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1.
Proc Natl Acad Sci U S A ; 121(5): e2308776121, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38252831

RESUMO

We present a drug design strategy based on structural knowledge of protein-protein interfaces selected through virus-host coevolution and translated into highly potential small molecules. This approach is grounded on Vinland, the most comprehensive atlas of virus-human protein-protein interactions with annotation of interacting domains. From this inspiration, we identified small viral protein domains responsible for interaction with human proteins. These peptides form a library of new chemical entities used to screen for replication modulators of several pathogens. As a proof of concept, a peptide from a KSHV protein, identified as an inhibitor of influenza virus replication, was translated into a small molecule series with low nanomolar antiviral activity. By targeting the NEET proteins, these molecules turn out to be of therapeutic interest in a nonalcoholic steatohepatitis mouse model with kidney lesions. This study provides a biomimetic framework to design original chemistries targeting cellular proteins, with indications going far beyond infectious diseases.


Assuntos
Influenza Humana , Vírus , Animais , Camundongos , Humanos , Proteoma , Peptídeos/farmacologia , Descoberta de Drogas
2.
EBioMedicine ; 93: 104635, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37285616

RESUMO

BACKGROUND: Urinary biomarkers may improve the prediction of chronic kidney disease (CKD) progression. Yet, data reporting the applicability of most commercial biomarker assays to the detection of their target analyte in urine together with an evaluation of their predictive performance are scarce. METHODS: 30 commercial assays (ELISA) were tested for their ability to quantify the target analyte in urine using strict (FDA-approved) validation criteria. In an exploratory analysis, LASSO (Least Absolute Shrinkage and Selection Operator) logistic regression analysis was used to identify potentially complementary biomarkers predicting fast CKD progression, determined as the 51CrEDTA clearance-based measured glomerular filtration rate (mGFR) decline (>10% per year) in a subsample of 229 CKD patients (mean age, 61 years; 66% men; baseline mGFR, 38 mL/min) from the NephroTest prospective cohort. FINDINGS: Among the 30 assays, directed against 24 candidate biomarkers, encompassing different pathophysiological mechanisms of CKD progression, 16 assays fulfilled the FDA-approved criteria. LASSO logistic regressions identified a combination of five biomarkers including CCL2, EGF, KIM1, NGAL, and TGF-α that improved the prediction of fast mGFR decline compared to the kidney failure risk equation variables alone: age, gender, mGFR, and albuminuria. Mean area under the curves (AUC) estimated from 100 re-samples was higher in the model with than without these biomarkers, 0.722 (95% confidence interval 0.652-0.795) vs. 0.682 (0.614-0.748), respectively. Fully-adjusted odds-ratios (95% confidence interval) for fast progression were 1.87 (1.22, 2.98), 1.86 (1.23, 2.89), 0.43 (0.25, 0.70), 1.10 (0.71, 1.83), 0.55 (0.33, 0.89), and 2.99 (1.89, 5.01) for albumin, CCL2, EGF, KIM1, NGAL, and TGF-α, respectively. INTERPRETATION: This study provides a rigorous validation of multiple assays for relevant urinary biomarkers of CKD progression which combination may improve the prediction of CKD progression. FUNDING: This work was supported by Institut National de la Santé et de la Recherche Médicale, Université de Paris, Assistance Publique Hôpitaux de Paris, Agence Nationale de la Recherche, MSDAVENIR, Pharma Research and Early Development Roche Laboratories (Basel, Switzerland), and Institut Roche de Recherche et Médecine Translationnelle (Paris, France).


Assuntos
Insuficiência Renal Crônica , Fator de Crescimento Transformador alfa , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Prognóstico , Lipocalina-2 , Estudos Prospectivos , Fator de Crescimento Epidérmico , Progressão da Doença , Biomarcadores/urina , Taxa de Filtração Glomerular
3.
J Hepatol ; 78(3): 479-492, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36334688

RESUMO

BACKGROUND & AIMS: The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). METHODS: This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12. RESULTS: One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively. CONCLUSIONS: In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit. CLINICAL TRIAL NUMBER (EUDRACT): 2018-003119-22. GOV IDENTIFIER: NCT03812029. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Fígado/patologia , Cirrose Hepática/complicações , Peso Corporal , Rim , Método Duplo-Cego , Resultado do Tratamento
4.
Commun Biol ; 5(1): 437, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538231

RESUMO

Elevated levels of mitochondrial iron and reactive oxygen species (ROS) accompany the progression of diabetes, negatively impacting insulin production and secretion from pancreatic cells. In search for a tool to reduce mitochondrial iron and ROS levels, we arrived at a molecule that destabilizes the [2Fe-2S] clusters of NEET proteins (M1). Treatment of db/db diabetic mice with M1 improved hyperglycemia, without the weight gain observed with alternative treatments such as rosiglitazone. The molecular interactions of M1 with the NEET proteins mNT and NAF-1 were determined by X-crystallography. The possibility of controlling diabetes by molecules that destabilize the [2Fe-2S] clusters of NEET proteins, thereby reducing iron-mediated oxidative stress, opens a new route for managing metabolic aberration such as in diabetes.


Assuntos
Diabetes Mellitus Experimental , Proteínas Ferro-Enxofre , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Ferro/metabolismo , Proteínas Ferro-Enxofre/química , Camundongos , Proteínas Mitocondriais/metabolismo , Espécies Reativas de Oxigênio/metabolismo
5.
J Viral Hepat ; 28(12): 1690-1698, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34467593

RESUMO

The nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR agonist treatment leads to inhibition of viral replication and a decline in viral proteins, pregenomic RNA (pgRNA) and HBV DNA levels. We aimed to translate this to a clinical use by primarily evaluating the safety and secondary the anti-viral effect of Vonafexor, a FXR agonist, in chronic hepatitis B (CHB) patients. In total, 73 CHB patients were enrolled in a two-part Phase Ib double-blind, placebo-controlled trial. Patients were randomized to receive oral Vonafexor (100, 200 and 400 mg once daily, or 200 mg twice daily), placebo, or entecavir (Part A, n = 48) or to receive Vonafexor (300 mg once daily or 150 mg twice daily), or placebo, combined with pegylated-interferon-α2a (Part B, n = 25) for 29 days. Patients were followed up for 35 days. Enrolled CHB patients were mostly HBeAg-negative. Vonafexor was overall well tolerated and safe. The most frequent adverse events were moderate gastrointestinal events. Pruritus was more frequent with twice-daily compared with once-daily regimens (56%-67% vs. 16%, respectively, p < 0.05). Vonafexor monotherapy of 400 mg once daily decreased HBsAg concentrations (-0.1 log10  IU/mL, p < 0.05), and Vonafexor/pegylated-IFN-α2a combination therapy decreased HBcrAg and pgRNA. In conclusion, Vonafexor was safe with a decline in HBV markers observed in CHB patients suggesting a potential anti-viral effect the therapeutic potential of which has to be evaluated in larger trials.


Assuntos
Hepatite B Crônica , Preparações Farmacêuticas , Antivirais/efeitos adversos , DNA Viral , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos
7.
PLoS Pathog ; 17(2): e1009340, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33596274

RESUMO

Influenza virus infections are major public health threats due to their high rates of morbidity and mortality. Upon influenza virus entry, host cells experience modifications of endomembranes, including those used for virus trafficking and replication. Here we report that influenza virus infection modifies mitochondrial morphodynamics by promoting mitochondria elongation and altering endoplasmic reticulum-mitochondria tethering in host cells. Expression of the viral RNA recapitulates these modifications inside cells. Virus induced mitochondria hyper-elongation was promoted by fission associated protein DRP1 relocalization to the cytosol, enhancing a pro-fusion status. We show that altering mitochondrial hyper-fusion with Mito-C, a novel pro-fission compound, not only restores mitochondrial morphodynamics and endoplasmic reticulum-mitochondria contact sites but also dramatically reduces influenza replication. Finally, we demonstrate that the observed Mito-C antiviral property is directly connected with the innate immunity signaling RIG-I complex at mitochondria. Our data highlight the importance of a functional interchange between mitochondrial morphodynamics and innate immunity machineries in the context of influenza viral infection.


Assuntos
Antivirais/administração & dosagem , Retículo Endoplasmático/patologia , Interações Hospedeiro-Patógeno , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Retículo Endoplasmático/virologia , Humanos , Imunidade Inata , Influenza Humana/patologia , Influenza Humana/virologia , Mitocôndrias/patologia , Mitocôndrias/virologia , Replicação Viral
8.
EMBO Rep ; 21(12): e49019, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33180995

RESUMO

Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito-C. Mito-C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito-C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF-1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER-mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito-C counteracts dengue virus-induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including Mito-C is of therapeutic relevance for pathologies where altered mitochondria dynamics is part of disease etiology and NEET proteins are highlighted as important therapeutic targets in anti-viral research.


Assuntos
Mitocôndrias , Proteínas Mitocondriais , Homeostase , Humanos , Ferro , Proteínas Mitocondriais/genética
9.
Genome Med ; 6(11): 115, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25593595

RESUMO

The current therapeutic arsenal against viral infections remains limited, with often poor efficacy and incomplete coverage, and appears inadequate to face the emergence of drug resistance. Our understanding of viral biology and pathophysiology and our ability to develop a more effective antiviral arsenal would greatly benefit from a more comprehensive picture of the events that lead to viral replication and associated symptoms. Towards this goal, the construction of virus-host interactomes is instrumental, mainly relying on the assumption that a viral infection at the cellular level can be viewed as a number of perturbations introduced into the host protein network when viral proteins make new connections and disrupt existing ones. Here, we review advances in interactomic approaches for viral infections, focusing on high-throughput screening (HTS) technologies and on the generation of high-quality datasets. We show how these are already beginning to offer intriguing perspectives in terms of virus-host cell biology and the control of cellular functions, and we conclude by offering a summary of the current situation regarding the potential development of host-oriented antiviral therapeutics.

10.
PLoS One ; 7(1): e29979, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22276136

RESUMO

Blood consists of different cell populations with distinct functions and correspondingly, distinct gene expression profiles. In this study, global miRNA expression profiling was performed across a panel of nine human immune cell subsets (neutrophils, eosinophils, monocytes, B cells, NK cells, CD4 T cells, CD8 T cells, mDCs and pDCs) to identify cell-type specific miRNAs. mRNA expression profiling was performed on the same samples to determine if miRNAs specific to certain cell types down-regulated expression levels of their target genes. Six cell-type specific miRNAs (miR-143; neutrophil specific, miR-125; T cells and neutrophil specific, miR-500; monocyte and pDC specific, miR-150; lymphoid cell specific, miR-652 and miR-223; both myeloid cell specific) were negatively correlated with expression of their predicted target genes. These results were further validated using an independent cohort where similar immune cell subsets were isolated and profiled for both miRNA and mRNA expression. miRNAs which negatively correlated with target gene expression in both cohorts were identified as candidates for miRNA/mRNA regulatory pairs and were used to construct a cell-type specific regulatory network. miRNA/mRNA pairs formed two distinct clusters in the network corresponding to myeloid (nine miRNAs) and lymphoid lineages (two miRNAs). Several myeloid specific miRNAs targeted common genes including ABL2, EIF4A2, EPC1 and INO80D; these common targets were enriched for genes involved in the regulation of gene expression (p<9.0E-7). Those miRNA might therefore have significant further effect on gene expression by repressing the expression of genes involved in transcriptional regulation. The miRNA and mRNA expression profiles reported in this study form a comprehensive transcriptome database of various human blood cells and serve as a valuable resource for elucidating the role of miRNA mediated regulation in the establishment of immune cell identity.


Assuntos
Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , RNA Mensageiro/genética , Adolescente , Adulto , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Eosinófilos/metabolismo , Feminino , Humanos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Neutrófilos/metabolismo , Adulto Jovem
11.
Nat Rev Drug Discov ; 9(6): 435-45, 2010 06.
Artigo em Inglês | MEDLINE | ID: mdl-20514070

RESUMO

Heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses are major challenges in drug development. To address these challenges, biomarker strategies based on a range of platforms, such as microarray gene-expression technologies, are increasingly being applied to elucidate these sources of variability and thereby potentially increase drug development success rates. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US Food and Drug Administration initiated a programme in 2004 to allow sponsors to submit exploratory genomic data voluntarily, without immediate regulatory impact. In this article, a selection of case studies from the first 5 years of this programme - which is now known as the voluntary exploratory data submission programme, and also involves collaboration with the European Medicines Agency - are discussed, and general lessons are highlighted.


Assuntos
Aprovação de Drogas , Perfilação da Expressão Gênica , United States Food and Drug Administration , Alanina Transaminase/sangue , Azetidinas/efeitos adversos , Azetidinas/uso terapêutico , Benzilaminas/efeitos adversos , Benzilaminas/uso terapêutico , Carcinoma de Células Renais/diagnóstico , Europa (Continente) , Fluoruracila/efeitos adversos , Marcadores Genéticos , Humanos , Cooperação Internacional , Neoplasias Renais/diagnóstico , Transplante de Rim , Farmacogenética , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Cloridrato de Prasugrel , Medicina de Precisão , Tiofenos/farmacocinética , Tiofenos/uso terapêutico , Estados Unidos
13.
Nat Biotechnol ; 28(5): 446-54, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20458314

RESUMO

Application of any new biomarker to support safety-related decisions during regulated phases of drug development requires provision of a substantial data set that critically assesses analytical and biological performance of that biomarker. Such an approach enables stakeholders from industry and regulatory bodies to objectively evaluate whether superior standards of performance have been met and whether specific claims of fit-for-purpose use are supported. It is therefore important during the biomarker evaluation process that stakeholders seek agreement on which critical experiments are needed to test that a biomarker meets specific performance claims, how new biomarker and traditional comparators will be measured and how the resulting data will be merged, analyzed and interpreted.


Assuntos
Biomarcadores , Descoberta de Drogas , Preparações Farmacêuticas , Animais , Descoberta de Drogas/legislação & jurisprudência , Descoberta de Drogas/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Preparações Farmacêuticas/normas
14.
Nat Biotechnol ; 28(5): 455-62, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20458315

RESUMO

The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.


Assuntos
Biomarcadores Farmacológicos , Aprovação de Drogas/legislação & jurisprudência , Rim , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Europa (Continente) , Humanos , Rim/efeitos dos fármacos , Rim/lesões , Preparações Farmacêuticas/normas , Estados Unidos , United States Food and Drug Administration
15.
Nat Biotechnol ; 28(5): 463-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20458316

RESUMO

Earlier and more reliable detection of drug-induced kidney injury would improve clinical care and help to streamline drug-development. As the current standards to monitor renal function, such as blood urea nitrogen (BUN) or serum creatinine (SCr), are late indicators of kidney injury, we conducted ten nonclinical studies to rigorously assess the potential of four previously described nephrotoxicity markers to detect drug-induced kidney and liver injury. Whereas urinary clusterin outperformed BUN and SCr for detecting proximal tubular injury, urinary total protein, cystatin C and beta2-microglobulin showed a better diagnostic performance than BUN and SCr for detecting glomerular injury. Gene and protein expression analysis, in-situ hybridization and immunohistochemistry provide mechanistic evidence to support the use of these four markers for detecting kidney injury to guide regulatory decision making in drug development. The recognition of the qualification of these biomarkers by the EMEA and FDA will significantly enhance renal safety monitoring.


Assuntos
Biomarcadores Farmacológicos/urina , Clusterina/urina , Cistatina C/urina , Testes de Função Renal/métodos , Microglobulina beta-2/urina , Animais , Biomarcadores Farmacológicos/metabolismo , Distribuição de Qui-Quadrado , Clusterina/genética , Clusterina/metabolismo , Creatinina/sangue , Creatinina/metabolismo , Cistatina C/genética , Cistatina C/metabolismo , Perfilação da Expressão Gênica , Histocitoquímica , Rim/química , Rim/efeitos dos fármacos , Rim/lesões , Rim/patologia , Nefropatias/diagnóstico , Nefropatias/patologia , Glomérulos Renais/patologia , Túbulos Renais Proximais/patologia , Masculino , Prognóstico , Proteinúria/urina , Curva ROC , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Microglobulina beta-2/genética , Microglobulina beta-2/metabolismo
16.
Nat Biotechnol ; 28(5): 478-85, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20458318

RESUMO

Kidney toxicity accounts both for the failure of many drug candidates as well as considerable patient morbidity. Whereas histopathology remains the gold standard for nephrotoxicity in animal systems, serum creatinine (SCr) and blood urea nitrogen (BUN) are the primary options for monitoring kidney dysfunction in humans. The transmembrane tubular protein kidney injury molecule-1 (Kim-1) was previously reported to be markedly induced in response to renal injury. Owing to the poor sensitivity and specificity of SCr and BUN, we used rat toxicology studies to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-beta-D-glucosaminidase (NAG) as predictors of kidney tubular damage scored by histopathology. Kim-1 outperforms SCr, BUN and urinary NAG in multiple rat models of kidney injury. Urinary Kim-1 measurements may facilitate sensitive, specific and accurate prediction of human nephrotoxicity in preclinical drug screens. This should enable early identification and elimination of compounds that are potentially nephrotoxic.


Assuntos
Biomarcadores Farmacológicos/urina , Moléculas de Adesão Celular/urina , Testes de Função Renal/métodos , Rim , Acetilglucosaminidase/urina , Animais , Biomarcadores Farmacológicos/metabolismo , Nitrogênio da Ureia Sanguínea , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Cisplatino/toxicidade , Creatinina/sangue , Ciclosporina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Gentamicinas/toxicidade , Histocitoquímica , Rim/efeitos dos fármacos , Rim/lesões , Testes de Função Renal/normas , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Curva ROC , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Traumatismo por Reperfusão , Tioacetamida/toxicidade
17.
Nat Biotechnol ; 28(5): 486-94, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20458319

RESUMO

The Predictive Safety Testing Consortium's first regulatory submission to qualify kidney safety biomarkers revealed two deficiencies. To address the need for biomarkers that monitor recovery from agent-induced renal damage, we scored changes in the levels of urinary biomarkers in rats during recovery from renal injury induced by exposure to carbapenem A or gentamicin. All biomarkers responded to histologic tubular toxicities to varied degrees and with different kinetics. After a recovery period, all biomarkers returned to levels approaching those observed in uninjured animals. We next addressed the need for a serum biomarker that reflects general kidney function regardless of the exact site of renal injury. Our assay for serum cystatin C is more sensitive and specific than serum creatinine (SCr) or blood urea nitrogen (BUN) in monitoring generalized renal function after exposure of rats to eight nephrotoxicants and two hepatotoxicants. This sensitive serum biomarker will enable testing of renal function in animal studies that do not involve urine collection.


Assuntos
Biomarcadores Farmacológicos , Cistatina C/sangue , Nefropatias/diagnóstico , Testes de Função Renal/métodos , Animais , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Farmacológicos/urina , Nitrogênio da Ureia Sanguínea , Carbapenêmicos/toxicidade , Creatinina/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Gentamicinas/toxicidade , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Curva ROC , Ratos , Ratos Sprague-Dawley , Ratos Wistar
18.
PLoS One ; 4(9): e7037, 2009 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-19750006

RESUMO

Systemic and local inflammation plays a prominent role in the pathogenesis of atherosclerotic coronary artery disease, but the relationship of whole blood gene expression changes with coronary disease remains unclear. We have investigated whether gene expression patterns in peripheral blood correlate with the severity of coronary disease and whether these patterns correlate with the extent of atherosclerosis in the vascular wall. Patients were selected according to their coronary artery disease index (CADi), a validated angiographical measure of the extent of coronary atherosclerosis that correlates with outcome. RNA was extracted from blood of 120 patients with at least a stenosis greater than 50% (CADi > or = 23) and from 121 controls without evidence of coronary stenosis (CADi = 0). 160 individual genes were found to correlate with CADi (rho > 0.2, P<0.003). Prominent differential expression was observed especially in genes involved in cell growth, apoptosis and inflammation. Using these 160 genes, a partial least squares multivariate regression model resulted in a highly predictive model (r(2) = 0.776, P<0.0001). The expression pattern of these 160 genes in aortic tissue also predicted the severity of atherosclerosis in human aortas, showing that peripheral blood gene expression associated with coronary atherosclerosis mirrors gene expression changes in atherosclerotic arteries. In conclusion, the simultaneous expression pattern of 160 genes in whole blood correlates with the severity of coronary artery disease and mirrors expression changes in the atherosclerotic vascular wall.


Assuntos
Doença da Artéria Coronariana/sangue , Regulação da Expressão Gênica , Adulto , Idoso , Aorta/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Doença da Artéria Coronariana/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Risco
19.
Curr Opin Drug Discov Devel ; 11(1): 60-71, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18175268

RESUMO

Drug-induced kidney injury is a serious and not uncommon adverse event which needs to be considered during drug development. The current standards used to monitor kidney function, such as blood urea nitrogen and serum creatinine, are late indicators of kidney injury and thus do not allow for timely intervention before loss of function. Improving the diagnosis and monitoring of kidney damage goes hand-in-hand with the identification of new biomarkers and the development of technologies that enable their sensitive and specific measurements. In order to move beyond restriction to internal company decisions, every entity that demonstrates the qualities of a biomarker must gain acceptance by health authorities if it is to be used for regulatory decision making in preclinical studies and clinical trials. This review focuses on the most promising achievements of new technologies applied to monitoring drug-induced nephrotoxicity (eg, gene expression, imaging, in vitro screening, protein assays) and on the use and implications of peripheral biomarkers such as the urinary protein biomarkers glutathione S-transferase-alpha, N-acetyl-beta-d-glucosaminidase, total protein, cystatin C, beta2-microglobulin, KIM-1, lipocalin-2 and serum cystatin C. Finally, the associated regulatory processes for use in clinics are also discussed.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Nefropatias/induzido quimicamente , Nefropatias/diagnóstico , Animais , Ensaios Clínicos como Assunto , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Genômica , Humanos , Nefropatias/diagnóstico por imagem , Nefropatias/genética , Legislação de Medicamentos , Circulação Renal/fisiologia , Segurança , Ultrassonografia
20.
Am Heart J ; 152(3): 478-85, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16923417

RESUMO

BACKGROUND: Relating a disease state to an entire population of proteins provides an opportunity to gain new insights into a disease. METHODS: Male populations of 53 patients with angiographic coronary artery disease and 53 control subjects without coronary disease from the Duke Databank for Cardiovascular Disease were established and matched for age and race as well as extremes of risk factors. Major plasma protein abnormalities were excluded. Plasma samples of each group were pooled to make large volumes (6 L each) to identify low-abundance proteins. After removal of albumin as well as immunoglobulins and enrichment of smaller proteins (<20-40 kDa), samples were separated into 12,960 fractions by cation exchange and 2 reversed-phase chromatography steps. Proteins were analyzed by liquid chromatography-electrospray ionization tandem mass spectrometry. RESULTS: There were 731 plasma proteins or fragments identified. Of these proteins, 95 were differentially displayed in the case versus control populations. These represent broad categories of proteins involved with natural defenses, inflammation, growth, and coagulation. CONCLUSION: We identified a large number of proteins that differ in abundance in populations with and those without angiographic coronary disease. These proteins now comprise candidates for validation studies in individual patients and in larger clinical data sets to better define disease pathways and establish novel markers for disease.


Assuntos
Proteínas Sanguíneas/isolamento & purificação , Doença da Artéria Coronariana/sangue , Proteômica/métodos , Adulto , Idoso , Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
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