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This book covers the molecular structures and the cellular and in vivo function of endosomes and lysosomes, i.e. intracellular vesicles which are involved in many cellular processes such as endocytosis, intracellular trafficking, degradation of material from inside (e.g. autophagy) and outside the cell as well as exocytosis. Membranes of endolysosomal organelles contain an amazing number and diversity of ion channels. These ion channels are the topic of the present book that focusses on describing the structure, the biophysical properties, physiological functions of endolysosomal ion channels at the molecular, cellular and in vivo level.

This volume of the Handbook of Experimental Pharmacology, which celebrated its 100th anniversary in 2019, addresses the rapidly growing and evolving field of metabolomics. It has been compiled and designed to broaden and enrich your understanding as well as simplify a complicated picture of the diverse field of metabolomics. This is accomplished by chapters from experts in the field on basic principles as well as reviews and updates of analytical techniques. The variety and different perspectives of the NMR approaches are described in the chapters By David Wishart, Daniel Raftery and Ryan McKay, while mass spectrometry advances are covered by Charles R. Evans and Stefan Kempa. This book also reflects the state of the art in the application of metabolomics to cell biology (Marta Cascante and Ulrich Guenther) and chapters that share insights into the application of metabolomics in various diseases (Paola Turano and Claudio Luchinat, Rachel S. Kelly and Jessica Lasky-Su,Paige Lacy, and Angela Rogers. Relationships of metabolomics with drugs are highlighted by Robert Verpoorte (natural products drug discovery), by Oscar Millet and by Turano and Luchinat (perspectives in precision medicine) and by Daniel L. Hertz (drug-induced peripheral neuropathy). From the above list of diverse topics, we believe this book has interdisciplinary appeal and scholars with an interest in the role of metabolomics in achieving precision medicine will find it of particular or special interest.

The current book is focussed on the Toll-like receptors (TLRs), which are the first pattern recognition receptors (PRRs) discovered in humans. For example, TLR4 was first recognized in humans in 1997 as a PRR recognizing the Gram-negative bacterial lipopolysaccharide (LPS). This discovery revolutionized the field of innate immunity and filled the long-standing gap in the pathogen recognition by the immune system. Now, it is well established that humans have 10 (TLR1-TLR10) and mice have 12 (TLR1-TLR13) functional TLRs, excluding TLR10 that is present as a defective pseudogene. TLRs are present as both membrane-bound extracellular (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10) and intracellular (TLR3, TLR7, TLR8, and TLR9) PRRs in humans, which identify different pathogen or microbe-associated molecular patterns (PAMPs or MAMPs) and death or damage-associated molecular patterns (DAMPs) released by the host cells. A lot of development in the TLR biology has occurred in last 24 years since there first discovery in humans.The book is intended to describe their role in the host defence, human reproduction, non-infectious sterile inflammatory conditions, including brain immunity and cerebrovascular diseases, signaling mechanisms, adaptive immunity, and their targeting for drug development.

The goal of this book is to provide a guide and detailed review of immunosuppression in terms of molecular mechanisms of action, side effects and clinical trials that validated their utility. This includes their use in solid organ transplantation, bone marrow transplantation and autoimmune diseases and inflammatory diseases. This book is a critical review of these topics and a vital resource.

Obesity is a major risk factor for the development of type 2 diabetes and its associated complications, a major socio-economic burden for health care systems. The worldwide prevalence of obesity doubled since 1980 and as a consequence the number of patients with diabetes has been continuously rising with more than 450 Mio. people suffering from this disease at the present time. Substantial progress has been made in understanding the molecular pathways leading from excessive fat accumulation to metabolic perturbation and finally diabetes manifestation. This edition of the "e;Handbook of Experimental Pharmacology"e; aims to analyze new insight into the pathophysiology of obesity, to decipher the complex links to diabetes and its complications, and to collect most recent information on new strategies for prevention and treatment of obesity and diabetes.

This book presents a comprehensive collection of current knowledge and leading research about the blood-brain barrier. The chapters are organized in four main parts providing basic information and novel insights about the physiology of the blood-brain barrier, the challenges related to finding and developing drugs crossing the blood-brain barrier, experimental methods to study the blood-brain barrier and the role of the blood-brain barrier in disease mechanisms and its consequences for drug development. In the first part the readers will discover the structure, function and developmental aspects of the blood-brain barrier and gain novel insights into the complexity and functionality of the neurovascular unit and energy metabolism of brain endothelial cells. Chapters of the second part focus on translational challenges from the bench to the bedside in CNS drug development, shed light on the importance to understand the brain distribution of drugs related to their efficacy, elaborate on general pharmacokinetic considerations for CNS drugs and introduce current and novel drug delivery strategies to overcome the blood-brain barrier. The experimental part of the book covers mathematical and in vitro models as well as animal and human methods in blood-brain barrier research. Specific emphasis is set on the description of the methods, the role of species differences for data interpretation, novel human models based on stem cells with the potential for personalized medicine and technical considerations and tips helpful for readers interested in working with these models. In the fourth part particular attentions is given to the blood-brain barrier, its changes and participation during disease progression. Chapters summarize alterations of the blood-brain barrier that are present in common disorders such as Alzheimer's disease, multiple sclerosis, stroke, traumatic brain injury, epilepsy and brain tumors. Present therapies will be discussed and the consequences for novel treatment approaches that need to bypass the blood-brain-barrier will be explored. In addition, experts discuss the question in how far changes at the blood-brain barrier are causally linked to disease progressions and consequently could serve as therapeutic targets. This collection is designed to appeal to a wide readership from students through basic and applied scientist to pharmacologists, medical doctors and stakeholders from the pharmaceutical industry and regulatory affairs. Due its comprehensive content the book has the potential to become a standard work in the field of blood-brain barrier research.

This book reflects the state of the art of our understanding of the WNT signaling system, which comprises a network of signaling pathways initiated by the secreted WNT lipoglycoproteins, which are crucial for embryonal development, stem cell regulation, tissue homeostasis and repair. Dysfunction of this evolutionarily conserved signaling system leads to many diseases including developmental disorders, diverse forms of cancer, fibrosis, neurodegenerative disease and many more. The WNT signaling system is built upon 19 mammalian, secreted WNT lipoglycoproteins that interact with a plethora of distinct receptors, such as the G protein-coupled receptors called Frizzleds (FZD1-10), LDL receptor-like proteins (LRP5/6), receptor tyrosine kinases (ROR1, 2, RYK and PTK7). In addition, WNT pathways are tightly regulated by many secreted and cell-intrinsic negative regulators, such as soluble FZD-related proteins (SFRPs), Dickkopfs (DKKs), WNT-inhibitory proteins, TIKI, RNF43 and more. Understanding the basic mechanism in terms of receptor-ligand interaction, receptor selectivity, signal initiation and desensitization remain poorly understood, even though substantial advances have been made the recent years. Due to the involvement of the WNT signaling system in human disease, it appears obvious to target diverse branches pharmacologically and therapeutically. However, given the complexity of the system and its importance for stem cell regulation and tissue maintenance, therapy comes with obvious risks for severe side effects. The field is addressing the challenge to identify suitable targets and selective compounds for therapy allowing disease-selective therapeutic effects and balancing unwanted side effects. This book summarizes the current understanding of the basic and applied pharmacology in the WNT signaling system and bridges disciplines such as pharmacology, physiology, neurosciences, oncology and drug development.

Rapidly growing interest in the role of organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in central monoamine homeostasis makes this book especially timely, given its thematic alignment with the role of OCTs and PMAT in CNS. This book discusses latest insights into the field laying an emphasis on health, disease and therapeutics. The chapter, "e;General Overview of Organic Cation Transporters in Brain"e;, of this book is available open access under a CC BY 4.0 license at link.springer.com

The purpose of this book is to provide a broad scope of substance use disorder research and how these findings can impact treatment outcomes. The research and outcomes described in this book represent important principles related to identifying and understanding factors related to substance use disorders.

Lipids are an integral part of cell membrane architecture, are intermediaries in cell metabolism, and are involved in transmitting cell signals from hormones, growth factors and nutrients.

This volume is designed to provide an understanding of current and potential therapies for osteoporosis. Several following chapters describe factors affecting bone including systemic hormones with significant effects on bone, and local mediators including growth factors, prostaglandins, cytokines and chemokines.

This volume is designed to provide an understanding of current and potential therapies for osteoporosis. Several following chapters describe factors affecting bone including systemic hormones with significant effects on bone, and local mediators including growth factors, prostaglandins, cytokines and chemokines.

This book focusses on the latest results related to the field of bile acids as signaling molecules and describes how these receptors have become a major pharmacological target.

This open access book, published under a CC BY 4.0 license in the Pubmed indexed book series Handbook of Experimental Pharmacology, provides up-to-date information on best practice to improve experimental design and quality of research in non-clinical pharmacology and biomedicine.

Further attention is paid to the drug discovery pathway where recent findings show the beneficial effect of small molecule antagonists of the CGRP receptors for the relief of the migraine attack and of monoclonal antibodies against CGRP or the CGRP receptor for migraine prevention.

The aim of this book is not only to introduce readers with a broad spectrum of biological actions of the NOP receptor, but also to feature a detailed look at the N/OFQ-NOP receptor system, medicinal chemistry, pharmacology, and clinical data of NOP-targeted ligands.

In addition, the topic of rare diseases and special challenges for pharmacotherapy will be included and will provide readers with the necessary knowledge to handle complex diseases and treatment strategies especially in relation to pharmacotherapy of rare and orphan diseases.

The purpose of this book is to provide a broad scope of substance use disorder research and how these findings can impact treatment outcomes. The research and outcomes described in this book represent important principles related to identifying and understanding factors related to substance use disorders.

Lipids are an integral part of cell membrane architecture, are intermediaries in cell metabolism, and are involved in transmitting cell signals from hormones, growth factors and nutrients.

Celebrating 100 years of HEP, this volume will discuss key pharmacological discoveries and concepts of the past 100 years. These discoveries have dramatically changed the medical treatment paradigms of many diseases and these concepts have and will continue to shape discovery of new medicinies.

This volume of the Handbook of Experimental Pharmacology features contributions from recognized experts on the actions of different xanthines, focusing on caffeine and theophylline. There is a special chapter on theobromine, an active component of chocolate.