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PubMed2000

Co-repressors 2000.

In the last 5 years, many co-repressors have been identified in eukaryotes that function in a wide range of species, from yeast to Drosophila and humans. Co-repressors are coregulators that are recruited by DNA-bound transcriptional silencers and play essential roles in many pathways including differentiation, proliferation, programmed cell death, and cell cycle. Accordingly, it has been shown that aberrant interactions of co-repressors with transcriptional silencers provide the molecular basis of a variety of human diseases. Co-repressors mediate transcriptional silencing by mechanisms that include direct inhibition of the basal transcription machinery and recruitment of chromatin-modifying enzymes. Chromatin modification includes histone deacetylation, which is thought to lead to a compact chromatin structure to which the accessibility of transcriptional activators is impaired. In a general mechanistic view, the overall picture suggests that transcriptional silencers and co-repressors act in analogy to transcriptional activators and coactivators, but with the opposite effect leading to gene silencing. We provide a comprehensive overview of the currently known higher eukaryotic co-repressors, their mechanism of action, and their involvement in biological and pathophysiological pathways. We also show the different pathways that lead to the regulation of co-repressor-silencer complex formation.

Chromatin↗
PubMed2007

Pathway mapping tools for analysis of high content data.

The complexity of human biology requires a systems approach that uses computational approaches to integrate different data types. Systems biology encompasses the complete biological system of metabolic and signaling pathways, which can be assessed by measuring global gene expression, protein content, metabolic profiles, and individual genetic, clinical, and phenotypic data. High content screening assays can also be used to generate systems biology knowledge. In this review, we will summarize the pathway databases and describe biological network tools used predominantly with this genomics, proteomics, and metabolomics data but which are equally as applicable for high content screening data analysis. We describe in detail the integrated data-mining tools applicable to building biological networks developed by GeneGo, namely, MetaCore and MetaDrug.

Computational Biology↗
PubMed2005

Using 3D animations to teach intracellular signal transduction mechanisms: taking the arrows out of cells.

Traditional methods of teaching intracellular biological processes and pathways use figures or flowcharts with the names of molecules linked with arrows. Many veterinary students, presented with such material, simply memorize the names or chemical structures of the molecules and are then likely to forget the material once the examination is completed. To address this problem, the authors designed, created, and field-tested new teaching media that incorporate realistic three-dimensional (3D) animations depicting the dynamic changes that occur in intracellular molecules during cellular activation. Testing found that veterinary students taught using traditional teaching media (e.g., lectures, handouts, textbooks) are proficient in memorizing the names and order of intracellular molecules but unable to appreciate the interactions between these elements or their spatial relationships within cells. In contrast, more than 90% of veterinary students taught using 3D animations not only recall the facts about the intracellular elements but also develop accurate mental images of the interactions among these molecules and their spatial relationships. These findings strongly suggest that the comprehension of complex biological processes by veterinary students can be enhanced by the use of dynamic 3D depictions of these processes in the classroom.

Cell Physiological Phenomena↗
PubMed2005

Distinctive features of the biological catch bond in the jump-ramp force regime predicted by the two-pathway model.

The receptor-ligand unbinding in the biological catch bond is analyzed within a simple model that comprises a single bound state and two unbinding pathways. This model is investigated in detail for the jump-ramp force regime, where the pulling force quickly jumps to a finite value and then is ramped linearly with time. Two qualitative criteria are identified that distinguish the catch bond from the slip bond. First, the rupture force probability density of the catch-bond exhibits a maximum-minimum pair, which develops at finite forces. In contrast, the slip bond produces a maximum that first appears at zero force. Second, the catch bond can be identified over a wide range of ramp rates by high rupture probabilities at low forces relative to the probability at the maximum, in contrast to the slip bond, where the probability at the maximum always corresponds to the most likely rupture force. Both distinctive features of the catch bond are masked by large jump forces, indicating that the catch bond is best identified in experiments with moderate loading rates and small jump forces. The catch-bond lifetime in the constant force regime is related to the probability density in the jump-ramp regime, allowing one to determine the bond lifetime for a constant force by measuring the initial probability density in the jump-ramp experiments with different jump forces and a fixed ramp rate. The key analytic results are illustrated with the P -selectin/P-selectin glucoprotein ligand-1 bond.

Biophysics↗
PubMed1992

Experimental study on radioactive pathways of hypodermically injected technetium-99m.

The objective of this study was to investigate the biological substrate of radioactive pathways of migration of hypodermically injected 99mTc into points of low electrical resistance. Sixteen anesthetized adult male beagles were used. Control and test points were defined by comparing their electrical resistance to that of the pinna. Seventy-three experiments of three different types were performed: (1) separate hypodermic injections of [99mTc] sodium pertechnetate, 201Tl-chloride, 131INa and 99mTc-rhenium sulfide into control and test points; (2) simultaneous injections of [99mTc]sodium pertechnetate and 201Tl chloride into control and test points; and (3) intravascular injections of 99mTcO4 into blood vessels underlying test points. Only the hypodermic injection of 99mTc into points of low electrical resistance gave rise to a specific radioactive pathway characterized by rapid and longitudinal migration, clearly independent of background activity. The specific radioactive pathway detected is not the result of diffusion of the radiotracer through nerves, veins or lymphatic vessels, but its trajectory coincides with that described for one of the acupuncture meridians in the dog.

Animals↗
PubMed1996

Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation.

Interleukin-3 (IL3) was shown recently to utilize the transcription factor Stat5, but the genes regulated by this pathway and the biological consequence of Stat5 activation remained to be determined. In order to study the role of Stat5 in IL3 signalling, we constructed a dominant-negative Stat5 protein by C-terminal truncation, and inducibly expressed it in an IL3-dependent cell line. The effect of dominant-negative Stat5 induction on expression of IL3 early response genes was examined, and expression of several genes, including cis, osm and pim-1 was inhibited profoundly. The expression of c-fos was also reduced, but to a lesser extent. While activated Ras alone (though not Stat5 alone) could induce c-fos, maximal expression required the action of both Ras and Stat5. Interestingly, although the membrane-proximal region of the IL3 receptor beta-chain is responsible for both Jak2-Stat5 activation and c-myc induction, c-myc levels were not affected by the dominant-negative Stat5. Thus, the signals directed by this membrane-proximal domain, which is essential for transducing a DNA synthesis signal, can be separated further into Stat5 or c-myc pathways. The net effect of dominant-negative Stat5 expression was partial inhibition of IL3-dependent growth. This provides the first direct evidence that Stat5 is involved in regulation of cell proliferation.

Animals↗
PubMed2006

Some bio-medical mechanisms in athletic prowess.

Variations in somato-genetic patterns in muscle-fibre biology, biochemical metabolic pathways and pulmonary physiology are hypothesized to have been concentrated by natural selection over the centuries in the Afrocentric peoples displaced from West Africa to the New World. These phenotypic and genotypic characteristics are attributed to provide the athletic prowess so well documented in African-Americans. Not the least of coincidence seems to be the influence of the compensatory mechanisms on oxygen transport and its availability to the tissues, in response to the sickle cell gene. The reduced availability coupled with reduced myoglobin in the preponderant fast-twitch muscle fibres which are adapted for rapid energy (ATP) regeneration, all give a NET outcome of muscle anatomical and biochemical advantages which support outstanding performances in athleticism.

Africa, Western↗
PubMed2006

A UbcH5/ubiquitin noncovalent complex is required for processive BRCA1-directed ubiquitination.

Protein ubiquitination is a powerful regulatory modification that influences nearly every aspect of eukaryotic cell biology. The general pathway for ubiquitin (Ub) modification requires the sequential activities of a Ub-activating enzyme (E1), a Ub transfer enzyme (E2), and a Ub ligase (E3). The E2 must recognize both the E1 and a cognate E3 in addition to carrying activated Ub. These central functions are performed by a topologically conserved alpha/beta-fold core domain of approximately 150 residues shared by all E2s. However, as presented herein, the UbcH5 family of E2s can also bind Ub noncovalently on a surface well removed from the E2 active site. We present the solution structure of the UbcH5c/Ub noncovalent complex and demonstrate that this noncovalent interaction permits self-assembly of activated UbcH5c approximately Ub molecules. Self-assembly has profound consequences for the processive formation of polyubiquitin (poly-Ub) chains in ubiquitination reactions directed by the breast and ovarian cancer tumor susceptibility protein BRCA1.

Amino Acid Sequence↗
PubMed2003

Factors associated with detection of bromoxynil in a sample of rural residents.

In regions of intensive crop production residents may be exposed to herbicides through direct contact or environmental sources. The environmental herbicide exposures of rural populations and resultant potential health effects are not well understood. Epidemiologic studies or herbicides have focused on occupational exposures using, primarily, self-reported data (e.g., information on occupational and non-occupational herbicide use, agricultural practices and exposures, farm residence). Herbicide exposure characterization in epidemiologic research would be strengthened by the use of self-reported data and biological monitoring (e.g. measuring the herbicide parent compound or its metabolites in blood or urine specimens) to classify individual exposures, identify factors associated with exposure, and obtain integrated estimates of exposure. As both exposure metrics are susceptible to measurement error and some self-reported and biological monitoring data might not be correlated, a worthwhile first step is to identify self-reported data that are statistically associated with biological measures or exposure. This study use gas chromatography/mass spectrometry analysis to measure blood plasma concentrations of target herbicides in a sample of rural residents (men, women, and youths) of Saskatchewan, Canada, and identified factors, based on self-reported data, associated with detection. The questionnaire data and blood specimens were collected in February/March 1996 during winter (frozen soil and water and snow cover) conditions. Sixty-four of the 332 study participants (19.3%) had detectable levels of the herbicide bromoxynil although herbicide application in the region had not occurred for approximately 5 mo and bromoxynil has a relatively short environmental half-life. The prevalence of detection of other target herbicides (2,4-D, triallate, trifluralin, dicamba, fenoxaprop, MCPA, and ethalfluralin) varied from 0.3% to 2.7%. Self reported factors identified in the multiple-variable analysis as statistically significant predictors of bromoxynil detection included recent exposure to grain production as the main farming operation (statistically significant for producers and for non-farming family members of producers), a history of bromoxynil use, a history of having felt ill with a pesticide exposure and a history of pesticide spill on skin or clothing, with apparent gender differences in the relative importance of these factors. Detection of bromoxynil in this rural sample, 3-4 mo after freeze-up and winter snow cover, suggests either that bromoxynil is very slowly metabolized/excreted from the body or study participants were environmentally or occupationally exposed tothe herbicide during this period. Further research is needed to elucidate the pathways of exposure, biological half-life, and potentialhuman health effects of bromoxynil.

Adolescent↗
PubMed2003

The morphogenesis of herpes simplex virus type 1 in infected parental mouse L fibroblasts and mutant gro29 cells.

Mutants of cell lines and viruses are important biological tools. The pathway of herpesvirus particle maturation and egress are contentious issues. The mutant gro29 line of mouse L cells is defective for egress of herpes simplex virus type 1 (HSV-1) virions, and a candidate for studies of virus-cell interactions. The properties of uninfected and HSV-1-infected L fibroblasts and gro29 cells investigated by protein assay, immunoblot, titration assay, immunofluorescence light microscopy and immunogold cryosection electron microscopy are reported. The ultrastructure of both HSV-1-infected L and gro29 cells confirmed primary envelopment of virions at the nuclear membranes followed by maturing multiple de-envelopments and re-envelopments in the endoplasmic reticulum and in the Golgi complex. The gro29 cells presented changed cytoskeleton, abolished egress of virions, and were defective in the trafficking of glycoproteins, giving rise to accumulation of viral particles and glycoproteins in the endoplasmic reticulum and the Golgi complex. The results suggest that gro29 cells harbour a causal underlying defect of the cytoskeleton in addition to the HSV-1-induced cytoskeletal changes.

Actins↗
PubMedDate not supplied

Estradiol induction of cAMP in breast cancer cells is mediated by foetal calf serum (FCS) and sex hormone-binding globulin (SHBG).

Plasma sex hormone-binding globulin (SHBG or SBP), the specific carrier for estradiol and androgens, after binding to its membrane receptor (SHBG-R), causes a significant increase of cAMP in the presence of estradiol, in both breast (MCF-7) and prostate (LNCaP) cancer cells maintained in serum-free medium. On the other hand, it has been proposed that estrogens, in addition to the well-known nuclear receptor pathway, exert their biological effect inducing cAMP, as a consequence of a direct membrane action, in breast cancer and uterine cells. The aim of the present study was to clarify this controversial issue by verifying if the cAMP increase in MCF-7 cells was a direct effect of estradiol, or if it was mediated by FCS proteins, such as bovine sex hormone-binding globulin; and to reevaluate the effect of human SHBG on cAMP induction in the presence of FCS. MCF-7 cells were maintained in DCC-FCS (treated with DCC to remove steroids), in SHBG-FREE/DCC-FCS (treated with DCC and with a specific affinity chromatography to remove bovine sex hormone-binding globulin), or in serum-free medium (SFM). It was observed that estradiol determined a significant time-dependent increase of cAMP only in MCF-7 cells maintained in 10% DCC-FCS. When cells were maintained in 10% SHBG-FREE/DCC-FCS, estradiol had no detectable effect. However, its ability to increase cAMP was observed again after the addition of human SHBG, in doses ranging from 5 to 50 nM. Moreover, in the presence of 10% SHBG-FREE/DCC-FCS, SHBG, even in the absence of estradiol, caused a significant increase of cAMP. In conclusion, the data reported in the present study suggest that the ability of estradiol to induce cAMP in MCF-7 cells is not due to a direct membrane effect of the hormone, but rather it is mediated by FCS. SHBG is one of the serum factors mediating estradiol action. Lastly, it was proven that SHBG triggers the cAMP pathway in MCF-7 cells in a physiologic culture condition and at physiologic concentrations.

Animals↗
PubMedDate not supplied

Nuclear factor kappa B activation by NADPH oxidases.

Reactive oxygen species (ROS) initiate activation of the transcription factor NF-kappaB in a variety of cell systems. Perhaps the most potent biological source of ROS is the NADPH oxidase of phagocytic cells, a multi-component system that catalyzes the formation of superoxide anion. Although phagocytes use this oxidase to kill ingested microorganisms, the products also mediate a broad range of biological oxidation reactions and some evidence exists for activation of NF-kappaB through this mechanism. Moreover, the components of the phagocyte NADPH oxidase are present in certain non-phagocytic cells and recently discovered homologues of the catalytic component gp91(phox) are expressed in a number of tissues. We explored the hypothesis that the products of NADPH oxidases cause the activation of NF-kappaB. K562 human erythrokeukemia cells transfected with constructs for expression of gp91(phox), plus other essential NADPH oxidase components generated substantial amounts of superoxide when activated with phorbol ester, lesser amounts with arachidonic acid exposure, and none with TNFalpha. Gel shift assays demonstrated induction of NF-kappaB in K562 cells exposed to TNFalpha and specificity was shown by oligonucleotide competition. Supershift assays demonstrated the presence in nuclear complexes of the NF-kappaB components p65/RelA and p50. Nuclear complexes of identical electrophoretic mobility were induced in phorbol ester-stimulated K562 cells that expressed the complete NADPH oxidase system, but not in cells lacking one of the essential oxidase components. K562 cells were relatively resistant to NF-kappaB induction by exogenous peroxide, but certain other cell types (HEK293 and HeLaS3) demonstrated such induction upon exposure to reagent hydrogen peroxide or glucose oxidase plus glucose and this was blocked by catalase. Finally, we found a biphasic pattern of gp91(phox) expression in rat liver during aging. High levels observed in young animals decreased in middle age, but increased again in old age. Collectively, these studies demonstrate the potential for NADPH-dependent induction of NF-kappaB and raise the possibility of a role for this pathway in the biology of aging.

Aging↗
PubMed2004

VEGF increases paracellular transport without altering the solvent-drag reflection coefficient.

Vascular endothelial growth factor (VEGF) increases microvascular permeability and has been implicated in the development of numerous pathologies including diabetic retinopathy (DR), hypoxia/ischemia, and tumor biology. The transport pathways by which water and solutes cross the endothelium in response to VEGF, however, are not completely understood. We measured, in real time, bovine retinal endothelial cell (BREC) hydraulic conductivity (Lp), 70 kDa dextran permeability (Pe), and the solvent-drag reflection coefficient (sigma) before and after addition of 50 ng/ml VEGF. The diffusional permeability coefficient for dextran (Pd) was measured before pressure gradient application. The sudden application of a 10-cm H2O hydrostatic pressure gradient induced water and solute fluxes that decayed to steady-state values after approximately 2 h. Subsequently, the addition of VEGF significantly increased Lp and Pe by 4.3-fold +/- 0.7-fold and 3.0-fold +/- 0.3-fold, respectively, after 110 min; however, the reflection coefficient remained approximately constant throughout the experiment (approximately 0.8). These observations suggest that water and dextran utilize common paracellular channels across BREC monolayers. Furthermore, the addition of VEGF increases the number or availability of channels but does not alter the selectivity of the monolayer to 70 kDa dextran.

Animals↗
PubMed1985

Complement and cancer: activation of the alternative pathway as a theoretical base for immunotherapy.

Activation of the APC is pointed out as the common factor in all sufficiently studied cancer treatments employing nonspecific, active immunotherapy. This chapter outlines the molecular biology of both APC and classical pathway of complement, summarizes the alternative pathway's biologic activities especially in relation to the C3/C5 convertase C3b,Bb, and its implications in the mechanism of host defense against malignancies, particularly relating to the activated macrophage. The many involvements of the APC in the various agents used for nonspecific active immunotherapy are reviewed, and possible clinical implications outlined. It is concluded that activation of the APC can be proposed as the specific theoretical basis so far lacking for this treatment modality and that it is accordingly feasible to attempt to monitor clinical application of this principle by fine-tuning of APC activation in cases of human cancer.

Adjuvants, Immunologic↗
PubMed2026

Elucidating the Mechanism of Xiaoqinglong Decoction in Chronic Urticaria Treatment: An Integrated Approach of Network Pharmacology, Bioinformatics Analysis, Molecular Docking, and Molecular Dynamics Simulations.

INTRODUCTION: Xiaoqinglong Decoction (XQLD) is a traditional Chinese medicinal formula commonly used to treat chronic urticaria (CU). However, its underlying therapeutic mechanisms remain incompletely characterized. This study employed an integrated approach combining network pharmacology, bioinformatics, molecular docking, and molecular dynamics simulations to identify the active components, potential targets, and related signaling pathways involved in XQLD's therapeutic action against CU, thereby providing a mechanistic foundation for its clinical application. METHODS: The active components of XQLD and their corresponding targets were identified using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. CU-related targets were retrieved from the OMIM and GeneCards databases. Subsequently, core components and targets were determined via protein-protein interaction (PPI) network analysis and component-target-pathway network construction. Topological analyses were performed using Cytoscape software to prioritize core nodes within these networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database to identify enriched biological processes and signaling pathways. Molecular docking was performed to evaluate binding interactions between key components and core targets, while molecular dynamics (MD) simulations were employed to assess the stability of the component-target complexes with the lowest binding energy. Finally, CU-related targets of XQLD were validated using datasets from the Gene Expression Omnibus (GEO) database. RESULTS: A total of 135 active components and 249 potential targets of XQLD were identified, alongside 1,711 CU-related targets. Core components, such as quercetin, kaempferol, beta-sitosterol, naringenin, stigmasterol, and luteolin, exhibited high degree values in the constructed networks. The core targets identified included AKT1, TNF, IL6, TP53, PTGS2, CASP3, BCL2, ESR1, PPARG, and MAPK3. GO and KEGG pathway enrichment analyses revealed the PI3K-Akt signaling pathway as a central regulatory mechanism. Molecular docking studies demonstrated strong binding affinities between active components and core targets, with the stigmasterol-AKT1 complex exhibiting the lowest binding energy (-11.4 kcal/mol) and high stability in MD simulations. Validation using GEO datasets identified 12 core genes shared between CU-related targets and XQLD-associated targets, including PTGS2 and IL6, which were also prioritized as core targets in the network pharmacology analyses. DISCUSSION: This study comprehensively integrates multidisciplinary approaches to clarify the potential molecular mechanisms of XQLD in treating CU, highlighting its multitarget and multipathway synergistic effects. Molecular docking and dynamics simulations confirm the stable interaction between stigmasterol and the core target AKT1. Additionally, GEO dataset analysis verifies the pathogenic relevance of targets such as PTGS2 and IL6, significantly enhancing the credibility of our findings. These results provide a modern scientific basis for the traditional therapeutic effects of XQLD on CU and have important implications for developing multitarget treatments for this condition. However, this study mainly relies on database mining and computational simulations. Further in vitro and in vivo experimental validations are needed to confirm the predicted component-target-pathway interactions. CONCLUSION: This study identifies the active components, potential targets, and pathways through which XQLD exerts therapeutic effects on CU. These findings provide a theoretical foundation for further mechanistic studies and support their clinical application in the treatment of CU.

Molecular Docking Simulation↗
PubMedDate not supplied

Alteration of the vascular endothelial growth factor and angiopoietins-1 and -2 pathways in transitional cell carcinomas of the urinary bladder associated with tumor progression.

Neoangiogenesis is assumed to play an important role in the progression, metastasis and prognosis of a wide variety of tumors. To get insights into the molecular-genetic pathways and the biological role of angiogenesis in urothelial carcinogenesis, we analyzed comparatively the expression of the mRNA of the vascular endothelial growth factor (VEGF) and of the angiopoietins-1 and -2 (Ang-1 and Ang-2) in 71 transitional cell carcinomas (TCC) of the urinary bladder in relation to the tumor grades and stages, and referring to epidemiological risk factors. Using real-time quantitative reverse transcription-polymerase chain reaction, low-stage superficial TCC expressed VEGF and Ang-2 mRNA at a significantly higher level than high-stage muscle invasive carcinomas, and low-grade TCC at an insignificantly higher level than high-grade tumors. The activity of both angiogenic factors was found to be significantly correlated. Conversely, Ang-1 mRNA was expressed at a 3-fold significantly lower level in low-grade, low-stage compared to high-grade, high-stage TCC. A significantly 3- and 2-fold respectively, drop of the VEGF and Ang-2 mRNA expression in conjunction with a 2-fold significantly higher expression of Ang-1 mRNA in the group of grade 2 TCC when infiltrating the muscle layer may represent a crucial event during urothelial carcinogenesis, and possibly indicates an important step in promoting the conversion of bladder cancer from a low to a high malignancy in this subset of carcinomas. By immunhistochemistry, high-grade, high-stage carcinomas less frequently displayed areas with a strong reactivity for the VEGF protein ('hot spots") than low-grade, low-stage TCC, paralleling the expression of the mRNA. The expression patterns observed are compatible with a reduced vascular destabilization and decreased formation of new blood vessels in advanced TCC, suggesting a balance between vessel regression and vascular growth, with a less pronounced vascular remodeling during late phases of urothelial carcinogenesis. Analyzing the effect of life-style bladder cancer risk factors, habitual smoking and coffee consumption was not observed to substantially alter the expression of the angiogenic mediators, except for weakly elevated levels of VEGF and Ang-2 mRNA in TCC of strong smokers and a borderline significantly decreased VEGF mRNA expression associated with heavy coffee consumption. Certain hazardous occupational exposures (polycyclic hydrocarbons, paints and lacquer, stone dust) may play a role in modulating tumor angiogenesis. The current data indicate that the signaling molecular-genetic pathways underlying vascular remodeling are involved in the progression of urinary bladder cancer to a more malignant and aggressive behaviour.

Angiopoietin-1↗
PubMed2006

Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review.

BACKGROUND: There is mounting evidence in the literature that resveratrol is a promising natural compound for prevention and treatment of a variety of human cancers. This overview summarizes recent studies of the major apoptosis and survival pathways regulated by resveratrol. BIOLOGICAL MECHANISMS: Apoptosis or programmed cell death is a key regulator of tissue homeostasis during normal development and also in adult organism under various conditions including adaptive responses to cellular stress. For example, tissue homeostasis is maintained by tight control of signaling events regulating cell death and survival. Thus, uncontrolled proliferation or failure to undergo cell death is involved in pathogenesis and progression of many human diseases, for example in tumorigenesis or in cardiovascular disorders. Moreover, current cancer therapies primarily act by triggering apoptosis programs in cancer cells. THERAPEUTIC APPLICATIONS: Natural products such as resveratrol have gained considerable attention as cancer chemopreventive or cardioprotective agents and also because of their antitumor properties. Among its wide range of biological activities, resveratrol has been reported to interfere with many intracellular signaling pathways, which regulate cell survival or apoptosis. DISCUSSION: Further insights into the signaling network and interaction points modulated by resveratrol may provide the basis for novel drug discovery programs to exploit resveratrol for the prevention and treatment of human diseases.

Anticarcinogenic Agents↗
PubMed2005

Spatial trends and factors affecting variation of organochlorine contaminants levels in Canadian Arctic beluga (Delphinapterus leucas).

Organochlorine pesticides and PCBs were analysed in blubber from beluga (Delphinapterus leucas), or white whales, collected at 15 sites in the Canadian Arctic between 1993 and 2001. The objective of the study was to define and interpret the spatial trends of major organic contaminants in northern beluga in terms of sources and transport pathways, and the biological factors influencing accumulation. When compared on a lipid weight basis, the concentrations of beta-HCH, cis-CHL and SigmaCHL, cis-nonachlor, heptachlor epoxide and p,p'-DDT were significantly higher in males than females at all five sites in the eastern Arctic where the two sexes were harvested. The differences were attributed to losses from the females during fetal development and lactation as reported in previous studies. Major compounds increased with age in males at most sites, however the lack of a significant increase with age at some sites was in part due to high organochlorine concentrations in young year classes (2-5 years), particularly at eastern sites such as Iqaluit and Pangnirtung. Lower concentrations of SigmaHCH and SigmaDDT compounds in young males in 2001 relative to 1995 at Hendrickson Island could be due to declining levels in the environment, changes in the diet, or differences in organochlorine loads transferred from the female after birth. Age-corrected least square mean concentrations in males showed significantly higher levels of many compounds, such as p,p'-DDE and SigmaCHB, at south Baffin Island sites than those in the west. Two notable exceptions were HCBz and beta-HCH which were higher in the west. Methoxyclor was detected in males at Sanikiluaq (58 ng g-1) and in both sexes at Kimmirut, but at no other sites. Principal component analysis grouped the 16 sites into five major groupings based on the similarity of normalised organochlorine pesticide and PCB levels. Sites from the western Arctic were grouped by higher proportions of HCBz, beta-HCH and gamma-HCH and higher chlorinated PCBs. Endosulfan and alpha-HCH comprised a larger proportion of total organochlorine residues in the northern Hudson Bay sites, while methoxychlor, chlordane compounds and octachlorobiphenyls were enriched at Sanikiluaq in eastern Hudson Bay. The analysis showed that the relative amounts of several key compounds are similar in the beluga stocks over large spatial areas (i.e. eastern versus western sites), however, some stocks have distinct fingerprints which can be used to differentiate them from adjacent stocks. Ratios of major HCH isomers largely corresponded with air and surface water measurements conducted during the 1990s, but low alpha-/beta- and alpha-/gamma-HCH ratios in all three western Arctic collections indicate rapid losses of the alpha-isomer from the food web, proportionately higher beta- and gamma-isomers in the Beaufort Sea, or a combination of the two processes. Chlordane residue patterns generally correspond to those from previous studies, however, interpretation of spatial trends are difficult due to the aging of the probable sources in the south, possible atmospheric input from new sources and complex transport pathways.

Adipose Tissue↗