from impairment of central autonomic pathways (multiple system atrophy) or neurodegeneration of peripheral postganglionic autonomic

The secretory proprotein convertase (PC) family comprises nine members, as follows: PC1/3, PC2, furin, PC4, PC5/6, paired basic amino acid cleaving enzyme 4, PC7, subtilisin kexin isozyme 1/site 1 protease (SKI-1/S1P), and PC subtilisin/kexin type 9 (PCSK9). The first seven PCs cleave their substrates at single/paired basic residues and exhibit specific and often essential functions during development

Botanical dietary supplements are increasingly popular for women's health, particularly for older women. The specific botanicals women take vary as a function of age. Younger women will use botanicals for urinary tract infections, especially Vaccinium macrocarpon (cranberry), where there is evidence for efficacy. Botanical dietary supplements for premenstrual syndrome (PMS) are less commonly used,

Adolescence is a developmental period when physical and cognitive abilities are optimized, when social skills are consolidated, and when sexuality, adolescent behaviors, and frontal cortical functions mature to adult levels. Adolescents also have unique responses to alcohol compared with adults, being less sensitive to ethanol sedative-motor responses that most likely contribute to binge drinking and

Given that over 2% of the human genome codes for proteolytic enzymes and their inhibitors, it is not surprising that proteinases serve many physiologic-pathophysiological roles. In this context, we provide an overview of proteolytic mechanisms regulating inflammation, with a focus on cell signaling stimulated by the generation of inflammatory peptides; activation of the proteinase-activated receptor

The use of antibodies that target immune checkpoint molecules on the surface of T-lymphocytes and/or tumor cells has revolutionized our approach to cancer therapy. Cytotoxic-T-lymphocyte antigen (CTLA-4) and programmed cell death protein 1 (PD-1) are the two most commonly targeted immune checkpoint molecules. Although the role of antibodies that target CTLA-4 and PD-1 has been established in solid

The glucagon-like peptide (GLP)-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) that mediates the action of GLP-1, a peptide hormone secreted from three major tissues in humans, enteroendocrine L cells in the distal intestine, α cells in the pancreas, and the central nervous system, which exerts important actions useful in the management of type 2 diabetes mellitus and obesity, including

Modulation of neurotransmission by the monoamines dopamine (DA), norepinephrine (NE), and serotonin (5-HT) is critical for normal nervous system function. Precise temporal and spatial control of this signaling in mediated in large part by the actions of monoamine transporters (DAT, NET, and SERT, respectively). These transporters act to recapture their respective neurotransmitters after release, and

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current standard treatments for a variety of cancers is suboptimal. First, most cancer treatments lack specificity, meaning that these treatments affect both cancer cells and their normal counterparts. Second, many anticancer agents are highly toxic, and thus, limit their use in treatment. Third, a number

Excessive angiogenesis (i.e., the formation of new blood vessels) contributes to different pathologies, among them cancer and ocular disorders. Conversely, dysfunction of endothelial cells (ECs) contributes to cardiovascular complications, as is the case in diabetes. Inhibition of pathologic angiogenesis in blinding eye disease and cancer by targeting growth factors such as vascular endothelial growth

Multiple kinases play a critical role in orchestrating the chronic inflammation and structural changes in the respiratory tract of patients with asthma and chronic obstructive pulmonary disease (COPD). Kinases activate signaling pathways that lead to contraction of airway smooth muscle and release of inflammatory mediators (such as cytokines, chemokines, growth factors) as well as cell migration, activation

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur

Opioids are among the most effective analgesics available and are the first choice in the treatment of acute severe pain. However, partial efficacy, a tendency to produce tolerance, and a host of ill-tolerated side effects make clinically available opioids less effective in the management of chronic pain syndromes. Given that most therapeutic opioids produce their actions via µ-opioid receptors (MOPrs)

Proteinase 3 (PR3) has received great scientific attention after its identification as the essential antigenic target of antineutrophil cytoplasm antibodies in Wegener's granulomatosis (now called granulomatosis with polyangiitis). Despite many structural and functional similarities between neutrophil elastase (NE) and PR3 during biosynthesis, storage, and extracellular release, unique properties and

Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy

Cocaine use disorder is a persistent public health problem for which no widely effective medications exist. Self-administration procedures, which have shown good predictive validity in estimating the abuse potential of drugs, have been used in rodent, nonhuman primate, and human laboratory studies to screen putative medications. This review assessed the effectiveness of the medications development

The smooth muscle cell directly drives the contraction of the vascular wall and hence regulates the size of the blood vessel lumen. We review here the current understanding of the molecular mechanisms by which agonists, therapeutics, and diseases regulate contractility of the vascular smooth muscle cell and we place this within the context of whole body function. We also discuss the implications for

There are several established lipid-modifying agents, including statins, fibrates, niacin, and ezetimibe, that have been shown in randomized clinical outcome trials to reduce the risk of having an atherosclerotic cardiovascular event. However, in many people, the risk of having an event remains unacceptably high despite treatment with these established agents. This has stimulated the search for new

The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1

The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous

The purpose of this review is to discuss ways to think about and study sex differences in preclinical animal models. We use the framework of addiction, in which animal models have excellent face and construct validity, to illustrate the importance of considering sex differences. There are four types of sex differences: qualitative, quantitative, population, and mechanistic. A better understanding of

Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response

During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing

Heparin has been recognized as a valuable anticoagulant and antithrombotic for several decades and is still widely used in clinical practice for a variety of indications. The anticoagulant activity of heparin is mainly attributable to the action of a specific pentasaccharide sequence that acts in concert with antithrombin, a plasma coagulation factor inhibitor. This observation has led to the development

The mineralocorticoid receptor (MR) and its ligand aldosterone are the principal modulators of hormone-regulated renal sodium reabsorption. In addition to the kidney, there are several other cells and organs expressing MR, in which its activation mediates pathologic changes, indicating potential therapeutic applications of pharmacological MR antagonism. Steroidal MR antagonists have been used for decades

In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial

Antibody drug conjugates (ADCs) constitute a family of cancer therapeutics designed to preferentially direct a cytotoxic drug to cells expressing a cell-surface antigen recognized by an antibody. The antibody and drug are linked through chemistries that enable release of the cytotoxic drug or drug adduct upon internalization and digestion of the ADC by the cell. Over 40 distinct ADCs, targeting an