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PubMed1993

Nitric oxide synthase activity from a hematophagous insect salivary gland.

The salivary glands of the hematophagous insect, Rhodnius prolixus, contain a nitrosylhemeprotein that dissociates its ligand, NO, to the host tissues while the insect is searching for a blood meal. We now report a salivary nitric oxide synthase activity in this insect. The activity is dependent on NADPH, FAD, tetrahydrobiopterin, calmodulin, Ca2+, and converts arginine to citrulline while producing vasorelaxing activity. Molecular sieving indicates a molecular weight of 185 kDa, coeluting with a diaphorase activity. Results indicate similarity of this insect activity to the vertebrate constitutive NO synthase, suggesting NO synthesis is an evolutionary old biological pathway.

Amino Acid Oxidoreductases↗

PubMed1992

Bone hypertrophy and trabecular generation in Paget's disease and in fluoride-treated osteoporosis.

The replacement of lost trabeculae characteristic of postmenopausal osteoporosis is problematic, since a biological pathway has not been established for trabecular regeneration de novo in the healthy, intact, mature skeleton. Possible pathways for trabecular replacement may occur under pathological conditions, in particular those associated with bone hypertrophy. The topography of trabecular hypertrophy was compared in two groups of subjects with disease- or treatment-induced osteosclerosis following a period of atrophy. In Paget's disease and fluoride-treated osteoporosis a thickening of rarefied trabeculae in both was associated in Paget's disease only with an increase in the trabecular number and the transformation of a discontinuous arrangement into a more continuous network. The sequence seems to be a progression of intratrabecular resorption normally attendant upon a period of trabecular thickening. The failure of fluoride-treated bone in this respect, due to the unusual stability of the fluorotic skeleton, may provide insight to more effective anabolic regimens.

Adult↗

PubMed1986

Endometrial cancer and its precursors: a comparison of histological and clinical features.

In this study, the histological definition of endometrial cancer precursor (ECP) lesions is discussed and a comparison is made of clinical and histological parameters of ECP patients and endometrial cancer (EC) patients. ECP lesions were divided in 3 types: adenomatous hyperplasia, atypical hyperplasia and in situ adenocarcinoma. The following parameters were analyzed: age, menopausal status, gynecological and extragynecological familiar cancer incidence, other cancers in the proband, diabetes, obesity, primary infertility, fertility and previous estrogen therapy. Results give support to the hypothesis of the existence of a common biological pathway between ECP and EC. The high frequency of coexistence of both types of lesions in hysterectomy specimens from EC patients studied by step sections adds a confirmatory supporting argument. Measures for primary and secondary prevention of these lesions are proposed.

Adenocarcinoma↗

PubMed2025

Genetic analysis in African ancestry populations reveals genetic contributors to lung cancer susceptibility.

Striking disparities in lung cancer exist, with Black/African American individuals disproportionately affected by lung cancer, yet the genetic architecture in African ancestry individuals is poorly understood. We aimed to address this by performing a comprehensive genetic association study of lung cancer, incorporating local ancestry, across 6,490 African ancestry individuals (2,390 individuals with lung cancer and 4,100 control subjects). We identified a single genome-wide significant (p < 5 × 10-8) locus, 15q25.1 (lead SNP rs17486278, OR [95% CI] = 1.34 [1.23-1.45], p = 4.52 × 10-12), that has consistently shown a strong association with lung cancer across populations. Additionally, we identified nine suggestive (p < 1 × 10-6) loci. Four of these loci (3p12.1, 8q22.2, 14q11.2, and 18q22.3) have no prior reported associations with lung cancer. We performed a multi-ancestry lung cancer meta-analysis using prior large-scale summary statistics from European and Asian ancestry populations, incorporating our African ancestry results. The meta-analysis identified 17 genome-wide significant loci, including an association with locus 4q35.2 (p = 1.22 × 10-8), a genomic region that has been previously linked to forced expiratory volume. Genome-wide SNP-based heritability for lung cancer was 16% among African ancestry individuals. Follow-up in silico functional analyses identified genetically regulated gene expression (GReX) of nine genes (AC012184.3, ADK, CCDC12, CHRNA3, EML4, PSMA4, SNRNP200, TMEM50A, and ZYG11A) associated with lung cancer risk and biological pathways relevant to cancer and lung function. Cumulatively, these findings further elucidate the genetic architecture of lung cancer in African ancestry individuals, confirming prior loci and revealing new loci.

Female↗

PubMed2006

Relation of social integration to inflammatory marker concentrations in men and women 70 to 79 years.

The lack of social integration has predicted coronary heart disease morbidity and mortality in prospective observational studies; however, the biologic mechanisms by which this may occur are not well understood. The objective of this study was to determine whether social integration is associated with inflammatory risk factors for coronary heart disease, specifically C-reactive protein (CRP) and interleukin-6. The study participants (aged 70 to 79 years; 380 men and 425 women) were from the MacArthur Successful Aging Study, a longitudinal study of 3 community-based cohorts in the United States of older adults with relatively high physical and cognitive functioning at baseline (1988 to 1989). The plasma concentrations of interleukin-6 and CRP were assessed using a high-sensitivity enzyme-linked immunosorbent assay. Cross-sectional logistic regression analyses were performed. Multivariate adjusted analyses indicated that social integration was significantly inversely associated with CRP concentration in men after adjusting for age, race/ethnicity, smoking, alcohol consumption, physical activity, body mass index, cardiovascular disease, other major or chronic conditions, physical functioning, socioeconomic status, and depression (odds ratio 2.23, 95% confidence interval 1.05 to 4.76, for elevated CRP [>3.19 mg/L] in the least socially integrated quartile vs the most socially integrated quartile). No significant associations were found between social integration and interleukin-6 in men or either inflammatory marker in women. In conclusion, social integration was negatively associated with the plasma CRP concentration in men. These findings suggest a potential biologic mechanism for the observed associations between social integration and coronary heart disease in prospective studies. Differences may exist between women and men in the biologic pathways associated with social integration.

Age Factors↗

PubMed2006

Patterns of gene expression in carp liver after exposure to a mixture of waterborne and dietary cadmium using a custom-made microarray.

Gene expression changes in carp liver tissue were studied after acute (3 and 24h) and subchronic (7 and 28 days) exposure to a mixture of waterborne (9, 105 and 480 microg/l) and dietary (9.5, 122 and 144 microg/g) cadmium, using a custom-made microarray. Suppression subtractive hybridization-PCR (SSH-PCR) was applied to isolate a set of 643 liver genes, involved in multiple biological pathways, such as energy metabolism (e.g. glucokinase), immune response (e.g. complement C3) and stress and detoxification (e.g. cytochrome P450 2F2, glutathione-S-transferase pi). These genes were subsequently spotted on glass-slides for the construction of a custom-made microarray. Resulting microarray hybridizations indicated a highly dynamic response to cadmium exposure. At low exposure concentrations (9 microg/l through water and 9.5 microg/g dry weight through food) mostly energy-related genes (e.g. glucokinase, elastase) were influenced, while a general stress response was obvious through induction of several stress-related genes, including hemopexin and cytochrome P450 2F2, at high cadmium concentrations. In addition, fish exposed to the highest cadmium concentrations showed liver damage after 7 days of exposure, as measured by elevated alanine transaminase activity in plasma and increased liver water content (wet-to-dry weight ratio). Moreover, decreased hematocrit and growth were found at the end of the experiment. Altogether this study clearly demonstrated the importance of varying exposure conditions for the characterization of the molecular impact of cadmium and showed that microarray results can provide important information, required to unravel the molecular events and responses related to cadmium exposure.

Animals↗

PubMed2026

Handgrip strength and risk of common infections and sepsis: Two prospective cohorts with proteomic mediation analysis.

BACKGROUND: Recent evidence links adiposity with the risk of severe infections, but whether muscle strength may also be an independent risk factor is less studied. We investigated the association between handgrip strength and risk of common infections and sepsis and explored potential mediation by plasma proteomic biomarkers. METHODS: We analyzed data from 405,451 UK Biobank participants and replicated the main findings in 4474 Chinese adults from the Hong Kong Osteoporosis Study (HKOS). Baseline handgrip strength was measured by a dynamometer. Cox models were used to estimate its association with incidence of pneumonia, urinary tract infection (UTI), skin infection, and sepsis, adjusting for sociodemographic, lifestyle, and health-related factors. Mediation analyses were performed using 2912 plasma proteins in a UK Biobank subsample (n = 42,414) to identify biological pathways. RESULTS: In UK Biobank (median follow-up 13.6-15.3 years), lower handgrip strength was associated with significantly increased risk of pneumonia (hazard ratio per 5-kg decrement=1.10; 95% CI=1.09-1.11), UTI (1.10; 1.09-1.11), skin infection (1.05; 1.04-1.05), and sepsis (1.08; 1.07-1.10). Associations were largely consistent in HKOS, and the relative risks associated with low grip strength were generally most pronounced in underweight individuals. GDF15 and PLAUR were identified as the most important proteins which mediated 12-14% of these associations. CONCLUSION: Low handgrip strength is associated with increased risks of common infections and sepsis, particularly in underweight individuals, with partial mediation by proteins related to inflammation and immune-related pathways. Handgrip strength assessment may provide prognostic value beyond body mass index for clinical risk stratification.

Humans↗

PubMed2004

Diverse cellular transformation capability of overexpressed genes in human hepatocellular carcinoma.

For isolation of novel cellular transforming genes that potentially participated in hepatocarcinogenesis, we conducted anchorage-independent growth (AIG) assays on 10 human liver cancer cell lines and observed strong AIG capabilities in PLC5 and Huh7 but negligible in Tong cells. After cloning of genes by differential subtractive chain reactions (DSC) from strong AIG to AIG negative cells, we sequenced 2304 clones and identified 245 genes. After four stringent criteria for selection of transforming genes among DSC clones, our results of quantitative RT-PCR analysis indicated that six genes, DDX3, EIF3S2, CLIC1, HDGF, GPC3, and HSPCA were overexpressed in 64%, 62%, 60%, 58%, 49%, and 47%, respectively, of 45 hepatocellular carcinoma (HCC) tissues. The results of cellular transformation capability by AIG assays indicated that the transfectants of EIF3S2 showed the strongest (> 100-fold), DDX3 and CLIC1 were moderate, GPC3 and HSPCA were weak, and HDGF was none in forming colonies in soft agar. Together, our results suggested that Tong is a suitable human cell line for screening of overexpressed and/or cellular transforming genes. In addition, our results suggested that diverse functions of cellular transforming genes in various biological pathways could transform human Tong cells and potentially reveal new targets for drug development of HCC.

Blotting, Northern↗

PubMed2006

Regulation of gene expression in RAW 264.7 macrophage cell line by interferon-gamma.

Macrophages play an important role in immune responses and in inflammatory disease states such as atherosclerosis. Interferon-gamma (IFN-gamma) is a major cytokine involved in the activation of macrophages. To elucidate the primary response of various genes and biological pathways regulated by IFN-gamma in macrophage, we analyzed the gene expression profile in RAW 264.7 macrophage cells treated with IFN-gamma for 4h. Microarray analysis revealed that about 400 genes were differentially expressed, of which about 250 genes were up-regulated and 150 were down-regulated. Functional organization of the transcriptome revealed that induced genes are involved in antimicrobial and antiviral responses, antigen presentation, chemokine and cytokine signaling, and inhibition of cell growth. We also found that expression of genes involved in cell-cycle control, DNA repair, and lipid metabolism was suppressed by IFN-gamma. We also identified induction of multiple transcription factors by IFN-gamma in RAW 264.7 cells. Functional annotation of genes regulated by IFN-gamma in RAW 264.7 cells may provide novel insights into the role of macrophages in immunity and in inflammatory disease.

Animals↗

PubMed2004

Effects of triaryl phosphates on mouse and human nuclear receptors.

The constitutively active receptor (CAR) is a crucial regulator of genes encoding for enzymes active in drug/steroid oxidation, conjugation, and transport. In our attempt to isolate the endogenous inhibitory ligand(s) for the mouse CAR, we found surprisingly that the inhibitory activity was associated with di- and tri-isopropylated phenyl phosphates that were present in livers of untreated mice. Trans-activation experiments in mammalian cells with synthetic compounds verified that mouse CAR was inhibited by various isopropylated phenyl phosphates (40-80%). Such triaryl phosphates are widely used as fire retardants, lubricants, and plasticizers, and some of them are known to disturb reproduction by currently unknown mechanisms. Equipped with the finding that these compounds could interact with mouse CAR, we proceeded to determine their functional effects on other nuclear receptors. Human CAR and pregnane X receptor (PXR) were variably activated (2-5-fold) by triaryl phosphates while mouse PXR, peroxisome proliferator-activated receptor-alpha, and vitamin D receptor were refractory. Among steroid hormone receptors, the human androgen receptor was inhibited by triphenyl phosphate and di-ortho-isopropylated phenyl phosphate (40-50%) and activated by di- and tri-para-substituted phenyl phosphates (2-fold). Our results add to the list of CAR and PXR activators and suggest steroid-dependent biological pathways that may contribute to the reproductive effects of triaryl phosphates.

Animals↗

PubMed2005

Salicylic acid modulates oxidative stress and glutathione peroxidase activity in the rat colon.

Oxidative stress is a characteristic of cancerous colon tissue and inflammatory bowel diseases that increase colon cancer risk. Epidemiological evidence supports a protective effect of plant-derived compounds. Aspirin is also protective against colon cancer. The mechanism of action is unclear although salicylic acid, the main metabolite of aspirin, has been shown to decrease the synthesis of pro-inflammatory and potentially neo-plastic prostaglandins. Salicylic acid is found in significant quantities in a plant-based diet. However, in plants salicylic acid is also reported to modulate the expression of numerous enzymes with antioxidant activity. The aim of this study was to assess whether salicylic acid can modulate pro-cancerous biological pathways in the colon. Oxidative stress, prostaglandins and cytosolic glutathione peroxidase (cyGPX) were analysed in proximal, transverse and distal colon from a rat model of diet-induced oxidative stress. Elevated plasma pyruvate kinase activity (1293+/-206 U/ml) and increased indices of lipid peroxidation in colon (proximal 6.4+/-0.84 nM MDA/mg protein; transverse 6.9+/-0.97 nM MDA/mg protein; distal 5.2+/-0.62 nM MDA/mg protein) from rats fed a Vitamin E deficient diet were significantly decreased on supplementation with salicylic acid (plasma pyruvate 546+/-43 U/ml; salicylic acid proximal 3.6+/-0.39 nM MDA/mg protein; transverse 4.5+/-0.61 nM MDA/mg protein; distal 4.4+/-0.27 nM MDA/mg protein). Reductions in oxidative stress and prostaglandin production on supplementation with salicylic acid were associated with an elevation in glutathione peroxidase activity (Vitamin E deficient proximal 0.056+/-0.013 U/mg protein; transverse 0.073+/-0.008 U/mg protein; distal 0.088+/-0.010 U/mg protein; Vitamin E deficient with salicylic acid proximal 0.17+/-0.01 U/mg protein; transverse 0.23+/-0.016 U/mg protein; distal 0.16+/-0.020 U/mg protein). Gpx1 and Gpx2 gene transcripts were not elevated in association with increased activity of the soluble glutathione peroxidase activity. Glutathione peroxidases are key antioxidant enzymes, catalysing the decomposition of potentially toxic lipid peroxides. Gpx activity and regulation of Gpx gene transcription has been shown previously to be complex with activity not necessarily mirrored by a corresponding elevation in gene transcription. By supplementing the diet of Vitamin E deficient rats with salicylic acid (1 g/kg diet), this study assessed effects of salicylic acid on cytosolic glutathione peroxidase activity in the colon. The ability of salicylic acid to modulate antioxidant enzymes in colon tissue may be an important mechanism in inhibiting colon cancer development.

Animals↗

PubMed2005

BAG-1: a multi-functional pro-survival molecule.

BAG-1 is a multi-functional protein that exists as three functionally distinct and differentially localized isoforms which originate from a single mRNA and interact with a wide range of cellular targets. These include heat shock proteins, nuclear hormone receptors, signalling molecules, the anti-apoptotic BCL-2 protein and components of the ubiquitylation/proteasome machinery. Overexpression of BAG-1 isoforms has been demonstrated to regulate apoptosis, proliferation, transcription, metastasis and cell motility in a wide variety of cell systems. Since BAG-1 has a role in many biological pathways there is increasing evidence supporting the view that BAG-1 is an important molecule in disease, for example, potentially modulating both cell survival and response to nuclear hormones in breast cancer, and BAG-1 is a potential molecular target for therapeutic intervention.

Animals↗

PubMed2026

Unraveling causal links between chronic rhinosinusitis and peripheral artery diseases: insights from genetic correlations through genome-wide association studies.

OBJECTIVES: Chronic Rhinosinusitis (CRS) shares epidemiological links with Cardiovascular Diseases (CVDs), however, their shared genetic basis remains unclear. We hypothesized that pleiotropic genetic variants underlie CRS-CVDs links via distinct biological pathways. METHODS: Using large-scale GWAS data from European-ancestry individuals, we assessed global and local genetic correlations. We applied Genomic Structural Equation Modeling (Genomic SEM) to dissect shared genetic architecture, performed bidirectional Mendelian Randomization (MR) to infer causality, and conducted cis-eQTL colocalization to identify shared genetic signals. Finally, in vitro endothelial models (HUVECs) validated the functional dynamics of candidate genes under CRS-mimicking inflammatory stress. RESULTS: CRS showed significant genetic correlations with multiple CVDs. Genomic SEM revealed a latent factor structuring shared genetic risk through three pathways: artery diseases, myocardial diseases, and heart failure. Local genetic correlations identified significant local genetic correlations specifically between CRS and Peripheral Atherosclerosis (PAS)/Peripheral Artery Disease (PAD) specifically within the chr6: 31.57‒33.24 Mb locus. MR demonstrated causal effects of CRS on PAD (OR = 1.23, p = 0.022) and PAS (OR = 1.21, p = 0.011), but not vice versa. Genetically predicted HLA-DRB1, APOM, and COL11A2 expression conferred protection, while HLA-DQA2 increased risk. Crucially, in vitro validation corroborated these pathogenic trajectories, inflammatory stress significantly downregulated the protective APOM and upregulated the risk-associated HLA-DQA2 alongside pro-atherogenic VCAM-1, while HLA-DRB1 exhibited a compensatory upregulation (p < 0.05). CONCLUSION: CRS shares global genetic liability with CVDs, structured through three primary etiological pathways. Causal effects of CRS on peripheral artery diseases are mediated by immune and lipid-related genes within the chr6 locus, revealing divergent pleiotropic mechanisms. Our integrated genetic and in vitro evidence provides a mechanistic framework wherein chronic mucosal inflammation contributes to systemic endothelial vulnerability, thereby highlighting candidate targets for mechanism-directed therapy.

Humans↗

PubMed2005

Altering protein specificity: techniques and applications.

Protein engineering constitutes a powerful tool for generating novel proteins that serve as catalysts to induce selective chemical and biological transformations that would not otherwise be possible. Protocols that are commonly employed for altering the substrate specificity and selectivity profiles by mutating known enzymes include rational and random methods as well as techniques that entail evolution, selection and screening. Proteins identified by these techniques play important roles in a variety of industrial and medicinal applications and in the study of protein structure-function relationships. Herein we present a critical overview of methods for creating new functional proteins having altered specificity profiles and some practical case studies in which these techniques have been applied to solving problems in synthetic and medicinal chemistry and to elucidating enzyme function and biological pathways.

Biotechnology↗

PubMed2006

Multiple tissue gene expression analyses in Japanese medaka (Oryzias latipes) exposed to hypoxia.

Due in part to human population growth watersheds and coastal estuaries have been receiving increasing run-off of nutrients and genotoxins. As a consequence, the occurrences of nutrient-driven hypoxia in coastal waters appear to be increasing. Thus, understanding the molecular genetic response to hypoxia by model aquatic organisms is of interest both from environmental and physiological viewpoints. The major objectives of this study are to determine genome-wide gene expression profiles and to better understand how hypoxia influences global gene expression in medaka (Oryzias latipes), a well utilized aquatic model species. Herein we detail our development of a microarray containing 8046 medaka unigenes and describe our experimental results for measuring gene expression changes in the brain, gill, and liver of hypoxia exposed fish. Using conservative selection criteria, we determined that 501 genes in the brain, 442 in the gill, and 715 in the liver were differentially expressed in medaka exposed to hypoxia. These differentially expressed genes fell into a number of biological gene ontology groups related to general metabolism, catabolism, RNA and protein metabolism, etc. Two biological pathways, ubiquitin-proteasome and phosphatidylinositol signaling, were significantly dysregulated in medaka upon hypoxia exposure. Comparative genomics between medaka and human identified several human orthologies associated with known diseases.

Animals↗

PubMed2006

A multifaceted molecule, nitric oxide in oral and periodontal diseases.

Nitric oxide (NO) is a molecule with multiple effects on different tissues. NO takes important roles in vasodilatation, bacterial challenge and cytokine stimulation, regulation of mineralized tissue function, neurotransmission, and platelet aggregation, etc. However, under pathological conditions, NO has damaging effects. NO is synthesized by NO synthases (NOS) and inducible isoform of NOS (iNOS) is closely related to the pathophysiological characteristics of inflammatory diseases such as periodontal diseases. The expression of iNOS has been investigated in salivary gland-related diseases, temporomandibular joint disorders and oral cancer as well. The beneficial and damaging effects of NO in diseases related with periodontal, dental and maxillofacial area are discussed in this review. The biological pathways involved with NO and NO inhibitors may be good drug targets to have a role in the future management of patients with diseases in orofacial region.

Arginase↗

PubMed2006

Adjunctive therapy to mechanical ventilation: surfactant therapy, liquid ventilation, and prone position.

Acute lung injury and acute respiratory distress syndrome are associated with significant morbidity and mortality in critically ill patients. Although lung protective mechanical ventilation is the only therapy shown to reduce mortality and development of organ failure, several biologic pathways have been identified and provided an opportunity for therapeutic interventions. No pharmacologic or adjunctive treatments are available. Clinical studies demonstrated that prone position results in significant and clinically relevant improvement in oxygenation and ventilation, which persist when patients are returned to supine position; the beneficial response is not limited to patients turned early in disease course. Few complications are associated with prone ventilation. Clinical experience suggests that prone ventilation may protect the lung from potential detrimental effects of mechanical ventilation. Further studies are needed.

Humans↗

PubMed2005

Protein serine/threonine phosphatases: life, death, and sleeping.

Protein serine/threonine phosphatases control key biological pathways including early embryonic development, cell proliferation, cell death, circadian rhythm and cancer. Recent studies have provided important insights into how several of the many phosphatase regulators, through their interaction with a conserved phosphatase catalytic subunit, control the activity of critical substrates in these diverse pathways. Recent co-crystal structures provided a major insight into how the diverse protein serine/threonine regulators rein in the otherwise promiscuous catalytic subunits.

Animals↗