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      Effects of Silica on Mitochondrial Functions of the Proximal Tubule Cells in Rats

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          Abstract

          Aim: Despite the belief that silica (Si) is an inert and non-toxic ingredient, latest studies indicated that it is a potent mitochondria activator and Si-induced ROS generation is involved in the inflammatory reactions of silicotic lungs. Si cytotoxicity has been well studied in phagocytic cells, but its effects on the mitochondria of proximal tubule cells which are continuously exposed to filtered blood-borne soluble Si were not known. Methods: Using renal cortical slices and isolated mitochondria, the effect of high dietary Si on the mitochondrial functions of proximal tubule cells was studied in rats exposed to 50 mg/kg sodium metasilicate-containing water for 8 days. Results: Digested Si did not accumulate in kidney cortex, it was totally eliminated in the urine. Glomerular filtration rate as well as urine output were normal. Despite unaltered blood and cortex Si levels, ammonia production of cortical slices and isolated mitochondria was increased significantly and this was further increased by L-NAME pre-treatment. Elevated mitochondrial oxygen utilization was associated with increased ammonia production. Cyclosporin-A-sensitive mtPTP increase was associated with unchanged K<sub>ATP</sub> channels in the mitochondria of Si-exposed rats. Conclusion: These results suggested that dietary Si increases both extracellular and intracellular ammoniagenesis by elevating mitochondrial oxygen utilisation.

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          Most cited references 15

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          Mitochondria as a pharmacological target.

          Mitochondria play a central role in energy metabolism within the cell. Mitochondrial dysfunctions lead to various neurodegenerative disorders and to the so-called "mitochondrial diseases". A vast amount of evidence points to the implication of mitochondria in such complex processes as apoptosis and cardioprotection. The purpose of this review is to present a recent state of our knowledge and understanding of the action of various therapeutically applied substances on mitochondria. These include antitumor, immunosuppressant, and antiviral drugs, potassium channel openers, sulfonylureas, and anesthetics. Some of these substances are specifically designed to affect mitochondrial functions. In other cases, drugs with primary targets in other cellular locations may modify mitochondrial functions as side effects. In any case, identification of mitochondria as primary or secondary targets of a drug may help us to better understand the drug's mechanism of action and open new perspectives for its application. As far as possible, the molecular mechanisms of the interference of particular drugs in the mitochondrial metabolism will be described. In some cases, metabolic routes in which the drugs interfere will also be briefly outlined.
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            Glutamine and glutamate as vital metabolites

            Glucose is widely accepted as the primary nutrient for the maintenance and promotion of cell function. This metabolite leads to production of ATP, NADPH and precursors for the synthesis of macromolecules such as nucleic acids and phospholipids. We propose that, in addition to glucose, the 5-carbon amino acids glutamine and glutamate should be considered to be equally important for maintenance and promotion of cell function. The functions of glutamine/glutamate are many, i.e., they are substrates for protein synthesis, anabolic precursors for muscle growth, they regulate acid-base balance in the kidney, they are substrates for ureagenesis in the liver and for hepatic and renal gluconeogenesis, they act as an oxidative fuel for the intestine and cells of the immune system, provide inter-organ nitrogen transport, and act as precursors of neurotransmitter synthesis, of nucleotide and nucleic acid synthesis and of glutathione production. Many of these functions are interrelated with glucose metabolism. The specialized aspects of glutamine/glutamate metabolism of different glutamine-utilizing cells are discussed in the context of glucose requirements and cell function.
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              Silicic acid: its gastrointestinal uptake and urinary excretion in man and effects on aluminium excretion.

              Silicon (Si), as silicic acid, is suggested to be the natural antidote to aluminium (Al) toxicity, and was recently shown to promote the urinary excretion of Al from body stores. The metabolism of Si in man, however, remains poorly investigated. Here we report on the pharmacokinetics and metabolism of Si in healthy volunteers following ingestion of orthosilicic acid (27-55 mg/l Si) in water. We also investigated whether orthosilicic acid promotes the urinary excretion of endogenous Al. Minimum, median uptake of Si from the ingested dose was 50.3% (range: 21.9-74.7%, n = 8) based on urinary analysis following dosing. Significant correlations were observed between creatinine clearance and Si levels in serum or urine (r = 0.95 and 0.99, respectively). Renal clearance of Si was 82-96 ml/min suggesting high renal filterability. These results suggest that orthosilicic acid is readily absorbed from the gastrointestinal tract of man and then readily excreted in urine. There was no significant increase in Al excretion, over 32 h, following ingestion of the orthosilicic acid dose (P = 0.5; n = 5).
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                1420-4096
                1423-0143
                2005
                December 2005
                27 December 2005
                : 28
                : 4
                : 203-210
                Affiliations
                Akdeniz University, Medical Faculty, Department of Physiology, Kampus-Antalya, Antalya,Turkey
                Article
                86006 Kidney Blood Press Res 2005;28:203–210
                10.1159/000086006
                15925897
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 4, References: 31, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/86006
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