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PubMed2005

Revealing transforming growth factor-beta signaling transduction in human kidney by gene expression data mining.

Tumor growth factor-beta (TGF-beta) is a key mediator of glomerular and tubulointerstitial pathobiology in chronic kidney disease. Its signaling transduction controls a diverse number of biological processes in a dynamic and context-dependent manner. We applied a data mining strategy to deconvolute gene expression patterns across hundreds of microarray data sets to reveal members of the TGF-beta signaling network in human kidney. This strategy is composed of three major steps: (i) select genes known to be involved and expressionally regulated in TGF-beta signaling as "bait"; (ii) select microarray data sets in which the bait genes are strongly co-regulated; (iii) identify (or "fish") additional TGF-beta signaling genes by a non-parametric statistic-based gene scoring system (NP score). The 40 genes with highest NP scores and significant permutation p values were selected for in silico validation, and used to identify a network, in which 35 of these genes were found to be connected by literature- derived relationships. Transcription factors were found to be enriched in the top list. Among them, activated transcription factor 3 (ATF3) had the highest NP score, and was proposed to play a pivotal role in TGF-beta signaling in human kidney. Finally, we implemented a non-parametric pathway ranking (NPPR) tool (Mootha et al., 2003) to rank pathways and identified canonical biological pathways associated with the down-stream of TGF-beta signaling.

Computational Biology↗

PubMed2005

A microarray study of MPP+-treated PC12 Cells: Mechanisms of toxicity (MOT) analysis using bioinformatics tools.

BACKGROUND: This paper describes a microarray study including data quality control, data analysis and the analysis of the mechanism of toxicity (MOT) induced by 1-methyl-4-phenylpyridinium (MPP+) in a rat adrenal pheochromocytoma cell line (PC12 cells) using bioinformatics tools. MPP+ depletes dopamine content and elicits cell death in PC12 cells. However, the mechanism of MPP+-induced neurotoxicity is still unclear. RESULTS: In this study, Agilent rat oligo 22K microarrays were used to examine alterations in gene expression of PC12 cells after 500 muM MPP+ treatment. Relative gene expression of control and treated cells represented by spot intensities on the array chips was analyzed using bioinformatics tools. Raw data from each array were input into the NCTR ArrayTrack database, and normalized using a Lowess normalization method. Data quality was monitored in ArrayTrack. The means of the averaged log ratio of the paired samples were used to identify the fold changes of gene expression in PC12 cells after MPP+ treatment. Our data showed that 106 genes and ESTs (Expressed Sequence Tags) were changed 2-fold and above with MPP+ treatment; among these, 75 genes had gene symbols and 59 genes had known functions according to the Agilent gene Refguide and ArrayTrack-linked gene library. The mechanism of MPP+-induced toxicity in PC12 cells was analyzed based on their genes functions, biological process, pathways and previous published literatures. CONCLUSION: Multiple pathways were suggested to be involved in the mechanism of MPP+-induced toxicity, including oxidative stress, DNA and protein damage, cell cycling arrest, and apoptosis.

1-Methyl-4-phenylpyridinium↗

PubMed2000

Hematologic aspects of the porphyrias.

The porphyrias are disorders that can be inherited and acquired, in which the activities of the enzymes of the heme biosynthetic pathway are partially or almost totally deficient. There are 8 enzymes involved in the synthesis of heme, and, with the exception of the first enzyme, an enzymatic defect at every step leads to tissue accumulation and excessive excretion of porphyrins and/or their precursors, such as delta-aminolevulinic acid and porphobilinogen. Whereas heme, the final product of the biosynthetic pathway, is biologically important, porphyrins and their precursors are not only useless but also toxic. Porphyrias can be classified as either photosensitive or neurologic, depending on the type of symptoms, but some porphyrias cause both photosensitive and neurologic symptoms. Alternatively, they can be classified either hepatic or erythropoietic, depending on the principal site of expression of the specific enzymatic defect. The tissue-specific expression of porphyrias is largely due to the tissue-specific control of heme pathway gene expression, particularly at the level of delta-aminolevulinate synthase, the first and the rate-limiting enzyme of heme biosynthesis. In this chapter, hematologic aspects of the erythropoietic porphyrias will be described. The 3 major erythropoietic porphyrias are congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP) and erythropoietic protoporphyria (EPP).

Animals↗

PubMed2001

[Molecular genetics of Wilms' tumor].

Molecular genetics of the Wilms' tumor plays an important role in the elucidation of the genetic etiology of the tumor disease generally. Contrary to the genesis of retinoblastoma, where a single gene is inactivated by two hits, the biological signalling pathways determining the origin of the Wilms' tumor are more complex and several genes in several loci may participate. Formation of the Wilms' tumor is accompanied with the most frequent genetic alteration, which is the loss of heterozygosity on the short arm of chromosome 11. It indicates inactivation of one or several tumor suppressor genes located at 11p region. The most studied gene of the Wilms' tumor is WT1 gene, which has been cloned and sequenced. Biological function of WT1 protein is complex one and it requires probably an interaction with other proteins, DNA and also RNA. The development of the tumor determines not only the genetic changes, but also epigenetic changes, e.g., hypermethylation of promoter and genome imprinting.

Chromosome Mapping↗

PubMed2026

Genetic insights into the relationship between age at menarche and mental health-related phenotypes.

BACKGROUND: Multiple observational studies have reported associations between age at menarche (AAM) and mental health problems, yet their shared genetic architecture remains poorly characterized. METHODS: We leveraged genome-wide association study summary statistics for AAM and 15 mental health-related phenotypes. We conducted a multi-method integrative analysis encompassing linkage disequilibrium score regression, pleiotropic analysis under the composite null hypothesis, functional mapping and annotation, multi-marker analysis of genomic annotation, pathway enrichment, and bidirectional two-sample Mendelian randomization (MR) to explore shared genetic architecture and potential causal relationships. RESULTS: Our study identified significant genetic correlations between AAM and eight mental health-related phenotypes (miserableness, fed-up feelings, nervous feelings, ever thought that life is not worth living, ever self-harmed, depression, ever smoker, and age started smoking in former smokers). A total of 155 pleiotropic loci, 18 colocalized loci (e.g., 6q16.3), and 203 pleiotropic genes (e.g., LIN28B) were identified. These genes are expressed in multiple regions, including the cerebral cortex and hypothalamus, and are involved in various biological processes and signaling pathways. Additionally, MR analysis revealed causal associations between AAM and 5 mental health-related phenotypes (mood swings, miserableness, fed-up feelings, and age at which smokers started smoking in former/current smokers). CONCLUSIONS: Our study revealed extensive genetic associations between AAM and mental health-related phenotypes, and further explored the potential causal relationships between them. These findings enhance our understanding of the relationship from a genetic perspective and establish a foundation for future research to explore the biological pathways and environmental interactions contributing to these associations.

Genome-Wide Association Study↗

PubMed2004

Optimal sampling time selection for parameter estimation in dynamic pathway modeling.

Systems Biology is an emerging research area, which considers mathematical representations of inter- and intra-cellular dynamics. Among the many research problems that have been addressed, dynamic modeling of signal transduction pathways has received increasing attention. The usual approach to represent intra-cellular dynamics are nonlinear, usually ordinary, differential equations. The purpose of the models is to test and generate hypothesis of specific pathways and it is therefore required to estimate model parameters from experimental data. The experiments to generate data are complex and expensive, as a consequence of which the time series available are usually rather short, with few if any replicates. Almost certainly, not all variables one would like to include in a model can be measured. Parameter estimation is therefore an important research problem in Systems Biology and the focus of this paper. In particular, we are interested in optimizing the sampling time selection in order to minimize the variance of the parameter estimation error. With few sampling time points feasible, their selection is of practical importance in experimental design. Finally, the theoretical results are supported with an application.

Computer Simulation↗

PubMed2006

[Effects of high hydrostatic pressure on energy metabolism of Lactobacillus plantarum].

Effects of high hydrostatic pressure on energy metabolism were investigated with Lactobacillus plantarum ATCC8014 as the test microorganism in this work. An INT colorimetric method of oxidation-reduction was established to measure INT metabolic activity of deoxidization of L. plantarum ATCC8014 cells. The utilization of glucose and INT metabolic activity of deoxidization of the cells after HPP treatment were determined using colorimetric methods. The experimental results showed that survival counts of ATCC8014 cells on MRS agar medium and INT metabolic activity of deoxidization decreased significantly, and little changes of utilization of glucose took place with increasing pressure ranging from 150 to 250 MPa for 15 min. Utilization of glucose also reduced evidently at high pressure ( > 300 MPa) for 15 min. Whereas survival cell counts on MRS agar medium were below the detection limit and INT metabolic activity of deoxidization of ATCC8014 was 0% after a 15-min pressure holding time at 400MPa, utilization of glucose of the cells retained 56.1% compared with that of untreated cells. In summary, it can be concluded that enzymes absorbing and transporting glucose in cellular membrane appear to have a high resistance to pressure, enzymes and biological regulating systems involved in glycolysis are more resistant to pressure than those in TCA (tricarboxylic acid cycle) system, TCA of ATCC8014 is more sensitive to pressure than glycolysis, and the decrease of INT metabolic activity of deoxidization is highly related to cell reduction during HHP, which provide some theoretical evidences for mechanisms of HHP sterilization. Inhibition of TCA metabolism is a very important cause of ATCC8014 inactivation by HHP. High hydrostatic pressure can be used as an effective tool to explore pathways of biological metabolism.

Energy Metabolism↗

PubMed2026

Identification of putative causal associations between MicroRNAs and breast cancer via Mendelian randomization and bioinformatic analysis.

MicroRNAs (miRNAs) are implicated in breast cancer progression and prognosis. This study employed a Mendelian randomization (MR) framework to investigate causal relationships between plasma circulating miRNAs and breast cancer. miRNA expression quantitative trait loci were extracted from 2 independent cohorts. High-confidence miRNAs and their associated single-nucleotide polymorphisms were selected for 2-sample MR analyses using inverse-variance weighted and MR-Egger methods. Differential expression analysis and univariate Cox regression identified survival-associated genes in breast cancer, while enrichment analyses revealed pathways and biological processes linked to candidate targets. Pan-cancer analyses of miRNAs and targets were conducted via the ENCORI platform. Initial MR analyses in the discovery phase identified hsa-miR-100-5p, hsa-miR-125b-5p, and hsa-miR-339-5p as significantly associated with reduced breast cancer risk (P < .05), suggesting potential protective roles. A total of 1291 survival-associated differentially expressed genes were identified, with 39 overlapping targets implicated in miRNA-mediated breast cancer intervention. Enrichment analyses highlighted their involvement in cell cycle regulation and p53 signaling pathway. In the validation cohort, only hsa-miR-339-5p confirmed a protective effect on breast cancer risk, while hsa-miR-100-5p and hsa-miR-125b-5p did not reach significance. Pan-cancer profiling demonstrated aberrant miRNA expression across malignancies, prognostic relevance in multiple cancers, and significant negative correlations between miRNAs and target genes in breast tumors. Our findings provide novel insights into the causal roles of miRNAs in breast cancer pathogenesis and underscore their potential as noninvasive biomarkers and therapeutic targets. Future studies should prioritize functional validation and clinical translation of these miRNAs.

Humans↗

PubMed1985

[Simple compounds with high pharmacologic potential: beta-carbolines. Origins, syntheses, biological properties].

We reviewed the origins, the synthetic pathways and the biological properties of beta-carbolines, the condensation products of tryptophan and indole alkylamines with aldehydes. They were found in many plants, some of which have been used as hallucinogens. They also occur as minor constituents in tobacco smoke. In mammalian body, beta-carboline derivatives occur normally in plasma, platelets and urine, moreover it seems that some are formed in human body after alcohol intake. Due to interesting biological effects described in recent years (inhibition of monoamine oxidase, binding to benzodiazepine receptors, comutagenic and carcinogenic properties, 5-hydroxy tryptamine uptake inhibition), many attempts were made to prepare beta-carbolines starting from various indole derivatives. We reviewed the published methods up to 1975 and summarized the main patents related with pharmacological properties of synthetic beta-carbolines.

Alcohol Drinking↗

PubMed2001

Immunoregulatory effects of L-arginine and therapeutical implications.

Arginine, initially classified as a non-essential amino acid, participates to multiple biological processes including release of several hormones, collagen synthesis during wound healing, antitumor and antibacterial activities and non-specific immunity. Nitric oxide synthase and arginase competes for L-arginine as a substrate and this event appears to play a key role in the regulation of the inflammatory process. In this framework recent studies have identified complex patterns of interactions among these enzymes. This review will emphasizes some effects of L-arginine on immune cell functions, including triggering of L-arginine-nitric oxide and arginase pathways, its biological properties and therapeutical applications.

Animals↗

PubMed1996

Brainstem auditory evoked potentials in individuals exposed to long-term low concentrations of toluene.

Brainstem auditory evoked potentials (BAEPs) were examined in 49 workers employed in a printing press, who were occupationally exposed to low concentrations of toluene for an average of 20.3 years, and in 59 subjects in a control group. In the group of exposed workers, a significant decrease was found in all wave amplitudes examined, a significant prolongation of P1 wave latency, and an increased interval of interpeak latencies (P3-P5), indicating that the extramedullary and high medullary part of the auditory pathway are biologically most frequently affected by chronic exposure to low concentrations of toluene. The level of exposure to toluene in both groups was evaluated by defining the concentration of toluene in peripheral blood and the concentration of hippuric acid and ortho-cresol in urine.

Adult↗

PubMed1997

Cellular adhesion regulates p53 protein levels in primary human keratinocytes.

To gain insight into p53 tissue-specific regulatory pathways and biological activities, we investigated mechanisms that may account for the elevated levels of p53 protein in human foreskin keratinocytes, relative to levels in dermal fibroblasts in vitro. Here, we report that the loss of cell anchorage resulted in an approximately 5-fold decrease in p53 levels in keratinocytes, which was reversible upon reattachment of cells to a substratum. In contrast, fibroblasts did not exhibit such adhesion-dependent regulation of p53 protein. Furthermore, p53 function was attenuated in keratinocytes relative to fibroblasts. These results link p53 to cell adhesion pathways and may provide a molecular basis for epigenetic differences in the maintenance of genomic stability among normal cell types.

Cell Adhesion↗

PubMed1997

Zinc alters conformation and inhibits biological activities of nerve growth factor and related neurotrophins.

A role for Zn2+ in a variety of neurological conditions such as stroke, epilepsy and Alzheimer's disease has been postulated. In many instances, susceptible neurons are located in regions rich in Zn2+ where nerve growth factor (NGF) levels rise as a result of insult. Although the interaction of Zn2+ with this neurotrophin has previously been suggested, the direct actions of the ion on NGF function have not been explored. Molecular modeling studies predict that Zn2+ binding to NGF will induce structural changes within domains of this neurotrophin that participate in the recognition of TrkA and p75NTR. We demonstrate here that Zn2+ alters the conformation of NGF, rendering it unable to bind to p75NTR or TrkA receptors or to activate signal transduction pathways and biological outcomes normally induced by this protein. Similar actions of Zn2+ are also observed with other members of the NGF family, suggesting a modulatory role for this metal ion in neurotrophin function.

Animals↗

PubMed2001

Orphan nuclear receptors: from new ligand discovery technologies to novel signaling pathways.

Members of the nuclear receptor superfamily of ligand-regulated transcription factors play critical roles in multiple aspects of development, cellular differentiation and homeostasis. The ligand-dependent transcriptional effects of nuclear receptors are, in part, mediated by interactions with a group of proteins collectively known as transcriptional coactivators. Receptor agonists promote coactivator binding and receptor antagonists suppress coactivator binding. Recently, biochemical assays that detect ligand-binding based on coactivator recruitment have been developed for several 'orphan' nuclear receptors, i.e., receptors for which no bona fide endogenous ligands are known. We review how these assays have been used to identify naturally occurring and synthetic ligands for the liver X receptor, farnesoid X receptor and estrogen receptor-related receptor subfamilies of orphans, the use of these ligands in the discovery of novel biological signaling pathways and the potential clinical implications of these findings.

Amino Acid Sequence↗

PubMed2006

Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix (ECM). Caveolin-1 (cav-1), a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin (BLM)-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 (TGF-beta1), the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase (JNK) pathway. Interestingly, highly activated JNK was detected in IPF- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.

Actins↗

PubMed2001

ERK mediates effects of glycated albumin in mesangial cells.

The alterations in glomerular cell biology induced by glycated albumin resemble those caused by high ambient glucose, but are operative in physiologic (5.5 mM) glucose concentration. Recently, high glucose has been shown to activate extracellular signal-related kinase (ERK) in mesangial cells, but whether the mitogen-activated protein kinase (MAPK) cascade participates in signal transduction triggered by glycated albumin is unknown. Using a specific inhibitor of MAPK/ERK kinase, we demonstrate for the first time that activation of ERK is required for the inhibition of cell growth and enhanced elaboration of extracellular matrix protein provoked by glycated albumin. These findings indicate that the MAPK/ERK pathway mediates biologic activities of this glycated protein.

Animals↗

PubMed2026

Investigation of the Causal Association Between Biological Aging Indicators and Vascular Disease Through Two-Sample Mendelian Randomization Analysis.

ObjectiveThis study used two-sample Mendelian Randomization to investigate the causal link between multiple biological aging indicators and vascular disease.MethodsSummary genetic data was obtained from genome-wide association studies (GWAS) focusing on aging-related exposures and various vascular disease outcomes. The exposures included granulocyte proportions, PAI-1 (plasminogen activator inhibitor-1), telomere lengths, and the Frailty Index. The primary analysis employed the Inverse Variance Weighted (IVW) method to estimate causal relationships, supported by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including Cochran's Q test, MR-Egger regression, leave-one-out test, and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test, were conducted to evaluate heterogeneity and pleiotropy.ResultsThe analysis revealed distinct pathways after sensitivity adjustments. A higher genetically predicted Frailty Index was associated with an increased risk of abdominal aortic aneurysm (OR=2.5935, 95% CI: 1.3936-4.8268, P=0.0026, false discovery rate (FDR)=0.0475), atherosclerosis excluding cerebral and coronary sclerosis (OR=2.0262, 95% CI:1.5179-2.705, P=1.66×10-6, FDR=1×10-4), and arterial thromboembolic events (OR = 4.0306, 95% CI: 1.7133-9.4818, P = 0.0014, FDR = 0.0337). Conversely, longer telomere length demonstrated a strong, specific protective effect against abdominal aortic aneurysm (OR=0.5008, 95% CI:0.4111-0.6100, P=6.42×10-12, FDR=9.25×10-10), indicating that shorter telomere length is associated with an increased risk of AAA. Furthermore, a lower granulocyte proportion was causally linked to an increased risk of thoracic aortic aneurysm (OR=0.0181, 95% CI: 0.0014-0.2376, P=0.0023, FDR=0.0465).ConclusionThis study identifies three genetic pathways linking biological aging to vascular disease, offering new molecular targets for its prevention and treatment.

Humans↗

PubMed1999

Angiosperm phylogeny inferred from multiple genes as a tool for comparative biology.

Comparative biology requires a firm phylogenetic foundation to uncover and understand patterns of diversification and evaluate hypotheses of the processes responsible for these patterns. In the angiosperms, studies of diversification in floral form, stamen organization, reproductive biology, photosynthetic pathway, nitrogen-fixing symbioses and life histories have relied on either explicit or implied phylogenetic trees. Furthermore, to understand the evolution of specific genes and gene families, evaluate the extent of conservation of plant genomes and make proper sense of the huge volume of molecular genetic data available for model organisms such as Arabidopsis, Antirrhinum, maize, rice and wheat, a phylogenetic perspective is necessary. Here we report the results of parsimony analyses of DNA sequences of the plastid genes rbcL and atpB and the nuclear 18S rDNA for 560 species of angiosperms and seven non-flowering seed plants and show a well-resolved and well-supported phylogenetic tree for the angiosperms for use in comparative biology.

DNA, Plant↗