- •Preface
- •Contents
- •1 Extracellular and Intracellular Signaling – a New Approach to Diseases and Treatments
- •1.1 Introduction
- •1.1.1 Linear Model of Drug Receptor Interactions
- •1.1.2 Matrix Model of Drug Receptor Interactions
- •1.2 Experimental Approaches to Disease Treatment
- •1.3 Adipokines and Disease Causation
- •1.4 Questions in Disease Treatment
- •1.5 Toxic Lifestyles and Disease Treatment
- •References
- •2.1 Introduction
- •2.2 Heterogeneity of Adipose Tissue Composition in Relation to Adipokine and Cytokine Secretion
- •2.3 Feedback between FA and the Adipocyte
- •2.6 Metabolic Programming of Autocrine Signaling in Adipose Tissue
- •2.8 Cell Heterogeneity in the Pancreatic Islet
- •2.16 Concluding Remarks
- •Acknowledgements
- •References
- •3 One Receptor for Multiple Pathways: Focus on Leptin Signaling
- •3.1 Leptin
- •3.2 Leptin Receptors
- •3.3 Leptin Receptor Signaling
- •3.3.4 AMPK
- •3.3.5 SOCS3
- •3.4 Leptin Receptor Interactions
- •3.4.1 Apolipoprotein D
- •3.4.2 Sorting Nexin Molecules
- •3.4.3 Diacylglycerol Kinase Zeta
- •3.4.4 Apolipoprotein J
- •References
- •4.1 Introduction
- •4.2 Leptin: A Brief Introduction
- •4.3 Expression of Leptin Receptors in Cardiovascular Tissues
- •4.6 Post Receptor Leptin Signaling
- •4.6.2 Mitogen Activated Protein Kinase Stimulation
- •4.7 Adiponectin
- •4.7.1 Adiponectin and Cardiovascular Disease
- •4.7.2 Adiponectin and Experimental Cardiac Hypertrophy
- •4.8 Resistin
- •4.8.1 Cardiac Actions of Resistin
- •4.8.1.1 Experimental Studies on the Cardiac Actions of Resistin
- •4.9 Apelin
- •4.9.1 Apelin and Heart Disease
- •4.10 Visfatin
- •4.11 Other Novel Adipokines
- •4.12 Summary, Conclusions and Future Directions
- •Acknowledgements
- •References
- •5 Regulation of Muscle Proteostasis via Extramuscular Signals
- •5.1 Basic Protein Synthesis
- •5.2.1 Hormones
- •5.2.1.1 Mechanisms of Action: Glucocorticoids
- •5.2.1.2 Mechanisms of Action: TH (T3)
- •5.2.1.3 Mechanisms of Action: Testosterone
- •5.2.1.4 Mechanisms of Action: Epinephrine
- •5.2.2 Local Factors (Autocrine/Paracrine)
- •5.2.2.1 Mechanisms of Action: Insulin/IGF Spliceoforms
- •5.2.2.2 Mechanisms of Action: Fibroblast Growth Factor (FGF)
- •5.2.2.3 Mechanisms of Action: Myostatin
- •5.2.2.4 Mechanisms of Action: Cytokines
- •5.2.2.5 Mechanisms of Action: Neurotrophins
- •5.2.2.7 Mechanisms of Action: Extracellular Matrix
- •5.2.2.8 Mechanisms of Action: Amino Acids (AA)
- •5.3 Regulation of Muscle Proteostasis in Humans
- •5.3.1 Nutrients as Regulators of Muscle Proteostasis in Man
- •5.3.2 Muscular Activity (i.e. Exercise) as a Regulator of Muscle Proteostasis
- •5.4 Conditions Associated with Alterations in Muscle Proteostasis in Humans
- •5.4.2 Disuse Atrophy
- •5.4.3 Sepsis
- •5.4.4 Burns
- •5.4.5 Cancer Cachexia
- •References
- •6 Contact Normalization: Mechanisms and Pathways to Biomarkers and Chemotherapeutic Targets
- •6.1 Introduction
- •6.2 Contact Normalization
- •6.3 Cadherins
- •6.4 Gap Junctions
- •6.5 Contact Normalization and Tumor Suppressors
- •6.6 Contact Normalization and Tumor Promoters
- •6.7 Conclusions
- •References
- •7.1 Introduction
- •7.2 Background on Migraine Headache
- •7.3 Migraine and Neuropathic Pain
- •7.4 Role of Astrocytes in Pain
- •7.5 Adipokines and Related Extracellular Signalling
- •7.6 The Future of Signaling Research to Migraine
- •Acknowledgements
- •References
- •8.1 Alzheimer’s Disease
- •8.1.2 Target for AD Therapy
- •8.2 AD and Metabolic Dysfunction
- •8.2.1 Impaired Glucose Metabolism
- •8.2.2 Lipid Disorders
- •8.2.3 Obesity
- •8.3 Adipokines
- •8.3.1 Leptin
- •8.3.2 Adiponectin
- •8.3.3 Resistin
- •8.3.4 Visfatin
- •8.3.5 Plasminogen Activator Inhibitor
- •8.3.6 Interleukin-6
- •8.4 Conclusions
- •References
- •9.1 Introduction
- •9.1.1 Structure and Function of Astrocytes
- •9.1.1.1 Morphology
- •9.1.1.2 Astrocyte Functions
- •9.1.2 Responses of Astrocytes to Injury
- •9.1.2.1 Reactive Astrocytosis
- •9.1.2.2 Cell Swelling
- •9.1.2.3 Alzheimer Type II Astrocytosis
- •9.2 Intracellular Signaling System in Reactive Astrocytes
- •9.2.1 Oxidative/Nitrosative Stress (ONS)
- •9.2.2 Protein Kinase C (PKC)
- •9.2.5 Signal Transducer and Activator of Transcription 3 (STAT3)
- •9.3 Signaling Systems in Astrocyte Swelling
- •9.3.1 Oxidative/Nitrosative Stress (ONS)
- •9.3.2 Cytokines
- •9.3.3 Protein Kinase C (PKC)
- •9.3.5 Protein Kinase G (PKG)
- •9.3.7 Signal Transducer and Activator of Transcription 3 (STAT3)
- •9.3.10 Ion Channels/Transporters/Exchangers
- •9.4 Conclusions and Perspectives
- •Acknowledgements
- •References
- •10.1 Adipokines, Toxic Lipids and the Aging Brain
- •10.1.1 Toxic Lifestyles, Adipokines and Toxic Lipids
- •10.1.2 Ceramide Toxicity in the Brain
- •10.3 Oxygen Radicals, Hydrogen Peroxide and Cell Death
- •10.4 Gene Transcription and DNA Damage
- •10.5 Conclusions
- •References
- •11.1 Introduction
- •11.2 Cellular Signaling
- •11.2.1 Types of Signaling
- •11.2.2 Membrane Proteins in Signaling
- •11.3 G Protein-Coupled Receptors
- •11.3.1 Structure of GPCRs
- •11.3.1.1 Structure Determination
- •11.3.1.2 Structural Diversity of Current GPCR Structures
- •11.3.1.3 Prediction of GPCR Structure and Ligand Binding
- •11.3.2 GPCR Activation: Conformation Driven Functional Selectivity
- •11.3.2.2 Ligand or Mutation Stabilized Ensemble of GPCR Conformations
- •11.3.2.4 GPCR Dimers and Interaction with Other Proteins
- •11.3.3 Functional Control of GPCRs by Ligands
- •11.3.3.1 Biased Agonism
- •11.3.3.2 Allosteric Ligands and Signal Modulation
- •11.3.4 Challenges in GPCR Targeted Drug Design
- •11.4 Summary and Looking Ahead
- •Acknowledgements
- •References
- •12.1 Introduction
- •12.5.1 Anthocyanins
- •12.5.2 Gallates
- •12.5.3 Quercetin
- •12.5.5 Piperine
- •12.5.6 Gingerol
- •12.5.7 Curcumin
- •12.5.8 Guggulsterone
- •12.6.1 Phytanic Acid
- •12.6.2 Dehydroabietic Acid
- •12.6.3 Geraniol
- •12.7 Agonists of LXR that Reciprocally Inhibit NF-jB
- •12.7.1 Stigmasterol
- •12.7.3 Ergosterol
- •12.8 Conclusion
- •References
- •13.1 Introduction
- •13.2 Selective Dopaminergic Neuronal Death
- •13.3 Signaling Pathways Involved in Selective Dopaminergic Neuronal Death
- •13.3.1 Initiators and Signaling Molecules
- •13.3.1.1 Response to Oxidative and Nitrosative Stress
- •13.3.1.2 Response to Altered Proteostasis
- •13.3.1.3 Response to Glutamate
- •13.3.1.4 Other Initiators
- •13.3.2 Signal Transducers, Intracellular Messengers and Upstream Elements
- •13.3.2.2 Small GTPases
- •13.3.3 Intracellular Signaling Cascades
- •13.3.3.1 Mitogen Activated Protein Kinases (MAPK) Pathway
- •13.3.3.2 PI3K/Akt Pathway
- •13.3.3.4 Unfolded Protein Response (UPR)
- •13.3.4 Potentially Involved Intracellular Signaling Components
- •13.3.4.3 PINK1
- •13.3.5.2 Dopamine Metabolism
- •13.3.5.3 Cell Cycle
- •13.3.5.4 Autophagy
- •13.3.5.5 Apoptosis
- •13.4 Conclusions
- •References
- •Subject Index
140 |
Chapter 8 |
Although direct information is missing, what is known to date, which includes the indirect proinflammatory action exerted through upregulation of inflammatory cytokines, increased expression under several inflammatory brain states and the antagonism of leptin e ects in the CNS, seems to indicate an unfavorable action of resistin in AD.
8.3.4Visfatin
Visfatin, also known as pre-B cell colony enhancing factor (PBEF) and nicotinamide phosphoribosyl transferase (Nampt), in most species, is a 491 amino acids protein with several functions including enhancement of cell proliferation, maturation of B cells, biosynthesis of nicotinamide monoand di-nucleotide and hypoglycemic e ects derived from reduction of glucose release from liver
and stimulation of glucose utilization in adipocytes and myocytes. Serum levels of visfatin are elevated in obesity and type 2 diabetes115,116 and visfatin mimics
insulin binding to its receptor at a site di erent from that of insulin.
Visfatin is recognized as a proinflammatory agent, stimulating inflammatory cytokine expression, such as TNFa, IL-6 and promoting smooth muscle cell maturation. High visfatin serum levels have been associated with inflammatory conditions and ischemic stroke,117 but a protective e ect of visfatin in cerebral ischemia has also been shown.118 One interesting aspect that may help in identifying a specific role for visfatin in AD resides in its nicotinamide phosphoribosyl transferase activity. NAD originates in fact from nicotinamide, substrate for visfatin, which is converted to nicotinamide mononucleotide (NMN) and then to NAD, and further reduced to NADH. The latter is a substrate for NADH oxidase that forms superoxides. Ab seems to be endowed with NADH oxidase activity to form oxygen radicals from extracellular NADH. Hence, an enhanced production of visfatin, in the presence of Ab, results in increased formation of free oxygen species that can contribute to an increased damage to neurons and the BBB.119 It is suggested that visfatin represents the central factor of a vicious cycle in which enhanced oxygen radicals cause damage to the brain vasculature, increasing chemotaxis of blood cells that contribute to produce visfatin with ensuing proinflammatory cytokines. As visfatin levels may increase with age, an excessive accumulation, with other concomitant factors, may be responsible for a cumulative brain damage that characterizes AD or other neurodegenerative conditions.
8.3.5Plasminogen Activator Inhibitor
Plasminogen activator inhibitors (PAI-1 and -2) are protease inhibitors belonging to the serpin family. PAI regulates the plasminogen activator (PA)/ plasmin system that is involved in a variety of functions including cell migration, invasive growth, neuronal migration and plasticity. Overexpression of PAI causes adipocyte hypotrophy whereas mice deficient in
Adipokines and Alzheimer’s Disease |
141 |
PAI-1 have faster weight gain in diet-induced obesity indicating a protective role of PAI-1 in this condition.120 However, increased PAI-1 concentrations are considered a risk factor for thrombotic diseases. Elevated PAI levels correlate also with the metabolic syndrome and insulin resistance. PAI-1 is positively controlled by TGF-b both in the periphery and in the CNS where TGF-b exerts its neuroprotective e ect by stimulating production of PAI-1 in astrocytes.
PAI is expressed in the human brain in both neurons and astrocytes121 and has been reported to exert anti-apoptotic and neurotrophic activities in the CNS.122 Evidence also exists to suggest a role for PAI-1 in AD. Plasmin in fact contributes to Ab clearance, cleaving both monomeric and fibrillar Ab and its protein levels are reduced in AD.123 In addition PA activity in the frontal cortex of AD patients is dramatically reduced, although PAI-1 concentrations are not changed.124 These data confirm results obtained in animal models of AD in which elevated Ab correlates with inhibition of PA/plasmin system and upregulation of PAI-1. Moreover, in mice lacking PA or plasminogen, but not in wild-type mice, injection of Ab causes PAI expression and neuronal damage.125 Available data seem to suggest that inhibition of the PA/plasmin system by PAI-1 contrasts with clearance of Ab favoring its accumulation. However, controversies still exist in this regard as the increased PAI-1 levels observed in the AD mouse model have also been considered neuroprotective against Ab-induced neuronal damage.122
8.3.6Interleukin-6
IL-6 is a pleiotropic proinflammatory cytokine produced by adipocytes whose plasma levels correlate with insulin resistance and obesity. In obese patients about 30% of total IL-6 can originate from adipocytes. Although IL-6 is
produced both in the periphery and centrally, its levels have been reported to be elevated in plasma, CSF and brains of AD patients.126,127 As cerebral inflam-
matory processes may play a main role in AD, several inflammatory molecules including IL-6, either produced by resident cells surrounding the plaque, such as microglia, or periphery-derived cells, are elevated in AD patients.128 However, although peripheral IL-6 can cross the BBB, its real contribution to the cerebral inflammatory process is not clear. Despite this, peripheral blood levels of IL-6 have been suggested as potential biomarkers of AD severity.129 Although the upregulation of IL-6 in the AD brain might suggest a detrimental role on neuronal viability, a recent report very elegantly supports a protective function of IL-6 with reduction of Ab deposition consequent to enhanced Ab clearance.130
8.3.7Transforming Growth Factor-b1
TGF-b1, a 25-kDa protein, is a potent anti-inflammatory molecule produced by adipocytes as well as other tissues. The ratio of TGF-b1 mRNA produced in