Endocrine, Metabolic & Immune Disorders - Drug Targets

ISSN: 1871-5303

Endocrine, Metabolic & Immune Disorders - Drug Targets
Volume 6, Number 1, March 2006

Contents


Metabolic Transformation and Mechanism of Action of Mononitroso Caffeidine- A New Interpretation Pp. 1-16
G.S. Panda, R.K. Bhattacharya and S.K. Choudhuri
[Abstract]


Family C 7TM Receptor Dimerization and Activation Pp. 7-16
M.M. Bonde, S.P. Sheikh and J.L. Hansen
[Abstract]


Matrix Metalloproteinases in Cancer Metastasis: Molecular Targets for Prostate Cancer Prevention by Green Tea Polyphenols and Grape Seed Proanthocyanidins Pp. 17-24
S.K. Katiyar
[Abstract]


Recent Advances on Neural Tube Defects with Special Reference to Valproic Acid Pp. 25-31
A. Verrotti, M. Tana, P. Pelliccia, F. Chiarelli and G. Latini
[Abstract]


Selective Modulators of PPAR Activity as New Therapeutic Tools in Metabolic Diseases Pp. 33-43
B.L. Balint and L. Nagy
[Abstract]


Activin Receptor-Like Kinases: Structure, Function and Clinical Implications Pp. 45-58
H. Graham and C. Peng
[Abstract]


The Roles of Parathyroid Hormone and Calcitonin in Bone Remodeling: Prospects for Novel Therapeutics Pp. 59-76
P.H. Carter and E. Schipani
[Abstract]


Role of Antioxidants, Essential Fatty Acid, Carnitine, Vitamins, Phytochemicals and Trace Elements in the Treatment of Diabetes Mellitus and its Chronic Complications Pp. 77-93
V. Triggiani, F. Resta, E. Guastamacchia, C. Sabbà, B. Licchelli, S. Ghiyasaldin and E. Tafaro
[Abstract]


Roles of Type 10 17beta-Hydroxysteroid Dehydrogenase in Intracrinology and Metabolism of Isoleucine and Fatty Acids Pp. 95-102
X.-Y. He and S.-Y. Yang
[Abstract]


Targeting Type 1 Diabetes Before and at the Clinical Onset of Disease Pp. 103-124
L.M. Bekris, T.J. Kavanagh and A. Lernmark
[Abstract]




Abstracts

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Metabolic Transformation and Mechanism of Action of Mononitroso Caffeidine- A New Interpretation
G.S. Panda, R.K. Bhattacharya and S.K. Choudhuri

Although caffeine is not carcinogenic, its hydrolysed product, caffeidine causes human cancer, possibly through endogenous nitrosation to form mononitroso caffeidine (MNC). MNC undergoes enzymatic demethylation and reacts with cellular nucleophiles, notably DNA, via the formation of a putative imidazole diazonium ion. Its interaction with proteins has not been reported. The present work is based on the hypothesis that some active metabolites of MNC covalently interact with cellular DNA and/or proteins to initiate carcinogenesis. We report here the synthesis of a possible reactive metabolite of MNC, viz., N, 1-methyl-4(N-methyl-N-nitrosamino)-imidazole-5-carboxylic acid (MNIC). Its structure has been determined by uv, ir, nmr and mass spectral analyses and its interaction with egg albumin and human serum protein has been examined by uv and CD spectroscopy. We concluded that metabolic activation of MNC occurs through the formation of MNIC. Avoiding consumption of salted tea or coffee that prevents the intake of caffeidine will possibly eliminate the risk of MNC carcinogenicity.


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Family C 7TM Receptor Dimerization and Activation
M.M. Bonde, S.P. Sheikh and J.L. Hansen

The family C seven transmembrane (7TM) receptors constitutes a small and especially well characterized subfamily of the large 7TM receptor superfamily. Approximately 50% of current prescription drugs target 7TM receptors, this biologically important family represents the largest class of drug-targets today. It is well established that family C 7TM receptors form homo- or hetero-dimers on the cell surface of living cells. The large extra-cellular domains (ECD) have been crystallized as a dimer in the presence and absence of agonist. Upon agonist binding, the dimeric ECD undergoes large conformational changes that lead to receptor activation. Despite extensive studies of the receptor transmembrane domain, several key features, including the exact organization of the complete receptor dimer, the sequence of events leading to receptor activation, and the functional significance of dimerization, have yet to be fully defined. This review presents the biochemical support for family C 7TM receptor dimerization and discusses its importance for receptor biosynthesis, surface expression, ligand binding and activation, since lessons learnt here may well be applicable to the whole superfamily of 7TM receptors.


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Matrix Metalloproteinases in Cancer Metastasis: Molecular Targets for Prostate Cancer Prevention by Green Tea Polyphenols and Grape Seed Proanthocyanidins
S.K. Katiyar

Matrix metalloproteinases (MMP) play a crucial role in the development and metastatic spread of cancer. One of the earliest events in the metastatic spread of cancer is the invasion through the basement membrane and proteolytic degradation of the extracellular matrix proteins, such as, collagens, laminin, elastin and fibronectin etc, and non-matrix proteins. MMPs are the important regulators of tumor growth, both at the primary site and in distant metastases. Given the clear implications of MMPs in many human cancers, MMPs remain important targets of cancer therapy. Metastatic spread of cancer continues to be the greatest barrier in prevention or cure of cancer. The recognition that MMPs facilitate tumor cell growth, invasion and metastasis of cancer has led to the development of MMP inhibitors as cancer therapeutic agents. Understanding the molecular mechanism of metastasis is also crucial for the design and effective use of novel therapeutic strategies to combat metastases. In this short review article, we discuss the evidences that MMPs are associated with cancer metastasis and that they make a functional contribution to the process. Further, since considerable interest among human population is increasing with regard to the use of dietary botanical supplements for the prevention of age-associated diseases like some forms of cancer, we also discuss the beneficial effects of dietary botanicals, such as green tea polyphenols and grape seed proanthocyanidins, in chemoprevention of cancer with particular emphasis on the involvement of MMPs in prostate cancer.


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Recent Advances on Neural Tube Defects with Special Reference to Valproic Acid
A. Verrotti, M. Tana, P. Pelliccia, F. Chiarelli and G. Latini

Epilepsy is a common medical problem and many studies have demostrated that infants of women with epilepsy (WWE) have a two to threefold higher risk of congenital malformations compared with the background population. The majority of WWE have normal, healthy children. However, WWE have an increased risk of congenital malformations. Congenital malformations are twice as common in infants exposed to antiepilectic drugs in utero. A variety of congenital malformations have been reported, with a particular preponderance of orofacial clefts. Valproate is often associated with the development of neural tube defects.

In this review, we analyse the problem of neural tube defects and report in detail the main pathogenetic theories about the onset of this type of congenital malformation. There is strong evidence for a protective effect of adequate folate consumption.


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Selective Modulators of PPAR Activity as New Therapeutic Tools in Metabolic Diseases
B.L. Balint and L. Nagy

Peroxisome Proliferator Activated Receptors (PPARs) are regulators of metabolic pathways mainly of lipid metabolism and energy balance. Their medical importance is given by the fact that they have been implicated in development of insulin resistance, obesity and atherosclerosis. In recent years, major progress has been made in understanding the molecular basis of the function of these receptors. As a result of structural studies and identification of putative natural as well as synthetic ligands and activators of PPARs a new concept emerged and new drugs are on their ways to the clinic. The concept of Selective PPAR Modulators (SPPARM) was suggested by analogy to Selective Estrogen Receptor Modulators (SERM). SPPARMs activate the receptors in distinct ways leading to differential gene expression and biological response. The key features in understanding their action is most likely at the molecular details of ligand binding and the subsequently induced conformational changes as well as cofactor binding. A key aspect of this is that unlike classical steroid hormone receptors such as the retinoic acid receptor, the PPAR receptors have a rather large ligand-binding pocket which is not filled with the ligand entirely and the ligand also stabilizes the receptor’s structure. The liganded receptor can have distinct conformations and this leads to different binding affinities for the various cofactors (coactivators and corepressors). In this review, we will introduce this concept, review the literature that supports it and present an overview of the receptor selective ligands including data about their mechanism of action and biological effects.


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Activin Receptor-Like Kinases: Structure, Function and Clinical Implications
H. Graham and C. Peng

The transforming growth factor-β (TGF-β) superfamily regulates a multitude of cellular processes from fertilization to adulthood in vertebrates. Signaling by the TGF-β superfamily occurs via formation of heteromeric complexes consisting of type I and type II receptors. The type I receptors, referred to as activin receptor-like kinases (ALK), lie at the epicenter of the signaling cascade as they transduce TGF-β signals to intracellular regulators of transcription known as Smad proteins. Currently, seven ALKs have been identified in mammals. Structurally, ALKs possess an extracellular binding domain, a transmembrane domain, a GS domain that serves as the site of activation by type II receptors, and a kinase domain that activates downstream signaling molecules. ALKs mediate the effect of TGF-β superfamily on a variety of cellular processes such as proliferation, differentiation, apoptosis, adhesion and migration, and therefore play important roles in many biological processes. Some ALKs have been implicated in several disorders, including tumorigenesis, hemorrhagic telangiectasia (HHT), immune and renal diseases, and skeletal malfunctions, suggesting that these receptors can be used as drug targets.


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The Roles of Parathyroid Hormone and Calcitonin in Bone Remodeling: Prospects for Novel Therapeutics
P.H. Carter and E. Schipani

Inappropriate regulation of the bone resorption and bone formation processes that occur as a normal part of bone remodeling can lead to net bone loss, as found in osteoporosis. Parathyroid hormone (PTH) and calcitonin (CT) are two peptide hormones that play important roles in calcium homeostasis through their actions on osteoblasts (bone forming cells) and osteoclasts (bone resorbing cells), respectively. Paradoxically, even though genetic deletion of either PTH or CT produces mice with increased bone mass (presumably through different mechanisms), derivatives of both PTH and CT have now been approved for clinical use in the treatment of bone loss in osteoporosis.

In this review, we focus on the biology and pharmacology of these two peptides. Specifically, we sequentially address the following three topics in detail: (1) the biological mechanisms of action of PTH and CT, focusing on data from in vitro studies and animal models; (2) the clinical utility of PTH and CT in treating osteoporosis, examining how their pharmacological efficacy correlates with our understanding of their biological mechanism of action; and (3) future prospects for combination therapy, alternative formulation of PTH and CT into oral and transdermal therapies, and replacement of PTH and CT with modified peptides or small molecules. The past four years have witnessed dramatic advances in each of these three areas, and the review places in context the challenges that lie ahead for this complicated, but clinically-relevant field.


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Role of Antioxidants, Essential Fatty Acid, Carnitine, Vitamins, Phytochemicals and Trace Elements in the Treatment of Diabetes Mellitus and its Chronic Complications
V. Triggiani, F. Resta, E. Guastamacchia, C. Sabbà, B. Licchelli, S. Ghiyasaldin and E. Tafaro

Nowadays, the treatment of diabetes mellitus is based on the variable use and combination of diet, antidiabetic oral agents (metformin, sulphanylureas, glynides, acarbose and thiazolidinediones) and insulin or its analogs, depending on the type of diabetes and the needs of the patient. The prevention and treatment of chronic micro- and macrovascular complications, on the other hand, is based on the achievement and manteinance of an optimal glycaemic control and requires the combined use of adjunctive therapy such as antihypertensive drugs and cholesterol-lowering medications. Furthermore, several herbal preparations and dietary supplements, such as antioxidants, essential fatty acids, lipid metabolism activators, vitamins and trace elements, are advertised and prescribed to patients as a useful adjuvant to a diabetic diet and conventional medications in order to improve glycaemic control and reduce the impact of chronic complications. In this regard, we have attempted to review the current concepts dealing with the usefulness of these complementary therapies in treating diabetic patients.


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Roles of Type 10 17beta-Hydroxysteroid Dehydrogenase in Intracrinology and Metabolism of Isoleucine and Fatty Acids
X.-Y. He and S.-Y. Yang

Human type 10 17β-hydroxysteroid dehydrogenase (HSD) is a homotetrameric protein located in mitochondria. This enzyme was alternatively named short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHSD). This NAD(H)-dependent dehydrogenase is essential for the metabolism of branched-chain fatty acids and isoleucine, and is expressed in a variety of tissues, e.g., prostate, brain, liver, and heart. This enzyme inactivates 17β-estradiol and exhibits a strong oxidative 3α-HSD activity to convert 5α-androstanediol and allopregnanolone into 5α-dihydrotestosterone (5α-DHT) and 5α-dihydroprogesterone, respectively, in living cells. Certain malignant prostatic epithelial cells and activated astrocytes in Alzheimer’s disease patient's brain contain extraordinarily high levels of this enzyme. This mitochondrial dehydrogenase enables prostate cancer cells to generate 5α-DHT in the absence of testosterone. Its inactivation of allopregnanolone is important to the modulation of GABA(A) receptor. Among steroidogenic enzymes 17β-HSD10 plays a significant part in the intracrinology. Although this protein has an affinity for amyloid-β peptide, its role in the pathogenesis of Alzheimer's disease is far from clear. Additional knowledge of this versatile enzyme would provide the foundation for designing new drugs aimed at treating some neurological diseases and certain types of cancers.


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Targeting Type 1 Diabetes Before and at the Clinical Onset of Disease
L.M. Bekris, T.J. Kavanagh and A. Lernmark

Autoimmune type 1 diabetes is strongly associated with a number of immune abnormalities that manifest themselves before and at the time of clinical diagnosis. The clinical onset is associated with a major loss of the pancreatic islet beta cells. Insulin treatment is the only treatment option since numerous trials with agents that suppress or modulate immune function have failed to preserve beta cell function long term. Recent studies suggest that it is possible to predict clinical onset of diabetes by combining genetic with autoantibody testing. In this review we will summarize current and future drug targets for subjects at risk for type 1 diabetes as well as for subjects with recent onset disease. We will also discuss the possible importance of initiating as well as contributing factors such as reactive oxygen species and modified autoantigens. It is speculated that drug targets of factors important to disease pathogenesis may provide safe and effective adductive treatment to preservebeta cell function in autoantibody positive subjects who are at maximum risk for disease.