Chromogranin A as a Calcium-Binding Precursor for a Multitude of Regulatory Peptides for the Immune, Endocrine and Metabolic Systems Pp. 119-140
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An Update of Acyl-CoA:
Cholesterol Acyltransferase Inhibition in Animal and Human In Vitro and In Vivo
Models of Atherosclerosis
Pp-141-150
J. Wu, R. Doshi and A. Rodriguez
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On the Role of Neuropeptides in the Hypothalamic Regulation of Food Intake Pp-151-169
Richard
M. Söll and Annette G. Beck-Sickinger
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Changes in Immune and Endocrine Systems in Scrapie-Infected Animals Pp-171-184
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Discovery and Advancement of Farnesyl Transferase Inhibitors as Potential Anticancer Therapeutic Agents: SCH 66336 a Case Study Pp-185-198
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Chromogranin A as a Calcium-Binding Precursor for a Multitude of Regulatory
Peptides for the Immune, Endocrine and Metabolic Systems
A multitude of regulatory peptides derive from the main members of the “granin” family, i.e. the chromogranins A (CGA) and B (CGB) and secretogranin II. These proteins are co-secreted from the diffuse neuroendocrine system with a wide range of neurotransmitters and peptide hormones upon adequate stimuli. The recent developments provide ample evidence of widely different effects and targets for the CGA derived peptides, implicated in the regulation of plasma calcium, plasma glucose, adrenomedullary catecholamine release and vascular contractility, as well as in the innate immunity. This review aims to attract the attention of endocrinologists and immunologists to this novel family of regulatory peptides, notably those derived from CGA.The main emphasis has been placed on functional aspects of the precursor protein and the biologically active peptides, such as the vasostatins I and II, pancreastatin and catestatin. The majority of properties so far assigned to this calcium binding prohormone and its peptide derivatives fits into patterns of inhibitory effects, of postulated relevance not only for homeostatic processes, but also in the inflammatory response and the early defence against invading microorganisms.
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An Update of Acyl-CoA: Cholesterol Acyltransferase Inhibition in Animal and
Human In Vitro and In Vivo Models of Atherosclerosis
Acyl-CoA: cholesterol acyltransferase (ACAT) catalyzes the intracellular esterification of free cholesterol (FC) to cholesteryl ester (CE). Two subtypes of ACAT enzymes (ACAT1 and ACAT2) play important roles in lipoprotein assembly from the intestine and liver and intracellular CE accumulation in foam cell formation within vessel walls. Since hypercholesterolemia and foam cell formation are integral to the development of atherosclerosis, many ACAT inhibitors with varying activities against ACAT1 and 2 have been designed and studied for their effects on atherosclerosis. Indeed, these inhibitors lower cholesterol plasma levels and reduce atherosclerosis in animal models. However, in vitro and in vivo studies have suggested that ACAT inhibition could be adrenal toxic in animals and cytotoxic to rodent macrophage foam cells. Cytotoxicity has been linked to excess accumulation of intracellular FC content. In addition, double knockout mice with congenital hyperlipidemia and ACAT1 deficiency have increased extracellular accumulation of FC. These results contrast with in vitro studies examining the effects of ACAT inhibitors on cultured primary human macrophage foam cells. In addition, human subjects treated with ACAT inhibitors appear to tolerate the compound and have not shown signs of toxicity. This review addresses the toxicity concerns of ACAT inhibition and compares and contrasts the in vitro and in vivo studies of ACAT inhibition between experimental animal and human models.
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On the Role of Neuropeptides
in the Hypothalamic Regulation of Food Intake
Neuropeptides are molecules of outstanding importance in
the regulation of most different physiological and biochemical processes. They
act as signal transducting molecules that makes them an ideal target for
pharmacological treatment. Because of their possibility to act via different
receptor subtypes within a whole receptor family, the peptides are able to
selectively induce physiological processes. Therefore, peptide research
provides important contributions to a detailed understanding of physiological
processes. The hypothalamic regulation of food intake reveals a redundant
system of neuropeptides, acting and interacting with each other in order to
control energy homeostasis and body weight. Leptin and insulin are peripheral
adiposity signals, inducing first order neuronal signalling in the arcuate
nucleus of the hypothalamus. There, they inhibit anabolic peptides, whereas
they stimulate catabolic peptides. Neurons from the arcuate nucleus project to
candidate second-order neurons involved in hypothalamic response to leptin and
insulin, located in the paraventricular nucleus and the lateral hypothalamic
and perifornical area. However, anomalies in body weight, especially overweight
and obesity, are not only genetically determined, but also by the environment.
Cultural, socioeconomic and psychosocial factors, physical activity and other
environmental factors are known for sustained influence of body weight.
Medicinal chemistry importantly contributes to the molecular understanding of
anomalies and diseases, which likely culminates in the development of
appropriate medical treatments. Hereby, the development of receptor subtype
selective agonists and antagonists is a key step. This is exemplified on a set
of hypothalamic neuropeptides which are involved in the regulation of food
intake.
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Changes in Immune and Endocrine
Systems in Scrapie-Infected Animals
Scrapie is a slowly developing neurodegenerative disease occurring naturally in sheep and goats. The spectacular crisis involving TSE infection of cattle in the United Kingdom, has been followed by a chain of published speculations linking sheep Scrapie to bovine TSE (BSE or "mad cow" disease), and finally there are suggestions of a link between BSE and human new variant Creutzfeldt-Jakob disease (nvCJD). Although the number of people ultimately affected by the health effects of nvCJD cannot be predicted, the economic repercussions have been enormous. The TSE agents can be contaminants of products derived from blood and have been inadvertently added to animal food. Although such blood-borne or food-borne TSE agents have been proposed to be of immediate concern for human health following the United Kingdom BSE epidemic, a great deal of basic research on TSE pathophysiology remains to be conducted.
Neurotoxicants are generally considered to be
"exogenous" factors that affect normal metabolism of the central
nervous system. However, certain naturally occurring substances such as free
radicals, steroids, excitatory amino acids, cytokines, and amyloids may be
toxic to the central nervous system, and therefore can be considered as
"endogenous" neurotoxicants. Since these endogenous neurotoxicants
may accumulate in the brain due to the disruption of the normal protein
metabolic processes, they are of considerable interest to the public health
community. In this review we will emphasize that prion protein, as a special
metabolic agent, causes changes in immune and endocrine systems, which are a
function of pathology of the nervous system.
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Discovery and Advancement of
Farnesyl Transferase Inhibitors as Potential Anticancer Therapeutic Agents:
SCH 66336 a Case Study
Over the last two decades, we have seen intensive drug discovery efforts aimed at developing cancer therapeutics that specifically target the underlying defects in cellular growth regulation. By virtue of their specificity, these gene-targeted therapeutics are anticipated to be more effective and less toxic than the currently used chemotherapeutic agents. Among the oncogenes associated with human cancers, the ras oncogenes stand out as particularly attractive targets for creation of cancer therapeutics. These genes have been implicated in upto 30% of human cancers and are most commonly found in pancreatic cancer, colon cancer, and adenocarcinoma of the lung. The ras proto-oncogene encodes a 21-kd GTP-binding protein Ras, which is critical in cellular signal transduction associated with cell proliferation. To function in this signal transduction process, Ras must localize to the plasma membrane. A key step in this translocation is the post translational farnesylation of the cysteine residue near the carboxyl-terminal of Ras that is effected by the enzyme, farnesyl protein transferase. Inhibition of Ras farnesylation is therefore a promising approach for developing mechanism-based anticancer drugs.