Current Drug Targets, Volume 6, No. 4, 2005
Contents
Galectin-1 as an Essential Factor in Nervous System
Guest
Editor: Hidenori Horie
Editorial Pp.373-374
Hidenori Horie
Structural and Functional Studies of
Galectin-1: A Novel Axonal Regeneration-Promoting Activity for Oxidized
Galectin-1 Pp.375-383
Toshihiko Kadoya and
Hidenori Horie
Oxidized Galectin-1 is an Essential Factor
for Peripheral Nerve Regeneration Pp.385-394
Hidenori Horie,
Toshihiko Kadoya, Kazunori Sango and Mitsuhiro Hasegawa
Galectin-1 is a Novel Factor that Regulates
Myotube Growth in Regenerating Skeletal Muscles Pp.395-405
Katsuya Kami and Emiko
Senba
Galectin-1 as a Potential Therapeutic Agent
for Amyotrophic Lateral Sclerosis Pp.407-418
T. Kato, C.-H. Ren, M.
Wada and T. Kawanami
Expression and Functions of Galectin-1 in
Sensory and Motoneurons Pp.419-425
A.D. Gaudet, J.D.
Steeves, W. Tetzlaff and M.S. Ramer
Glycans and Glycan-Binding Proteins in Brain:
Galectin-1-Induced Expression of Neurotrophic Factors in Astrocytes Pp.427-436
Tamao Endo
Regulation of the Neuronal Fate by DFosB and its Downstream Target, Galectin-1 Pp.437-444
Tomofumi Miura,
Yoshinori Ohnishi, Hideaki Kurushima, Hidenori Horie, Toshihiko Kadoya and
Yusaku Nakabeppu
Potential
New Therapeutic Strategies of Diabetic Vascular Complications
Guest
Editor: Toyoshi Inoguchi
Editorial Pp.445-446
Toyoshi
Inoguchi
Blockade of Diabetic Vascular Injury by
Controlling of AGE-RAGE System Pp.447-452
Khin Mar Myint,
Yasuhiko Yamamoto, Shigeru Sakurai, Ai Harashima, Takuo Watanabe, Hui Li,
Akihiko Takeuchi, Kazunobu Yoshimura, Hideto Yonekura, Hiroshi Yamamoto
The Role of AGEs and AGE Inhibitors in
Diabetic Cardiovascular Disease Pp.453-474
M.C. Thomas, J.W.
Baynes, S.R. Thorpe and M.E. Cooper
Aldose Reductase in Diabetic Microvascular
Complications Pp.475-486
S.S.M. Chung and S.K.
Chung
Molecular Targets of Diabetic Cardiovascular
Complications Pp.487-494
Fatima K. Ahmad,
Zhiheng He and George L. King
NAD(P)H Oxidase Activation: A Potential
Target Mechanism for Diabetic Vascular Complications, Progressive b-Cell Dysfunction and Metabolic Syndrome Pp.495-501
Toyoshi Inoguchi and
Hajime Nawata
Molecular Targets of Diabetic Vascular
Complications and Potential New Drugs Pp.503-509
Roberto Da Ros,
Roberta Assaloni and Antonio Ceriello
Vascular Endothelial Growth Factor and
Diabetic Retinopathy: Role of Oxidative Stress Pp.511-524
Ruth B. Caldwell,
Manuela Bartoli, M. Ali Behzadian, Azza E.B. El-Remessy, Mohamed Al-Shabrawey,
Daniel H. Platt, Gregory I. Liou and R. William Caldwell
Adipokines: Therapeutic Targets for Metabolic
Syndrome Pp.525-529
Kunihisa Kobayashi and
Toyoshi Inoguchi
Abstracts
[Back
to top] Editorial
Hidenori Horie
The galectin family of proteins is defined by its affinity for b-galactoside sugars and a canonical amino acid sequence which encodes the carbohydrate-binding-domain (CRD), and fourteen members of the proteins have been identified in mammal. Galectin-1, the first member of the galectin family to be identified, is a 14.5-kDa protein that contains a single CRD. Galectin-1 is expressed in many tissues including skeletal muscle, liver, spleen and lung. It has been shown that galectin-1 is a multi-functional molecule involved in cell-cell and cell-extracellular matrix interactions, cell proliferation, and programmed cell death. Galectin-1 is also expressed widely in nervous tissues in embryonic stage, but its expression is restricted mainly to peripheral nervous tissues with maturation. Although galectin-1 is expressed in many adult mammalian peripheral neurons, research on its function in the adult nervous system did not elucidate a role for galectin-1 in the adult nervous system until recently. The 1999 discovery of the importance of galectin-1 in peripheral nerve regeneration initiated investigation on the functions of galectin-1 peripheral and central nervous systems following injury. Results from these experiments suggest that galectin-1 may be a novel therapeutic agent for the repair of injured nervous tissues. Therefore, now is a time good to introduce the recent findings of galectin-1 activity in the nervous system to CDT readers through the review entitled, “Galectin-1 as an essential factor in nervous system”.
This review is composed of seven review articles with preface. Each article will be written by authors actively engaged in research in the field corresponding to the article.
1) Structural and functional studies of galectin-1: a novel axonal regeneration-promoting activity for oxidized galectin-1. The oxidized form of galectin-1 loses typical lectin activity, but has a role in promoting axonal regeneration following nerve injury. Precise structural differences between oxidized galectin-1 and reduced galectin-1 shall be described.
2) Oxidized galectin-1 is an essential factor for peripheral nerve regeneration. Using recombinant human oxidized galectin-1, as well as an antibody that specifically blocks its function, in four in vivo models of peripheral nerve regeneration, it has been shown that oxidized galectin-1 is important in the initiation of axonal regrowth after axotomy. This suggests that it is the oxidized form of galectin-1 that enhances axonal regeneration in vivo . Since galectin-1 is expressed and externalized in the regenerating sciatic nerves as well as in both sensory neurons and motor neurons, recent findings indicate that galectin-1 present in the extracellular space may become oxidized and subsequently bind to macrophages, inducing the secretion of a factor that promotes axonal regrowth and Schwann cell migration.. The administration of oxidized galectin-1 was effective for enhancing functional recovery after sciatic nerve injury.
3) Galectin-1 plays essential roles in muscle regeneration and reinnervation after muscle injury. After crush injury, regenerative skeletal muscle expresses galectin-1. Administration of antibody to galectin-1 significantly decreased the size of myotubes in regenerating muscle. Endogenous galectin-1 may increase the proliferation and/or dissociation of satellite cells, which may increase the available myoblasts when myotubes are formed. Intramuscular nerve bundles also express galectin-1 after crush injury, suggesting that galectin-1 plays important roles reinnervation of injured muscles.
4) Galectin-1 as a potential therapeutic agent for amyotrophic lateral sclerosis (ALS). An accumulation of galectin-1 has been found in ALS spheroids, suggesting that galectin-1 may be involved in the pathological process of ALS. On the other hand, administration of oxidized galectin-1 to an ALS model mouse improved motor activity, delayed onset of ALS symptoms, and prolonged the survival of these mice. These results support galectin-1 as a candidate agent for the treatment of ALS.
5) Expression and functions of galectin-1 in sensory and motoneurons. During neurogenesis, galectin-1 is upregulated during axonal outgrowth. Similarly, an upregulation of galectin-1 is observed following peripheral, but not central axotomy. In PNS neurons, which are capable of regenerating following nerve injury, expression of galectin-1 increases several folds in response to axotomy. In contrast, rubrospinal neurons, which are confined to the CNS and fail to regenerate their axons, show decreased galectin-1 expression after axonal injury. The delayed regeneration and reconnection of axons in mice lacking galectin-1 demonstrates that galectin-1 is required for the typical regenerative process following peripheral nerve injury. These findings indicate that galectin-1 may become a potential target for therapeutic strategies of pain or neurotrauma.
6) Glycans and glycan-binding proteins in brain: galectin-1-induced expression of neurotrophic factors in astrocytes. Astrocytes are major cell type in CNS. Reduced galectin-1 has been found to induce astrocytes to differentiate, and also induces increased production of brain-derived neurotrophic factor (BDNF) from these cells. BDNF is known to promote neuronal survival, guide axonal pathfinding, and participate in activity-dependent synaptic plasticity during development. Thus, galectin-1 may be useful for the treatment of neurodegenerative disorders.
7) Regulation of the neuronal cell fate by DFosB and its downstream target, galectin-1. In the CNS, the expression of DFosB, one of the AP-1 (Activator protein-1) subunits encoded by alternatively-spliced fosB mRNA, is highly inducible in the adult brain in response to various insults. Galectin-1 is indeed expressed in the adult mouse hippocampus and cortex, and the induction of galectin-1 occurs in the rat hippocumpus after ischemic reperfusion injury. The expression of galectin-1 is required for the proliferative activation of quiescent rat1a cells by DFosB, indicating that galectin-1 is one of functional targets of DFosB for modulating cell fate.
The
editor would like to thank all the contributors to this volume for their
efforts to review specific and timely topics related to the importance of
galectin-1 in the nervous system, and for their willingness to speculate about
future lines of research.
[Back
to top] Structural
and Functional Studies of Galectin-1: A Novel Axonal Regeneration-Promoting
Activity for Oxidized Galectin-1
Toshihiko Kadoya and
Hidenori Horie
Recently, we discovered oxidized galectin-1 as a factor that regulates initial axonal growth in the peripheral nerve after axotomy. Galectin-1 is a member of the galectins, a family of animal lectins ranging from Caenorhabditis elegans to humans, which is defined by their affinity for b-galactosides and by significant sequence similarity in the carbohydrate-binding site. Galectin-1 is a homodimer with a subunit molecular mass of 14.5 kDa, which contains six cysteine residues per subunit. The cysteine residues should be in a free state in order to maintain a molecular structure that is capable of showing lectin activity. However, our structural analysis revealed that the axonal regeneration-promoting factor exists as an oxidized form of galectin-1, containing three intramolecular disulfide bonds. The oxidized galectin-1 exhibited marked peripheral nerve regeneration-promoting activity, although it showed no lectin activity. It was also revealed that oxidized galectin-1 exists as a monomer in a physiological solution. Galectin-1 seems to have a variety of biological functions. These functions could vary according to the time at which a biological function is taking place, as well as the site in which a biological function is taking place. In addition, these functions could vary according to the structure of galectin-1 by which a particular biological function is taking place. Disulfide bond formation alters the structure of galectin-1, so as to confer the novel ability to promote axonal regeneration. Oxidized galectin-1 likely acts as an autocrine or paracrine factor to promote axonal regeneration, functioning more like a cytokine than as a lectin.
[Back
to top] Oxidized Galectin-1 is an Essential Factor for Peripheral Nerve Regeneration
Hidenori Horie,
Toshihiko Kadoya, Kazunori Sango and Mitsuhiro Hasegawa
Although many factors have been implicated in the regenerative response of peripheral axons to nerve injury, the signals that prompt neurons to extend processes in peripheral nerves after axotomy are not well-understood. As shown in the first chapter, oxidized recombinant human galectin-1 (rhGAL-1/Ox), which lacks lectin activity, promotes initial axonal growth in an in vitro peripheral nerve regeneration model at low concentrations (pg/ml). At a similarly low concentration, rhGAL-1/Ox has also been shown to be effective in enhancing axonal regeneration using in vivo experiments. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited axonal regeneration in vivo as well as in vitro. Since galectin-1 (GAL-1) is expressed in the regenerating sciatic nerves as well as in both sensory and motoneurons, these results indicate that GAL-1, which is secreted into the extracellular space, is subsequently oxidized and then may regulate initial repair after axotomy. This possibility was confirmed by Western blot analysis, which revealed that both reduced and oxidized forms of GAL-1 are present in culture media of DRG neurons and immortalized adult mouse Schwann cells (IMS32). Externalized GAL-1/Ox has been found to stimulate macrophages to secrete an axonal regeneration-promoting factor. From these results, we propose that axonal regeneration occurs in axotomized peripheral nerves as a result of cytosolic reduced GAL-1 being released from Schwann cells and injured axons, which then becomes oxidized in the extracellular space. GAL-1/Ox in the extracellular space stimulates macrophages to secrete a factor that promotes axonal growth and Schwann cell migration, thus enhancing peripheral nerve regeneration and functional recovery. These results suggest that rhGAL-1/Ox may be a novel factor for functional restoration of injured peripheral nerves.
[Back
to top] Galectin-1
is a Novel Factor that Regulates Myotube Growth in Regenerating Skeletal
Muscles
Katsuya Kami and Emiko
Senba
Adult skeletal muscles have a vigorous regenerative capacity in response to chemical, mechanical or physical injuries. Muscle satellite cells play a critical role in skeletal muscle regeneration. Activated satellite cells (myoblasts) proliferate and then differentiate. Differentiated myoblasts fuse with each other to form multinucleated myotubes, and the growth of myotubes is induced by both fusion with additional myoblasts and reinnervation of motor neurons. Cellular and molecular events underlying the regenerative processes are regulated by critical factors, which are produced by satellite cells, myoblasts, myotubes, extracellular matrix and inflammatory cells. Galectin-1 is abundantly synthesized in adult skeletal muscles, but its roles in muscle regeneration have not been fully elucidated. We reviewed previous studies on the function of galectin-1 regarding myogenesis in vivo and in vitro, and discussed the roles of this lectin in regenerating skeletal muscles based on our observations. In intact adult muscles, galectin-1 was associated with basement membranes of myofibers. After muscle injury, galectin-1 immunoreactivity was increased within the cytoplasm of activated satellite cells. Thereafter, differentiated myoblasts lost galectin-1 immunoreactivity, but galectin-1 expression associated with basement membranes was detected in myotubes. Administration of anti-galectin-1 antibody, which perturbs the function of galectin-1, decreased the size of myotubes. Furthermore, muscle injury induced abundant expression of galectin-1 in damaged intramuscular nerve axons. We conclude that galectin-1 is a novel factor that promotes both myoblast fusion and axonal growth following muscle injury, and consequently, regulates myotube growth in regenerating skeletal muscles.
[Back
to top] Galectin-1
as a Potential Therapeutic Agent for Amyotrophic Lateral Sclerosis
T. Kato, C.-H. Ren, M.
Wada and T. Kawanami
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects almost selectively motor neurons in the central nervous system. Most ALS patients die within five years of onset. One of the neuropathological features of ALS is an “axonal spheroid,” a large swelling of a motor axon within the anterior horn of the spinal cord; this abnormal structure seems to be related to the pathogenesis of motor neuron degeneration in ALS. In 2001, using biochemical and immunohistochemical methods, we found an accumulation of galectin-1 in ALS spheroids. By immunoelectron microscopy, the galectin-1 accumulated in the spheroids was observed to be closely associated with neurofilaments. Furthermore, we observed a marked depletion of galectin-1 in the skin of ALS patients; another abnormality frequently observed in ALS. These findings, therefore, suggest that galectin-1 may be involved in the pathogenesis of ALS. It is known that an oxidized form of galectin-1 promotes axonal regeneration; however, it is not known whether oxidized galectin-1 has a beneficial or an adverse effect on the pathophysiology of ALS. To examine this issue, we administered oxidized galectin-1 to transgenic mice with H46R mutant SOD1, an ALS model mouse. The results showed that the administration of oxidized galectin-1 improved the motor activity, delayed the onset of symptoms, and prolonged the survival of the galectin-1-treated mice. Furthermore, the number of remaining motor neurons in the spinal cord was more preserved in the galectin-1-treated mice than in the non-treated mice. We conclude that galectin-1 could be a candidate agent for the treatment of ALS.
[Back
to top] Expression
and Functions of Galectin-1 in Sensory and Motoneurons
A.D. Gaudet, J.D.
Steeves, W. Tetzlaff and M.S. Ramer
Galectin-1 (Gal1) was the first identified member of the galectin family of b-galactosidase-binding proteins. Gal1 has important roles in processes fundamental to growth and survival of an organism, including cell adhesion, cell proliferation and apoptosis, and is expressed in many tissues, including the nervous system. In the 1980s, research focused on the developmental regulation of Gal1 expression during neurogenesis. Gal1 was found to be expressed mainly in peripherally-projecting neurons beginning early in neurogenesis, and its expression is maintained at high levels in subpopulations of these neurons in the adult rodent. Although the expression pattern of Gal1 implied that it may be involved in axonal guidance or targeting of subsets of sensory and motoneurons, possible roles of Gal1 in the nervous system had not been confirmed until recently. Gal1 has since been shown to be required for the proper guidance of subsets of primary olfactory axons (to targets in the olfactory bulb) and of primary somatosensory axons (to targets in the superficial dorsal horn). In addition, Gal1 has been implicated in the regenerative response of axons following peripheral nerve injury. Gal1 has been shown to promote axonal regeneration through the activation of macrophages. Also, Gal1 may act within the injured neuron to enhance regrowth: the injury-induced regulation of Gal1 in numerous types of peripherally- and centrally-projecting neurons correlates positively with the regenerative potential of their axons. In this review, we discuss the expression pattern of Gal1 in sensory and motoneurons, and the potential roles of Gal1 in development, axonal regeneration and neuropathic pain.
[Back
to top] Glycans
and Glycan-Binding Proteins in Brain: Galectin-1-Induced Expression of
Neurotrophic Factors in Astrocytes
Tamao Endo
Astrocytes are a major cell type in the central nervous system (CNS). They are considered to act in cooperation with neurons and other glial cells and to participate in the development and maintenance of functions of the CNS. Immature astrocytes possess a polygonal shape and have no processes, and continue to proliferate, while mature astrocytes have a stellate cell morphology, increased glial fibrillary acidic protein expression, and proliferate slowly. Stellate astrocytes, which immediately appear at the site of brain lesions by ischemia or other brain injuries, are thought to produce several neurotrophic factors to protect neurons from delayed post-lesion death. Previously we reported that galectin-1, a member of the family of b-galactoside-binding proteins, induced astrocyte differentiation, and the differentiated astrocytes greatly enhanced their production of brain-derived neurotrophic factor (BDNF). BDNF is known to promote neuronal survival, guide axonal pathfinding, and participate in activity-dependent synaptic plasticity during development. The effect of galectin-1 is astrocyte-specific and does not have any effect on neurons. Prevention of neuronal loss during CNS injuries is important to maintain brain function. Induction of neuroprotective factors in astrocytes by an endogenous mammalian lectin may be a new mechanism for preventing neuronal loss after brain injury, and may be useful for the treatment of neurodegenerative disorders.
[Back
to top] Regulation
of the Neuronal Fate by DFosB
and its Downstream Target, Galectin-1
Tomofumi Miura,
Yoshinori Ohnishi, Hideaki Kurushima, Hidenori Horie, Toshihiko Kadoya and
Yusaku Nakabeppu
In mammals, the regulation of the cell fate to either proliferate, differentiate, arrest cell growth, or initiate programmed cell death is the most fundamental mechanism for maintaining normal cell function and tissue homeostasis. Under multiple signaling pathways, Jun and Fos family proteins are known to play important roles as components of an AP-1 (activator protein-1) complex, to regulate the transcription of various genes involved in cell proliferation, differentiation and programmed cell death. DFosB, one of the AP-1 subunits encoded by alternatively spliced fosB mRNA, triggers one round of proliferation in quiescent rat embryo cell lines, followed by a different cell fate such as morphological alteration or delayed cell death. As one of the downstream targets of the DFosB in rat3Y1 cell line, we identified rat galectin-1 and its novel variant, galectin-1b, and demonstrated that the expression of galectin-1 is required for the proliferative activation of quiescent rat1A cells by DFosB, thus indicating that galectin-1 is one of functional targets of DFosB. The expression of DFosB is highly inducible in the adult brain in response to various insults such as ischemic reperfusion injury, seizure induced by electric stimulation or cocaine administration. On the other hand, galectin-1 has also been shown to be involved in the regeneration of damaged axons in the peripheral nerve, as well as in neurite outgrowth or synaptic connectivity in the olfactory system during development. We herein propose that DFosB together with galectin-1, may therefore mediate neuroprotection and neurogenesis in response to brain damage.
[Back
to top] Editorial
Toyoshi
Inoguchi
Diabetes mellitus is an increasing concern worldwide in terms of health. Diabetes leads to micro-vascular complications (retinopathy, nephropathy, neuropathy), and it is also paid an increasing attention as an important risk factor for cardiovascular disease. Although intense glycemic control and blood pressure control reduced the risks for micro-vascular complications in recent years, it still remains inadequate and diabetes is the most common cause of blindness and end-stage renal failure and a major cause for peripheral neuropathy. Moreover, the prevalence of diabetes is predicted to rise from 6% to 10% worldwide in the next decade. Therefore, it is becoming urgent to understand the underlying mechanisms and to establish the effective therapeutics that can prevent or reverse diabetic vascular complications.
A number of experimental and epidemiological studies have indicated that hyperglycemia is a major cause of micro-vascular complications. In addition, recent epidemiological reports have suggested that postprandial hyperglycemia is an important risk factor for cardiovascular disease. Several well-researched theories have been proposed to explain how chronic hyperglycemia or postprandial hyperglycemia causes the micro- or macro-vascular derangements. These theories include increased formation of advanced glycation endproduct (AGE), activation of protein kinase C (PKC), increased oxidative stress, increased polyol pathway and altered production of cytokines and growth factors (specially VEGF). Based on these theories, several specific interventions are now becoming feasible.
Modification of extracellular and intracellular proteins by sugars can result in the formation of AGEs. Prolonged hyperglycemia, dyslipidemia and oxidative stress in diabetes result in the accumulation of AGEs. The accumulated AGEs are thought to act through receptor-independent and dependent mechanisms to promote vascular damage, fibrosis and inflammation, and thus contribute to the development of both diabetic micro- and macro-vascular complications. Potential preventive and therapeutic approaches including inhibition of AGE formation, breakage of preformed AGE-protein crosslinks, blockade of AGE-RAGE interactions with RAGE competitors or antagonists and RAGE-specific signaling inhibition were reviewed by Myint KM et al. (for micro-vascular complications) and Thomas MC et al. (for macro-vascular complications).
Pharmacological and genetic studies in animal models have demonstrated that aldose reductase (AR) or the polyol pathway is an important initiating factor in the pathogenesis of various diabetic micro-vascular complications. However, clinical trials of the AR inhibitors were disappointing and several pharmaceutical companies had abandoned the development of this line of drugs. Chung SSM et al. reviewed the evidence for the involvement of the polyol pathway in diabetic complications and discussed the reasons for the unimpressive results of the clinical trials of the AR inhibitors. This review again emphasized that there should be renewed efforts to develop more potent and less toxic AR inhibitors to augment euglycemic agents for the prevention and treatment of diabetic complications.
PKC is a critical intracellular signaling molecule that can regulate many vascular functions, including permeability, endothelial activation and growth factor signaling. PKC is activated in various vascular tissues of diabetes. The mechanism is thought to be due to increased synthesis of diacylglycerol (DAG) that is a physiological activator via the de novo synthesis from glucose. The glucose-induced activation of DAG-PKC pathway is linked to the dysfunction of vascular walls in diabetes. Among various isoforms, preferential activation of the PKCb isoform is reported to occur in many vascular tissues in the diabetic states. Oral administration of PKC-b isoform specific inhibitor, LY333531, to diabetic rats has been reported to prevent many abnormal functions found in diabetic vascular tissues. Thus, clinical trials are now ongoing to assess the effects of PKCb inhibition on diabetic retinopathy and neuropathy. In this issue, Ahmad FK et al. reviewed the role of PKC in cardiovascular disease and the therapeutic potential of PKCb inhibitor in cardiovascular disease.
In recent years, the pathological role of oxidative stress has been implicated in both diabetic micro-vascular complications and acceleration of atherosclerosis associated with diabetes. Oxidative modification of lipoprotein is critical for atheromatous lesion formation. Superoxide anion reacts with nitric oxide, resulting in loss of nitric oxide’s anti-atherogenic properties. ROS affect a large number of various signaling pathways and cause DNA damage. In this review, Inoguchi T et al. showed that a PKC-dependent activation of NAD(P)H oxidase may be a major source for increased oxidative stress in diabetes and insulin resistant state. This review suggests the therapeutic potential of NAD(P)H oxidase inhibition for preventing diabetic vascular complications, progressive b- cell dysfunction and metabolic syndrome.
Ros RD et al. suggested that hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. Thus, they proposed the new and attractive “causal” antioxidant therapy using new antioxidant molecules, such as SOD and catalase mimetics that hopefully may inhibit at an early stage the mechanism leading to diabetic complications. This “causal” therapy also includes other promising tools such as LY 333531, PJ34 and FP15, which block PKCß isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. In addition, this review suggested that statins, ACE inhibitors, AT1 blockers, calcium channel blockers and thiazolidinediones should also be used for their effectiveness as “causal and preventive” antioxidants.
Angiogenic growth factor and vascular permeability factor, VEGF, is thought to be a pivotal role in the retinal micro-vascular complications of diabetes. Caldwell RB et al. reviewed the current understanding of the process by which VEGF gene expression is regulated and how VEGF's biological effects are altered in diabetes. They showed that high glucose-mediated oxidative stress was associated with such altered expression and action of VEGF. Potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological actions are discussed in this review.
Diabetes has been paid an increasing attention as an important risk factor for cardiovascualr disease. In this review, Ahmad FK showed how diabetes or hyperglycemia accelerated cardiovascular disease in diabetic patients and discussed the possibility of specific molecular targets independent of conventional cardiovascular risk factor control. In addition, the clustering of risk factors including diabetes, known as metabolic syndrome, has also been shown a steady but remarkable increase over recent years. Obesity is a central cause of metabolic syndrome and adipose tissues, especially the visceral adipose tissues that have been widely recognized as endocrine and paracrine organs that secrete many bioactive molecules, termed adipokines (adipocytokines), which influence metabolic processes such as insulin resistance, glucose and lipid metabolisms, food intake and inflammation. Kobayashi K et al. reviewed the role of adipocytokines in metabolic syndrome and discussed their feasibility as possible therapeutic targets.
I believe that this issue will be timely and will provide impetus to develop and establish new and more effective therapeutics that can prevent or reverse diabetic vascular complications.
[Back
to top] Blockade
of Diabetic Vascular Injury by Controlling of AGE-RAGE System
Khin Mar Myint,
Yasuhiko Yamamoto, Shigeru Sakurai, Ai Harashima, Takuo Watanabe, Hui Li,
Akihiko Takeuchi, Kazunobu Yoshimura, Hideto Yonekura, Hiroshi Yamamoto
Vascular complications result in disabilities and short life expectancy in diabetic patients. During prolonged hyperglycemic exposure, non-enzymatically glycated protein derivatives termed advanced glycation endproducts (AGE) are formed at an accelerated rate and accumulated in blood and in tissues. Studies performed in vitro and in vivo revealed AGE and their receptor RAGE as the major accounts for vascular cell derangement characteristic of diabetes. The AGERAGE system would thus be considered as a candidate molecular target for overcoming diabetic vascular complications. Potential preventive and therapeutic approaches toward it include inhibition of AGE formation, breakage of preformed AGE-proteins crosslinks, blockade of AGE-RAGE interactions with RAGE competitors or antagonists and RAGEspecific signaling inhibition.
[Back
to top] The
Role of AGEs and AGE Inhibitors in Diabetic Cardiovascular Disease
M.C. Thomas, J.W.
Baynes, S.R. Thorpe and M.E. Cooper
Prolonged hyperglycemia, dyslipidemia and oxidative stress in diabetes result in the production and accumulation of AGEs. It is now clear that AGEs contribute to the development and progression of cardiovascular disease in diabetes, as well as other complications. AGEs are thought to act through receptor-independent and dependent mechanisms to promote vascular damage, fibrosis and inflammation associated with accelerated atherogenesis. As a result, novel therapeutic agents to reduce the accumulation of AGEs in diabetes have gained interest as potential cardioprotective approaches. A variety of agents have been developed which are examined in detail in this review. These include aminoguanidine, ALT-946, pyridoxamine, benfotiamine, OPB-9195, alagebrium chloride, N-phenacylthiazolium bromide and LR-90. In addition, it has been demonstrated that a number of established therapies have the ability to reduce the accumulation of AGEs in diabetes including ACE inhibitors, angiotensin receptor antagonists, metformin, peroxisome proliferators receptor agonists, metal chelators and some antioxidants. The fact that many of these inhibitors of AGEs are effective in experimental models, despite their disparate mechanisms of action, supports the keystone role of AGEs in diabetic vascular damage. Nonetheless, the clinical utility of AGE inhibition remains to be firmly established. Optimal metabolic and blood pressure control, that is achieved early and sustained indefinitely, remains the best recourse for inhibition of AGEs until more specific interventions become a clinical reality.
[Back
to top] Aldose Reductase in
Diabetic Microvascular Complications
S.S.M. Chung and S.K.
Chung
Most long-term diabetic patients develop microvascular diseases such as retinopathy, nephropathy and neuropathy. Although tight control of blood glucose greatly reduces the incidence of these complications, a significant fraction of diabetic patients with good glycemic control still develop these diseases. Therefore, it is imperative to understand the underlying mechanisms of these diseases such that effective treatment or preventive methods can be developed to augment euglycemic control. In animal studies, there is strong evidence that aldose reductase, the first and rate-limiting enzyme of the polyol pathway that converts glucose to fructose, plays a key role in the pathogenesis of microvascular complications. However, clinical trials of the aldose reductase inhibitors were disappointing and several pharmaceutical companies had abandoned the development of this line of drugs. In this review, the potential pathogenic mechanisms of the polyol pathway are presented, the evidence for the involvement of the polyol pathway in diabetic complications summarized, and the reasons for the unimpressive results of the clinical trials of the aldose inhibitors discussed. It appears that renewed efforts to develop aldose reductase inhibitors for the treatment and prevention of diabetic complications are warranted.
[Back
to top] Molecular Targets of
Diabetic Cardiovascular Complications
Fatima K. Ahmad,
Zhiheng He and George L. King
Both the macro- and microvascular complications adversely affect the life quality of patients with diabetes and have been the leading cause of mortality and morbidity in this population. With the advancement of technologies in biomedical research, we have gained a great deal of understanding of the mechanisms underlying these complications. While euglycemic control still remains the best strategy, it is often difficult to maintain at a level that can completely prevent the vascular complications. Therefore, it is necessary to use the processes leading to vascular dysfunction as a framework for designing novel molecular therapeutic targets. Several of the mechanisms by which diabetes induces vascular complications include increased flux through the polyol pathway, increased oxidative stress, activation of protein kinase C (PKC), vascular inflammation, and abnormal expression and actions of cytokines in the vasculature. Many of the therapies that target these pathways have proven successful in experimental models of diabetic complications. However, clinical studies using these treatments have mainly yielded inconclusive results. The pathogenesis of diabetic vascular complications and results from animal studies and key clinical studies are reviewed here.
[Back
to top] NAD(P)H Oxidase
Activation: A Potential Target Mechanism for Diabetic Vascular Complications,
Progressive b-Cell
Dysfunction and Metabolic Syndrome
Toyoshi Inoguchi and
Hajime Nawata
Both protein kinase C (PKC) activation and increased oxidative stress have been paid attention to as important causative factors for diabetic vascular complications. In this article, we show a PKC-dependent increase in oxidative stress in vascular tissues of diabetes and insulin resistant state. High glucose level and free fatty acids stimulate de novo diacylglycerol (DAG)-PKC pathway and subsequently stimulate reactive oxygen species (ROS) production through a PKC-dependent activation of NAD(P)H oxidase. Increasing evidence has also shown that NAD(P)H oxidase components are upregulated in micro- and macro- vascular tissues of animal models and patients of diabetes and obesity. It is also noted that increased intrinsic angiotensin II production may amplify such a PKC-dependent activation of NAD(P)H oxidase in diabetic vascular tissues. These mechanisms may play an important role in the diabetic vascular complications and the accelerated atherosclerosis associated with diabetes and obesity. In addition, recent reports have shown that NAD(P)H oxidases exist in pancreatic b-cells and adipocytes, and this oxidase-generated ROS production may play an important role in both the progressive b-cell dysfunction and the dysregulated adipocytokine production and subsequent obesity-induced metabolic syndrome. These results suggest that an NAD(P)H oxidase activation may be a useful therapeutic target for preventing diabetic vascular complications, progressive b-cell dysfunction and metabolic syndrome.
[Back
to top] Molecular Targets of
Diabetic Vascular Complications and Potential New Drugs
Roberto Da Ros,
Roberta Assaloni and Antonio Ceriello
In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite, that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications.
These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive “causal” antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionylcarnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This “causal” therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase ß isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.
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Growth Factor and Diabetic Retinopathy: Role of Oxidative Stress
Ruth B. Caldwell,
Manuela Bartoli, M. Ali Behzadian, Azza E.B. El-Remessy, Mohamed Al-Shabrawey,
Daniel H. Platt, Gregory I. Liou and R. William Caldwell
Retinal neovascularization and macular edema are central features of diabetic retinopathy, a major cause of blindness in working age adults. The currently established treatment for diabetic retinopathy targets the vascular pathology by laser photocoagulation. This approach is associated with significant adverse effects due the destruction of neural tissue and is not always effective. Characterization of the molecular and cellular processes involved in vascular growth and hyperpermeability has led to the recognition that the angiogenic growth factor and vascular permeability factor VEGF (vascular endothelial growth factor) play a pivotal role in the retinal microvascular complications of diabetes. Thus, VEGF represents an important target for therapeutic intervention in diabetic retinopathy. Agents that directly inhibit the actions of VEGF and its receptors show considerable promise, but have not proven to be completely effective in blocking pathological angiogenesis. Therefore, a better understanding of the molecular events that control VEGF expression and mediate its downstream actions is important to define more precise therapeutic targets for intervention in diabetic retinopathy. This review highlights the current understanding of the process by which VEGF gene expression is regulated and how VEGF’s biological effects are altered during diabetes. In particular, cellular and molecular alterations seen in diabetic models are considered in the context of high glucose-mediated oxidative stress effects on VEGF expression and action. Potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological actions in the diabetic retina are considered.
[Back
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Therapeutic Targets for Metabolic Syndrome
Kunihisa Kobayashi and
Toyoshi Inoguchi
For a long time it has been known that obesity (adiposity) is linked to insulin resistance. Recently, many investigators have reported that adipocytes secrete a variety of bioactive molecules, termed adipokines (adipocytokines), including TNFa, IL-6, leptin, adiponectin, resistin and so on. These adipokines play pivotal roles in energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolisms, food intake, the coagulation system and inflammation. This review provides a summary of these adipose tissue-secreting biomolecules and discusses their feasibilities as drug targets for the treatment of metabolic syndrome.