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1.
Curr Med Chem ; 23(19): 2018-40, 2016.
Article in English | MEDLINE | ID: mdl-26769095

ABSTRACT

Kidney damage can be induced by ischemia, autoimmune diseases, hypertension, allograft rejection, metabolic or genetic disorders, infections or toxins. The influence of these factors could result in acute kidney injury (AKI) defined as an unexpected decrease in urine output or renal function, or encourage the development of chronic kidney disease (CKD). Biomarkers of renal function, measured in urine and serum, are in increasing use in order to estimate the severity and nature of kidney injury, and consequently apply appropriate therapy and improve patient management. The determined values of biomarkers can suggest the potential risk of kidney disease and the type of renal injury, predict the disease progression, as well as be helpful for assessing the response to an applied therapy. Although novel biomarkers are in practical use, serum creatinine, the indicator of glomerular filtration rate is still the most frequently used biomarker of renal function despite its known limitations. In recent decades, numerous studies resulted in discovering urinary and serum proteins that can serve as biomarkers for early and accurate detection of AKI and its development, as well as the identification of CKD. This review gives an overview of the most important renal biomarkers investigated in kidney diseases, classified in following types: functional biomarkers, up-regulated proteins, enzymes, and cycle arrest biomarkers. It describes their properties, physiological roles, and discusses the utility of these molecules in different clinical settings.


Subject(s)
Biomarkers/analysis , Kidney/metabolism , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Biomarkers/metabolism , Cell Cycle Proteins/metabolism , Creatinine/blood , Cystatin C/urine , Enzymes/metabolism , Hepatitis A Virus Cellular Receptor 1/metabolism , Humans , Lipocalin-2/metabolism , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/pathology
2.
Biomolecules ; 5(1): 121-41, 2015 Feb 13.
Article in English | MEDLINE | ID: mdl-25689234

ABSTRACT

Peroxisomal biogenesis and function critically depends on the import of cytosolic proteins carrying a PTS1 sequence into this organelle upon interaction with the peroxin Pex5p. Recent structural studies have provided important insights into the molecular recognition of cargo proteins by Pex5p. Peroxisomal import is a key feature in the pathogenesis of primary hyperoxaluria type 1 (PH1), where alanine:glyoxylate aminotransferase (AGT) undergoes mitochondrial mistargeting in about a third of patients. Here, we study the molecular recognition of PTS1 cargo proteins by Pex5p using oligopeptides and AGT variants bearing different natural PTS1 sequences, and employing an array of biophysical, computational and cell biology techniques. Changes in affinity for Pex5p (spanning over 3-4 orders of magnitude) reflect different thermodynamic signatures, but overall bury similar amounts of molecular surface. Structure/energetic analyses provide information on the contribution of ancillary regions and the conformational changes induced in Pex5p and the PTS1 cargo upon complex formation. Pex5p stability in vitro is enhanced upon cargo binding according to their binding affinities. Moreover, we provide evidence that the rational modulation of the AGT: Pex5p binding affinity might be useful tools to investigate mistargeting and misfolding in PH1 by pulling the folding equilibria towards the native and peroxisomal import competent state.


Subject(s)
Hyperoxaluria, Primary/metabolism , Oligopeptides/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , CHO Cells , Cricetinae , Cricetulus , Entropy , Humans , Models, Molecular , Mutation , Oligopeptides/chemistry , Peptide Fragments/metabolism , Peroxisome-Targeting Signal 1 Receptor , Protein Stability , Protein Structure, Tertiary , Protein Transport , Receptors, Cytoplasmic and Nuclear/chemistry , Transaminases/genetics , Transaminases/metabolism
3.
Perspect Biol Med ; 54(3): 332-53, 2011.
Article in English | MEDLINE | ID: mdl-21857125

ABSTRACT

Traits expected to be lost in the evolutionary history of a species occasionally reappear apparently out of the blue. Such traits as extra nipples or tails in humans, hind limbs in whales, teeth in birds, or wings in wingless stick insects remind us that certain genetic information is not completely lost, but can be reactivated. Atavisms seem to violate one of the central evolutionary principles, known as Dollo's law, that "an organism is unable to return, even partially, to a previous stage already realized in the ranks of its ancestors." Although it is still not clear what triggers and controls the reactivation of dormant traits, atavisms are a challenge to evolutionary biologists and geneticists. This article presents some of the more striking examples of atavisms, discusses some of the currently controversial issues like human quadrupedalism, and reviews the progress made in explaining some of the mechanisms that can lead to atavistic features.


Subject(s)
Biological Evolution , Mutation , Selection, Genetic , Animals , Body Patterning , Epigenesis, Genetic , Female , Gene Expression Regulation, Developmental , Gene Regulatory Networks , Genes, Regulator , Humans , Male , Phenotype , Phylogeny , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism
4.
Z Naturforsch C J Biosci ; 64(1-2): 103-8, 2009.
Article in English | MEDLINE | ID: mdl-19323274

ABSTRACT

The reaction between [PtCl2(DMSO)2] and L-cysteine (L-Cys) has been investigated in the presence of micelles of sodium dodecyl sulfate (SDS)--as a model for biological membranes. Additionally, the inhibitory effect of [PtCl2(DMSO)2] on the Na+,K+-ATPase activity and its partial prevention with 10 mM L-Cys were demonstrated. The interaction of L-Cys with [PtCl2(DMSO)2] resulted in the formation of a [Pt(DMSO)2(L-Cys)2]2+ (DMSO)2] complex, which most probably occurs through stepwise replacement of Cl(-) with L-Cys. It has also been demonstrated that neither the pH value nor SDS affects the composition of the new complex. On the other hand, the pH value and SDS do affect the reaction rate, most probably due to electrostatic interactions with reactants. In summary, this study can be used as a simple model approach for the investigation of reaction mechanisms between platinum complexes and various biomolecules, and for the determination of potential toxicity and/or side effects of antitumour platinum drugs.


Subject(s)
Cysteine/chemistry , Platinum/chemistry , Platinum/toxicity , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Brain/enzymology , Cisplatin/chemistry , Dimethyl Sulfoxide/chemistry , Dimethyl Sulfoxide/toxicity , Sodium-Potassium-Exchanging ATPase/metabolism , Spectrophotometry , Spectrophotometry, Ultraviolet
5.
J Enzyme Inhib Med Chem ; 21(4): 471-5, 2006 Aug.
Article in English | MEDLINE | ID: mdl-17059183

ABSTRACT

The in vitro influence of potassium ion modulations, in the concentration range 2 mM-500 mM, on digoxin-induced inhibition of porcine cerebral cortex Na+ / K+-ATPase activity was studied. The response of enzymatic activity in the presence of various K+ concentrations to digoxin was biphasic, thereby, indicating the existence of two Na+ / K+-ATPase isoforms, differing in the affinity towards the tested drug. Both isoforms showed higher sensitivity to digoxin in the presence of K+ ions below 20 mM in the medium assay. The IC50 values for high/low isoforms 2.77 x 10(-6) M / 8.56 x 10(-5) M and 7.06 x 10(-7) M / 1.87 x 10(-5) M were obtained in the presence of optimal (20 mM) and 2 mM K+, respectively. However, preincubation in the presence of elevated K+ concentration (50-500 mM) in the medium assay prior to Na+ / K+-ATPase exposure to digoxin did not prevent the inhibition, i.e. IC50 values for both isoforms was the same as in the presence of the optimal K+ concentration. On the contrary, addition of 200 mM K+ into the medium assay after 10 minutes exposure of Na+ / K+-ATPase to digoxin, showed a time-dependent recovery effect on the inhibited enzymatic activity. Kinetic analysis showed that digoxin inhibited Na+ / K+-ATPase by reducing maximum enzymatic velocity (Vmax) and Km, implying an uncompetitive mode of interaction.


Subject(s)
Cerebral Cortex/enzymology , Digoxin/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Ions , Potassium/chemistry , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/chemistry , Adenosine Triphosphatases/chemistry , Animals , Dose-Response Relationship, Drug , Drug Design , Inhibitory Concentration 50 , Models, Chemical , Protein Isoforms , Swine
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