The computational modeling of allosteric modulation of metabotropic glutamate receptors.
ern G Abstract Allosteric modulation of GPCRs, especially metabotropic glutamate (mGlu) receptors, has become an important strategy for drug discovery. Positive and negative allosteric modulators (PAM, NAM) are widely reported for the mGlu receptor family with leads mostly originating by high-throughput screening followed by iterative medicinal chemistry. The progression of the field from mutagenesis and homology modeling to elaborate structure-enabled drug discovery is described. We detail how computational methods have delivered new chemical matter and revealed the functional details of PAM and NAM activity. The...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Pérez-Benito L, Llinas Del Torrent C, Pardo L, Tresadern G Tags: Adv Pharmacol Source Type: research

RAMPs as allosteric modulators of the calcitonin and calcitonin-like class B G protein-coupled receptors.
Abstract Receptor activity-modifying proteins (RAMPs) are a family of three single span transmembrane proteins in humans that interact with many GPCRs and can modulate their function. RAMPs were discovered as key components of the calcitonin gene-related peptide and adrenomedullin receptors. They are required for transport of this class B GPCR, calcitonin receptor-like receptor (CLR), to the cell surface and determine its peptide ligand binding preferences. Soon thereafter RAMPs were shown to modulate the binding of calcitonin and amylin peptides to the related calcitonin receptor (CTR) and in the years since an e...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Pioszak AA, Hay DL Tags: Adv Pharmacol Source Type: research

Strategies and considerations of G-protein-coupled receptor photopharmacology.
Abstract G-protein-coupled receptor (GPCR) pharmacology tends to be complex and at times poorly understood. This has led to the development of GPCR-targeting agents that often demonstrate poor pharmacokinetic properties and poor selectivity for their target receptors. One approach that is emerging as a means of addressing these limitations is the use of molecules whose activity can be controlled by light. Photopharmacology involves the incorporation of a photoswitch into the structure of a given compound, cage or linker and following irradiation with light, undergoes a structural rearrangement, which changes its b...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Berizzi AE, Goudet C Tags: Adv Pharmacol Source Type: research

Discovery and pharmacology of the covalent GLP-1 receptor (GLP-1R) allosteric modulator BETP: A novel tool to probe GLP-1R pharmacology.
Abstract The glucagon-like peptide-1 receptor (GLP-1R) is a significant therapeutic target for small molecule drug discovery given the therapeutic impact of peptide agonists in the diabetes sphere. We review the discovery and subsequent characterization of the small molecule GLP-1R allosteric modulator 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP). BETP is a covalent modulator of the GLP-1R, and we discuss the pharmacological implications and possible structural basis of this novel mode of action. We highlight the insights into class B G-protein coupled receptor pharmacology and bi...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Willard FS, Ho JD, Sloop KW Tags: Adv Pharmacol Source Type: research

Allosteric modulation of metabotropic glutamate receptors in alcohol use disorder: Insights from preclinical investigations.
Abstract Metabotropic glutamate (mGlu) receptors are family C G protein-coupled receptors (GPCRs) that modulate neuronal excitability and synaptic transmission throughout the nervous system. Owing to recent advances in development of subtype-selective allosteric modulators of mGlu receptors, individual members of the mGlu receptor family have been proposed as targets for treating a variety of neurological and psychiatric disorders, including substance use disorders. In this chapter, we highlight preclinical evidence that allosteric modulators of mGlu receptors could be useful for reducing alcohol consumption and p...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Johnson KA, Lovinger DM Tags: Adv Pharmacol Source Type: research

Allosteric modulation of muscarinic receptors in alcohol and substance use disorders.
Abstract Alcohol and substance use disorders are chronic relapsing disorders, characterized by a compulsion to take drugs and loss of control in limiting intake. The impact of alcohol and substance abuse on morbidity and mortality is very high worldwide, and treatment options are inadequate at a population level. There is a need for the discovery and development of novel pharmacotherapies to treat alcohol and substance use disorders. The recent development of subtype selective muscarinic acetylcholine receptor (mAChR) allosteric modulators, is rapidly increasing our understanding of this system and revealing great...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Walker LC, Lawrence AJ Tags: Adv Pharmacol Source Type: research

M1 muscarinic acetylcholine receptors: A therapeutic strategy for symptomatic and disease-modifying effects in Alzheimer's disease?
This article will review the progress made in the development of M1 selective ligands for the treatment of cognitive decline in AD, and will discuss the current evidence that selective targeting of the M1 mAChR could also have the potential to modify AD progression. PMID: 32416870 [PubMed - as supplied by publisher] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Scarpa M, Hesse S, Bradley SJ Tags: Adv Pharmacol Source Type: research

Structure-based discovery and development of metabotropic glutamate receptor 5 negative allosteric modulators.
Abstract The metabotropic glutamate (mGlu) receptors are a family of eight class C G protein-coupled receptors (GPCRs) which modulate cell signaling and synaptic transmission to the major excitatory neurotransmitter l-glutamate (l-glutamic acid). Due to their role in modulating glutamate response, their widespread distribution in the central nervous system (CNS) and some evidence of dysregulation in disease, the mGlu receptors have become attractive pharmacological targets. As the orthosteric (glutamate) binding site is highly conserved across the eight mGlu receptors, it is difficult not only to generate ligands ...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Bennett KA, Christopher JA, Tehan BG Tags: Adv Pharmacol Source Type: research

The function and allosteric control of the human sweet taste receptor.
Abstract Humans perceive sweet taste via activation of a specific taste receptor expressed at the surface of taste receptor cells located on the tongue and soft palate papillae. The sweet taste receptor functions as an obligate heterodimer, comprising two different class C GPCR subunits. This receptor is unique in that it is activated or modulated by a plethora of ligands from highly diverse chemical classes, from small molecules to peptides and proteins and interacting with topologically distinct sites on each of its subunits. Modulators acting at separate functional domains of the sweet taste receptor can behave...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Servant G, Kenakin T, Zhang L, Williams M, Servant N Tags: Adv Pharmacol Source Type: research

The different aspects of the GABAB receptor allosteric modulation.
Abstract The GABAB receptor is activated by the main inhibitory neurotransmitter of the central nervous system, the γ-aminobutyric acid (GABA). The receptor is expressed in almost all neuronal and glial cells and plays a central role in the modulation of many physiological and pathological processes. The GABAB receptor has been considered for years as an interesting target for the treatment of spasticity, pain, addiction, anxiety or depression. This has prompted many studies aiming at understanding the activation of the receptor and its modulation. While it belongs to the super-family of G protein-coupled re...
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Kniazeff J Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 32416874 [PubMed - as supplied by publisher] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 18, 2020 Category: Drugs & Pharmacology Authors: Langmead CJ Tags: Adv Pharmacol Source Type: research

Chemical and pharmacological research on the polyphenol acids isolated from Danshen: A review of salvianolic acids.
Abstract Danshen, the dried root of Salvia miltiorrhiza Bge, is a common medicinal herb in Traditional Chinese Medicine, which has been used for the treatment of a number of diseases for thousands of years. More than 2000 years ago, the Chinese early pharmacy monograph "Shennong Materia Medica" recorded that Danshen could be used for the treatment of gastrointestinal diseases, cardiovascular diseases, certain gynecological diseases, etc. Since then, Danshen has been widely used clinically in many different prescriptions for many different diseases, especially for the treatment of cardiovascular diseases....
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Du G, Song J, Du L, Zhang L, Qiang G, Wang S, Yang X, Fang L Tags: Adv Pharmacol Source Type: research

Modern traditional Chinese medicine: Identifying, defining and usage of TCM components.
Abstract TCM-based medications have been used for millennia in China and have always been "different" from current Western-based medicines in that they frequently are still mixtures of predominately plant products. From the early 20th Century, there has been a move to identify both the actual compounds in these mixes, and then over the past approximately 50years, to utilize early information for current diseases, with an example being artemisinin for treatment of malaria. Since that discovery, Western scientists, together with their Chinese counterparts, have begun to investigate how TCM compositions can...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Newman DJ Tags: Adv Pharmacol Source Type: research

LW-AFC, a new formula from the traditional Chinese medicine Liuwei Dihuang decoction, as a promising therapy for Alzheimer's disease: Pharmacological effects and mechanisms.
Abstract LW-AFC is a new formula derived from the Liuwei Dihuang decoction, a classical traditional Chinese medicine prescription. Based on our research, LW-AFC is a promising drug for Alzheimer's disease (AD). The studies were conducted primarily in two typical AD mouse models: SAMP8 and APP/PS1 mice. The results showed that LW-AFC could improve many cognitive behaviors, such as spatial learning and memory ability, passive and active avoidance response, and object recognition memory capability. In addition, LW-AFC could also alleviate the AD-like pathology in animal models, such as neuron loss and Aβ deposit...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Cheng X, Huang Y, Zhang Y, Zhou W Tags: Adv Pharmacol Source Type: research

Pharmacological effects of icariin.
Abstract Icariin (ICA) is a principal active component from traditional Chinese medicine Epimedium grandiflorum. To explain its traditional medical usages by modern science, a variety of pharmacological effects have been studied for ICA. In this review, we summarized the pharmacokinetics of ICA as well as its pharmacological mechanisms in neurodegenerative disease, cardiovascular disease, anti-osteoporosis, anti-inflammation, anti-oxidative stress, anti-depression and anti-tumors. PMID: 32089233 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: He C, Wang Z, Shi J Tags: Adv Pharmacol Source Type: research

Seaweed-derived bioactives as potential energy regulators in obesity and type 2 diabetes.
Abstract There is epidemiological evidence that dietary intake of seaweeds is associated with a lower prevalence of chronic diseases. While seaweeds are of high nutritious value, due to their high content of fiber, polyunsaturated fatty acids and minerals, they also contain an abundance of bioactive compounds. There is a growing body of scientific data that these bioactive moieties exert effects that could correct the metabolic dysregulation that is present in obesity and Type 2 diabetes (T2D). In this review we describe how the molecular mechanisms, specific to different tissues, that underly obesity and T2D are ...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Bermano G, Stoyanova T, Hennequart F, Wainwright CL Tags: Adv Pharmacol Source Type: research

Preventive and therapeutic effect of Ganoderma lucidum on kidney injuries and diseases.
Abstract Ganoderma lucidum (G. lucidum, Lingzhi) is a well-known Chinese traditional medicine to improve health and to treat numerous diseases for over 2000 years in Asian countries. G. lucidum has the abundant chemical components such as triterpenes and polysaccharides, which have various biological activities including anti-oxidation, anti-inflammation, anti-liver disorders, anti-tumor growth and metastasis, etc. Recently, many lines of studies have elucidated the therapeutic effects of G. lucidum and its extractions on various acute kidney injury (AKI) and chronic kidney disease (CKD) pathogenesis, including au...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Geng X, Zhong D, Su L, Lin Z, Yang B Tags: Adv Pharmacol Source Type: research

Fungal polysaccharides.
Abstract Fungal bioactive polysaccharides are well known and have been widely used in Asia as a part of the traditional diet and medicine. In fact, some biopolymers (mainly β-glucans or glycoconjugate) have already made their way to the market as antitumor or immunostimulating drugs. In the last decades, the relationship between structure and activity of polysaccharides and their detailed mode of action have been the core of intense research to understand and utilize their medicinal properties. Most of the antitumor polysaccharides belong to conserved β-glucans, with a linear β-(1→3)-glucan bac...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Xiao Z, Zhou W, Zhang Y Tags: Adv Pharmacol Source Type: research

Toxicity of traditional Chinese medicine herbal and mineral products.
Abstract Traditional Chinese medicine (TCM) has been used to treat numerous kinds of diseases for more than 2000 years in eastern Asian countries. A portion of the TCM herbal and mineral products are believed to be toxic according to modern standards, and are still widely prescribed in the clinic. However, some TCM products considered to be non-toxic or low-toxic have been reported to possess significant toxicological effects on different organs in both animal and human models. In this review, we define the term "toxic" in TCM, and then we summarize the advances in pharmacology and toxicology research of...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Liu R, Li X, Huang N, Fan M, Sun R Tags: Adv Pharmacol Source Type: research

Pharmacological properties of tanshinones, the natural products from Salvia miltiorrhiza.
Abstract Danshen (Cai, et al. 2016) is the dry root and rhizome of the herbaceous plant Salvia miltiorrhiza Bge. of family labiatae, a perennial plant that is native to China and Japan. The primary modern clinical applications of Danshen are for heart disease, chronic hepatitis, early cirrhosis, cerebral ischemia and pulmonary heart disease. Emerging evidence from cellular, animal, and clinical studies has begun to illuminate the pharmacological attributes of the primary lipophilic tanshinones from Danshen, which include tanshinone I, tanshinone II, cryptotanshinone and dihydrotanshinone, etc. Tanshinones offer th...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Wang X, Yang Y, Liu X, Gao X Tags: Adv Pharmacol Source Type: research

Pharmacological action and potential targets of chlorogenic acid.
Abstract Chlorogenic acid is a widely distributed natural compound with many important pharmacological effects, which are found in a variety of plants. It is also an important secondary metabolite in plants. As a natural plant extract from a wide range of sources, in vitro and in vivo studies have found that the main pharmacological effects of chlorogenic acid are antioxidant, antiinflammatory, antibacterial, antiviral, hypoglycemic, lipid lowering, anticardiovascular, antimutagenic, anticancer, immunomodulatory, etc. Therefore it may play an important role in promoting human health. For example, it can provide ne...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Miao M, Xiang L Tags: Adv Pharmacol Source Type: research

Astragaloside IV derived from Astragalus membranaceus: A research review on the pharmacological effects.
Abstract Decoctions prepared from the roots of Astragali Radix are known as "Huangqi" and are widely used in traditional Chinese medicine for treatment of viral and bacterial infections, inflammation, as well as cancer. Astragaloside IV (AS-IV), one of the major compounds from the aqueous extract of Astragalus membranaceus, is a cycloartane-type triterpene glycoside chemical. To date, many studies in cellular and animal models have demonstrated that AS-IV possesses potent protective effects in cardiovascular, lung, kidney and brain. Based on studies over the past several decades, this review systematical...
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Zhang J, Wu C, Gao L, Du G, Qin X Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 32089241 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 26, 2020 Category: Drugs & Pharmacology Authors: Du G Tags: Adv Pharmacol Source Type: research

GPCR drug discovery-moving beyond the orthosteric to the allosteric domain.
Abstract Allosteric modulation of G protein coupled receptors (GPCRs) is rapidly becoming a standard option for development of therapeutics headed to the clinic. Although GPCRs represent about 35% of marketed drugs, to date only two allosteric modulators have been approved for human use. However, many are now in early clinical development are can provide unique regulation of GPCRs including high selectivity along with physiologic temporal and spatial signaling. These molecules bind to a site that is distinct from the site where the endogenous agonist binds yet can provide robust modulation effects that span from t...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Felder CC Tags: Adv Pharmacol Source Type: research

Nitric oxide: Antidepressant mechanisms and inflammation.
Abstract Millions of individuals worldwide suffers from mood disorders, especially major depressive disorder (MDD), which has a high rate of disease burden in society. Although targeting the biogenic amines including serotonin, and norepinephrine have provided invaluable links with the pharmacological treatment of MDD over the last four decades, a growing body of evidence suggest that other biologic systems could contribute to the pathophysiology and treatment of MDD. In this chapter, we highlight the potential role of nitric oxide (NO) signaling in the pathophysiology and thereby treatment of MDD. This has been i...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Ghasemi M Tags: Adv Pharmacol Source Type: research

Selective allosteric modulation of muscarinic acetylcholine receptors for the treatment of schizophrenia and substance use disorders.
Abstract Muscarinic acetylcholine receptor (mAChRs) subtypes represent exciting new targets for the treatment of schizophrenia and substance use disorder (SUD). Recent advances in the development of subtype-selective allosteric modulators have revealed promising effects in preclinical models targeting the different symptoms observed in schizophrenia and SUD. M1 PAMs display potential for addressing the negative and cognitive symptoms of schizophrenia, while M4 PAMs exhibit promise in treating preclinical models predictive of antipsychotic-like activity. In SUD, there is increasing support for modulation of mesocor...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Teal LB, Gould RW, Felts AS, Jones CK Tags: Adv Pharmacol Source Type: research

Medications development for food-based and drug use disorders.
Abstract Despite decades of research, few medications have gained Food and Drug Administration (FDA) approval for the management of substance abuse disorder. The paucity of successful medications can be attributed, in part, to the lack of clearly identified neurobiological targets for addressing the core pathology of addictive behavior. Commonalities in the behavioral and brain processes involved in the rewarding effects of drugs and foods has prompted the evaluation of candidate medications that target neural pathways involved in both drug and eating disorders. Here, pharmacological strategies for the development...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: de Moura FB, Kohut SJ, Bergman J Tags: Adv Pharmacol Source Type: research

Lipid rafts in psychiatry.
Abstract Lipid microenvironments in the plasma membrane are known to influence many signal transduction pathways. Several of those pathways are critical for both the etiology and treatment of depression. Further, several signaling proteins are modified, covalently, by lipids, a process that alters their interface with the microenvironments mentioned above. This review presents a brief discussion of the interface of the above elements as well as a discussion about the participation of lipids and lipid moieties in the action of antidepressants. PMID: 31378253 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Wray NH, Rasenick MM Tags: Adv Pharmacol Source Type: research

Obsessive compulsive disorder (OCD): Current treatments and a framework for neurotherapeutic research.
Abstract We briefly review current approaches to the diagnosis and treatment of OCD, noting their lack of a strong theoretical foundation. In keeping with the Research Domain Criteria project (RDoC) calls for reconceptualizing psychopathology in ways that better link up with normal brain systems, we advance an adaptationist, brain-network perspective on OCD and propose that OCD represents a dysfunction in the stopping dynamics of a normal brain network that evolved to handle potential danger. We then illustrate how this theoretical perspective can be used to organize possibilities for research on neurotherapeutics...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Woody EZ, Hoffman KL, Szechtman H Tags: Adv Pharmacol Source Type: research

Positive allosteric modulators of the dopamine D1 receptor: A new mechanism for the treatment of neuropsychiatric disorders.
Abstract The dopamine D1 receptor plays an important role in motor activity, reward, and cognition. Efforts to develop D1 agonists have been mixed due to poor drug-like properties, tachyphylaxis, and inverted U-shaped dose-response curves. Recently, positive allosteric modulators (PAMs) for the dopamine D1 receptor were discovered and initial pharmacological profiling has suggested that several of the above issues could be addressed with this mechanism. This paper presents an overview of key findings for DETQ (2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquino...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Svensson KA, Hao J, Bruns RF Tags: Adv Pharmacol Source Type: research

Rapid-acting antidepressants.
Abstract Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, large effect size, activity after only a single or few dose applications, and positive impact in treatment refractory patients and against some treatment-resistant symptoms (e.g., anhedonia). Rapid-acting antidepressant drug action has been demonstrated in control...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Witkin JM, Martin AE, Golani LK, Xu NZ, Smith JL Tags: Adv Pharmacol Source Type: research

mGlu2/3 receptor antagonists.
Abstract Abnormalities of glutamatergic transmission are implicated in neuropsychiatric disorders. Among the glutamate receptors, metabotropic (mGlu) 2/3 receptors have recently gained much attention as molecular targets for the treatment of several neuropsychiatric disorders including depression and anxiety. Both orthosteric and allosteric antagonists of mGlu2/3 receptors have been synthesized, and their therapeutic potential has been examined. These research activities have demonstrated the promise of mGlu2/3 receptor antagonists as potential treatment agents for the above-mentioned neuropsychiatric disorders. I...
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Chaki S Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 31378258 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - August 7, 2019 Category: Drugs & Pharmacology Authors: Witkin JM Tags: Adv Pharmacol Source Type: research

Primary hepatocytes and their cultures for the testing of drug-induced liver injury.
Abstract Drug-induced liver injury is a major reason for discontinuation of drug development and withdrawal of drugs from the market. Intensive efforts in the last decades have focused on the establishment and finetuning of liver-based in vitro models for reliable prediction of hepatotoxicity triggered by drug candidates. Of those, primary hepatocytes and their cultures still are considered the gold standard, as they provide an acceptable reflection of the hepatic in vivo situation. Nevertheless, these in vitro systems cope with gradual deterioration of the differentiated morphological and functional phenotype. Th...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Vilas-Boas V, Cooreman A, Gijbels E, Van Campenhout R, Gustafson E, Ballet S, Annaert P, Cogliati B, Vinken M Tags: Adv Pharmacol Source Type: research

Role and mechanisms of autophagy in alcohol-induced liver injury.
Abstract Alcoholic liver disease (ALD) is one of the major causes of chronic liver disease worldwide. Currently, no successful treatments are available for ALD. The pathogenesis of ALD is characterized as simple steatosis, fibrosis, cirrhosis, alcoholic hepatitis (AH), and eventually hepatocellular carcinoma (HCC). Autophagy is a highly conserved intracellular catabolic process, which aims at recycling cellular components and removing damaged organelles in response to starvation and stresses. Therefore, autophagy is considered as an important cellular adaptive and survival mechanism under various pathophysiologica...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Chao X, Ding WX Tags: Adv Pharmacol Source Type: research

Mechanisms of idiosyncratic drug-induced liver injury.
Abstract Idiosyncratic drug-induced liver injury (IDILI) is a significant problem. Little is known with certainty about the mechanisms of IDILI. However, there is growing evidence that most IDILI is immune mediated and caused by reactive metabolites. The two major and complementary hypotheses that link reactive metabolite formation with the induction of an immune response that can lead to IDILI are the hapten and danger hypotheses. Specifically, a reactive metabolite can bind to proteins and make them foreign; however, without activation of antigen presenting cells (APCs), the immune response will be immune tolera...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Uetrecht J Tags: Adv Pharmacol Source Type: research

Idiosyncratic drug-induced liver injury in patients: Detection, severity assessment, and regulatory implications.
Abstract Idiosyncratic Drug-Induced Liver Injury (IDILI) is a rare but potentially life-threatening event that is caused by drugs that, at usual therapeutic doses, do not cause any biochemical or clinical evidence of liver injury in the majority of treated patients. The most common clinical phenotypes of IDILI are "acute hepatitis," "mixed hepatocellular-cholestatic hepatitis," and "cholestatic hepatitis" and these are distinguished by clinical, biochemical and histologic characteristics. Anti-microbials, herbals and dietary supplements are now the agents most often implicated in the ...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Watkins PB Tags: Adv Pharmacol Source Type: research

Acetaminophen hepatotoxicity: A mitochondrial perspective.
Abstract Acetaminophen (APAP) is a highly effective analgesic, which is safe at therapeutic doses. However, an overdose can cause hepatotoxicity and even liver failure. APAP toxicity is currently the most common cause of acute liver failure in the United States. Decades of research on mechanisms of liver injury have established the role of mitochondria as central players in APAP-induced hepatocyte necrosis and this chapter examines the various facets of the organelle's involvement in the process of injury as well as in resolution of damage. The injury process is initiated by formation of a reactive metabolite, whi...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Ramachandran A, Jaeschke H Tags: Adv Pharmacol Source Type: research

Biomarkers of drug-induced liver injury.
Abstract Drug-induced liver injury (DILI) is a major clinical and regulatory challenge. As a result, interest in DILI biomarkers is growing. So far, considerable progress has been made in identification of biomarkers for diagnosis (acetaminophen-cysteine protein adducts), prediction (genetic biomarkers), and prognosis (microRNA-122, high mobility group box 1 protein, keratin-18, glutamate dehydrogenase, mitochondrial DNA). Many of those biomarkers also provide mechanistic insight. The purpose of this chapter is to review major advances in DILI biomarker research over the last decade, and to highlight some of the c...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: McGill MR, Jaeschke H Tags: Adv Pharmacol Source Type: research

Mechanisms and biomarkers of liver regeneration after drug-induced liver injury.
Abstract Liver, the major metabolic organ in the body, is known for its remarkable capacity to regenerate. Whereas partial hepatectomy (PHx) is a popular model for the study of liver regeneration, the liver also regenerates after acute injury, but less is known about the mechanisms that drive it. Recent studies have shown that liver regeneration is critical for survival in acute liver failure (ALF), which is usually due to drug-induced liver injury (DILI). It is sometimes assumed that the signaling pathways involved are similar to those that regulate regeneration after PHx, but there are likely to be critical diff...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Clemens MM, McGill MR, Apte U Tags: Adv Pharmacol Source Type: research

Evaluation and treatment of acetaminophen toxicity.
Abstract A review of the typical clinical course, diagnosis and treatment of acetaminophen toxicity is provided. For an acute overdose, most adults must ingest about 12g or more acetaminophen (APAP) before risk of serious hepatotoxicity is of concern. A nomogram of serum APAP concentration vs hours post-ingestion can assist in determining risk of liver injury and need for treatment. However, histories concerning the time of ingestion and the amount of drug ingested are usually unreliable. Peak serum transaminase activities usually occur 48-96h after acute ingestion. It is possible for patients to present in liver ...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Fisher ES, Curry SC Tags: Adv Pharmacol Source Type: research

Cell death in drug-induced liver injury.
Abstract Drug-induced liver injury (DILI) is an important cause of liver toxicity which can have varying clinical presentations, the most severe of which being acute liver failure. Hepatocyte death as a cause of drug toxicity is a feature of DILI. There are multiple cell death subroutines; some, like apoptosis, necroptosis, autophagy, and necrosis have been extensively studied, while others such as pyroptosis and ferroptosis have been more recently described. The mode of cell death in DILI depends on the culprit drug, as it largely dictates the mechanism and extent of injury. The main cell death subroutines in DIL...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Iorga A, Dara L Tags: Adv Pharmacol Source Type: research

Drug-induced liver injury in obesity and nonalcoholic fatty liver disease.
Abstract Obesity is commonly associated with nonalcoholic fatty liver (NAFL), a benign condition characterized by hepatic lipid accumulation. However, NAFL can progress in some patients to nonalcoholic steatohepatitis (NASH) and then to severe liver lesions including extensive fibrosis, cirrhosis and hepatocellular carcinoma. The entire spectrum of these hepatic lesions is referred to as nonalcoholic fatty liver disease (NAFLD). The transition of simple fatty liver to NASH seems to be favored by several genetic and environmental factors. Different experimental and clinical investigations showed or suggested that o...
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Allard J, Le Guillou D, Begriche K, Fromenty B Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 31307593 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - July 18, 2019 Category: Drugs & Pharmacology Authors: Ramachandran A, Jaeschke H Tags: Adv Pharmacol Source Type: research

The neurophysiology of hyperarousal in restless legs syndrome: Hints for a role of glutamate/GABA.
Abstract Restless legs syndrome (RLS) is a common sensory-motor circadian disorder, whose basic components include urge to move the legs, unpleasant sensory experience, and periodic leg movements during sleep, all associated with an enhancement of the individual's arousal state. Brain iron deficiency (BID) is considered to be a key initial pathobiological factor, based on alterations of iron acquisition by the brain, also moderated by genetic factors. In addition to the well-known dopaminergic involvement in RLS, previous studies pointed out that BID brings also a hyperglutamatergic state that influences a dysfunc...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Lanza G, Ferri R Tags: Adv Pharmacol Source Type: research

Iron uptake at the blood-brain barrier is influenced by sex and genotype.
Abstract Iron transport to the brain is a critically important and highly regulated process necessary for proper brain function. This review aims to summarize iron uptake mechanisms in the brain and the importance of sex and genotype on this uptake. In restless legs syndrome (RLS), brain iron uptake has been hypothesized to be dysregulated, leading to the clinically observed brain iron deficiency, so this review specifically comments on this disorder. The review covers transferrin-bound transport and the more recently discovered role of ferritin in brain iron delivery. Studies on the impact of sex, MEIS1 (associat...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Wade QW, Chiou B, Connor JR Tags: Adv Pharmacol Source Type: research

Caenorhabditis elegans and its applicability to studies on restless legs syndrome.
Abstract Restless legs syndrome (RLS) is a common neurological disorder in the United States. This disorder is characterized by an irresistible urge to move the legs, although the symptoms vary in a wide range. The pathobiology of RLS has been linked to iron (Fe) deficiency and dopaminergic (DAergic) dysfunction. Several genetic factors have been reported to increase the risk of RLS. Caenorhabditis elegans (C. elegans) is a well-established animal model with a fully sequenced genome, which is highly conserved with mammals. Given the detailed knowledge of its genomic architecture, ease of genetic manipulation and c...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Chen P, Ijomone OM, Lee KH, Aschner M Tags: Adv Pharmacol Source Type: research

Role of MEIS1 in restless legs syndrome: From GWAS to functional studies in mice.
Abstract MEIS1 is a transcription factor playing an important role in the development of several organs, including central and peripheral nervous systems. A genetic locus spanning the MEIS1 coding region has been associated with the risk of RLS in genome-wide association studies, with increasing evidence that MEIS1 is the causal RLS gene. The RLS-linked genetic signal has been mapped to an intronic regulatory element within MEIS1. This element plays a role in the ganglionic eminences of the developing forebrain, with the RLS risk allele related to a reduced activation of the enhancer. This suggests that the gangli...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Salminen AV, Lam DD, Winkelmann J Tags: Adv Pharmacol Source Type: research

Non-dopaminergic vs. dopaminergic treatment options in restless legs syndrome.
ero D Abstract Two types of drugs have been extensively investigated for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED): dopamine agonists and α2δ ligands to the α2δ subunit of calcium channels. Comparative studies show that both classes of drugs are similarly effective in treating RLS symptoms over the short- and long-term. While dopamine agonists are more effective in treating periodic limb movements (PLMs), α2δ ligands are more effective in consolidating sleep. However, given the fact that dopamine agonists cause high rates of augmentation of symptom...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Wanner V, Garcia Malo C, Romero S, Cano-Pumarega I, García-Borreguero D Tags: Adv Pharmacol Source Type: research

Idiopathic restless legs syndrome treatment: Progress and pitfalls?
Abstract The pathophysiology of Restless Legs Syndrome (RLS) remains uncertain. Although the dopaminergic and/or the iron breakdown homeostasis hypotheses are still considered to be the mainstay of the RLS underlying mechanism, therapeutic intervention aiming to alleviate RLS syndrome through dopamine agonists use and iron stores recovery failed so far to show short-term remarkable efficacy, and controlled trials to establish sustained long-term efficacy, tolerability and safety are lacking. Here we review available literature dealing with pharmacological treatment of RLS and consider some rational aspects of RLS ...
Source: Advances in Pharmacology - June 25, 2019 Category: Drugs & Pharmacology Authors: Ghorayeb I Tags: Adv Pharmacol Source Type: research