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- I have pursued the "Life of the mind" and am a "iconoclast" of prevailing paradigms. My background in human evolution... moreI have pursued the "Life of the mind" and am a "iconoclast" of prevailing paradigms. My background in human evolutionary genetics, radiation biology, chemical carcinogenesis, mutagenic and epigenetic toxicology , food safety mechanismsedit
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Firemaster BP-6 (FM), a mixture of polybrominated biphenyls (PBB), and the congeners 2,2',4,4',5,5'-hexabromobiphenyl (2,4,5-HBB), 3,3',4,4',5,5'-hexabromobiphenyl (3,4,5-HBB), and... more
Firemaster BP-6 (FM), a mixture of polybrominated biphenyls (PBB), and the congeners 2,2',4,4',5,5'-hexabromobiphenyl (2,4,5-HBB), 3,3',4,4',5,5'-hexabromobiphenyl (3,4,5-HBB), and 3,3',4,4'-tetrabromobiphenyl (3,4-TBB) were tested for their ability to induce mutations in mammalian cells in culture. A rat liver microsome-mediated (S 15) Chinese hamster V79 cell mutation assay was used to test the mutagenicity of PBB and 3,4-TBB. V79 cells and WB rat liver cells were used to detect the mutagenicity of 2,4,5-HBB and 3,4,5-HBB. No mutagenic effects were detected at the dose levels tested. The possibility that these compounds promote liver neoplasms via a nongenotoxic mechanism is discussed.
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Research Interests: Genetics, Molecular Biology, Biology, DNA replication, Medicine, and 15 moreBiological Sciences, Cell line, Mutation, Animals, Drug Resistance, Lung, Diterpenes, DNA Polymerase, Nucleotides, Biochemistry and cell biology, Chinese hamster, Dna Synthesis, Cricetinae, Medical and Health Sciences, and cytidine
Subsurface contamination by nonaqueous phase liquids containing various polycyclic aromatic hydrocarbons (PAHs) are common at many industrial sites. PAHs are known carcinogens and the assessment of the toxicity of such complex chemical... more
Subsurface contamination by nonaqueous phase liquids containing various polycyclic aromatic hydrocarbons (PAHs) are common at many industrial sites. PAHs are known carcinogens and the assessment of the toxicity of such complex chemical mixtures are required for human health-risk analysis models. In addition, the evaluation of the toxicity of residual chemicals that remain after remediation at contaminated sites is important in assessing the efficacy of remediation. In this study, a nonaqueous phase liquid comprised of toluene and eight PAHs was subjected to biodegradation under controlled conditions. The changes in chemical composition caused by biodegradation, and epigenetic toxicity of the residual after biodegradation in comparison to the epigenetic toxicity of the initial mixture have been evaluated. The epigenetic toxicity was determined using an assay of the gap junctional intercellular communication inhibition exhibited in rat liver epithelial cell cultures. The results suggest that some higher molecular weight components of the nonaqueous phase were not eliminated by biodegradation and the qualitative toxicity of the remaining fraction was comparable to the untreated nonaqueous phase liquid.
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To find a scientifically based method for evaluating mechanistic data related to risks to human beings, a new protocol for identifying, organizing, and summarizing mechanistic data for decision-making on cancer hazard identification was... more
To find a scientifically based method for evaluating mechanistic data related to risks to human beings, a new protocol for identifying, organizing, and summarizing mechanistic data for decision-making on cancer hazard identification was proposed by the International Agency for Research on Cancer and by an international working group of multidisciplinary experts. This Commentary examined the 10 key carcinogens’ characteristics proposed in the context of several paradigms assumed in the using of these 10 characteristics. These characteristics were assumed to represent a “carcinogen’s” mechanism of action but what was ignored were characteristics of the mechanisms of the “initiation,” “promotion,” and “progression” carcinogenic process. Challenges were made to the interpretation of genotoxicity data as well as from concepts and findings related to the promotion phase and the role of adult human stem cells. Reliance of interpretation of “genotoxicity” data (molecular-DNA lesions in DNA;...
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To investigate gap-junctional intercellular communication (GJIC) in LNCaP and DU145 human prostate cancer cells. Normal rat liver F344 (WB1) cells were used as positive controls. Functional GJIC was inspected using either the... more
To investigate gap-junctional intercellular communication (GJIC) in LNCaP and DU145 human prostate cancer cells. Normal rat liver F344 (WB1) cells were used as positive controls. Functional GJIC was inspected using either the scrape-loading/dye transfer (SL/DT) method or fluorescence recovery after photobleaching (FRAP) analysis. In the former, GJIC activity was expressed as a measure of the extent of diffusion of Lucifer Yellow after cell monolayers were scraped using a surgical blade and exposed to dye for a few minutes at room temperature. In the latter, cells were incubated for 15 minutes at 37 degrees C with 5,6-carboxyfluorescein diacetate dye and the dye transfer visualized by photobleaching individual cells with a 488-nm laser and monitoring the recovery of fluorescence using a laser cytometer. The preliminary results obtained indicate that neither LNCaP nor DU145 cells have functional GJIC, while, as expected, WB1 cells show unimpaired GJIC activity. Equivalent results were...
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During the evolution of single-celled organisms to multicellular metazoans, a family of highly conserved genes coding for proteins (connexins), which as hexameric units (connexins), has evolved to form intercellular channels (gap... more
During the evolution of single-celled organisms to multicellular metazoans, a family of highly conserved genes coding for proteins (connexins), which as hexameric units (connexins), has evolved to form intercellular channels (gap junctions). These gap junctions allow ions and small molecular weight molecules to flow between coupled cells, thereby facilitating synchronization of electrotonic or metabolic cooperation. Control of cell proliferation, cell differentiation and adaptive responses of differentiated cells have been speculated to be biological roles of gap junctions. The regulation of these gap junctions can occur at the transcriptional, translational and posttranslational levels. Transient downregulation by endogenous or exogenous chemicals can bring about adaptive or maladaptive consequences depending on circumstances. Stable abnormal regulation of gap junction function has been associated with the activation of several oncogenes. Several tumor suppressor genes have also been associated with the up-regulation of gap junction function. Since gap junctions exist in all organs of the multi-cellular organisms, the dysfunction of these gap junctions by various toxic chemicals which have cell type/tissue/organ specificity could bring about very distinct clinical consequences, such as embryo lethality or teratogenesis, reproductive dysfunction in the gonads, neurotoxicity of the CNS system, hyperplasia of the skin, and tumor promotion of initiated tissue. Understanding how many non-mutagenic chemicals might alter normal gap junction function should form the basis of "epigenetic" toxicology. On the other hand, restoring normal gap junction function to cells which have dysfunctional intercellular communication could be the basis for a new approach for therapeutic pharmaceuticals.
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The two hypotheses of the origin of cancer are the “stem cell” hypothesis and the “Dedifferentiation” or “Re-programming” hypothesis. Cancers are derived from a single cell, with all the cells within the tumor exhibiting heterogeneity of... more
The two hypotheses of the origin of cancer are the “stem cell” hypothesis and the “Dedifferentiation” or “Re-programming” hypothesis. Cancers are derived from a single cell, with all the cells within the tumor exhibiting heterogeneity of genotypes and phenotypes. Cancer cells, which do not contact inhibit; have growth control; terminally differentiate; are“immortal”; also, do not have function gap junctional intercellular communication (GJIC).The interpretation of animal experiments has suggested that the carcinogenic process consists of three phases, namely, the “initiation” phase; the “promotion” phase and the “progression” phase. With the isolation of embryonic-, induced pluripotent-, somatic nuclear transferand adult stem cells, observations have shown that stem cells express the embryonic gene, Oct4A, but not the gap junction genes. With the isolation of “side population” cells from cancer cell lines, which were shown to sustain the growth of tumors, the terms, “cancer-initiati...
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I would like to address myself not to a specific moral problem caused by the proliferation of scientific knowledge and technological advances in our culture, but to the underlying philosophical basis for the plethora of moral dilemmas we... more
I would like to address myself not to a specific moral problem caused by the proliferation of scientific knowledge and technological advances in our culture, but to the underlying philosophical basis for the plethora of moral dilemmas we are witnessing. In essence, I am saying that the ecological and psycho-social problems of today cannot be ameliorated by recycling pop bottles or training more psychiatrists. We must attack the cause not the symptoms. The cause, I propose, resides in our head in the form of a bankrupt philosophy of human nature. Moreover, I make the assumption, as others have that each individual holds a view of human nature which shapes policies and practices of human intervention which, in turn, influence biological and psycho-social development.
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To protect the public’s health from exposure to physical, chemical, and microbiological agents, it is important that any policy be based on rigorous scientifically based research. The concept of “linear no-threshold” (LNT) has been... more
To protect the public’s health from exposure to physical, chemical, and microbiological agents, it is important that any policy be based on rigorous scientifically based research. The concept of “linear no-threshold” (LNT) has been implemented to provide guideline exposures to these agents. The practical limitation to testing this hypothesis is to provide sufficient samples for experimental or epidemiological studies. While there is no universally accepted understanding of most human diseases, there seems to be better understanding of cancer that might help resolve the “LNT” model. The public’s concern, after being exposed to radiation, is the potential of producing cancer. The most rigorous hypothesis of human carcinogenesis is the “multistage, multimechanism” chemical carcinogenesis model. The radiation carcinogenesis LNT model, rarely, if ever, built it into their support. It will be argued that this multistage, multimechanism model of carcinogenesis, involving the “initiation” o...
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It has been proposed that many human cancers are generated by intrinsic mechanisms that produce “Bad Luck” mutations by the proliferation of organ-specific adult stem cells. There have been serious challenges to this interpretation,... more
It has been proposed that many human cancers are generated by intrinsic mechanisms that produce “Bad Luck” mutations by the proliferation of organ-specific adult stem cells. There have been serious challenges to this interpretation, including multiple extrinsic factors thought to be correlated with mutations found in cancers associated with these exposures. While support for both interpretations provides some validity, both interpretations ignore several concepts of the multistage, multimechanism process of carcinogenesis, namely, (1) mutations can be generated by both “errors of DNA repair” and “errors of DNA replication,” during the “initiation” process of carcinogenesis; (2) “initiated” stem cells must be clonally amplified by nonmutagenic, intrinsic or extrinsic epigenetic mechanisms; (3) organ-specific stem cell numbers can be modified during in utero development, thereby altering the risk to cancer later in life; and (4) epigenetic tumor promoters are characterized by species,...
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This segment of the report of the proceedings of the National Cancer Institute symposium is devoted to the presentations about studies with in vitro cell systems, in vitro-in vivo systems, and whole animals including humans. The NCI... more
This segment of the report of the proceedings of the National Cancer Institute symposium is devoted to the presentations about studies with in vitro cell systems, in vitro-in vivo systems, and whole animals including humans. The NCI symposium was designed to cover many aspects of carcinogenesis so that the similarities and differences of the manner in which ionizing radiation and chemical carcinogens initiate cancer and complete its expression could be examined. The hope was that the identification of both the common and the clearly distinct features would help elucidate mechanisms and indicate areas for new research.
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Cancer stem cells (CSCs) pose a challenge in cancer treatment, as these cells can drive tumor growth and are resistant to chemotherapy. Melatonin exerts its oncostatic effects through the estrogen receptor (ER) pathway in cancer cells,... more
Cancer stem cells (CSCs) pose a challenge in cancer treatment, as these cells can drive tumor growth and are resistant to chemotherapy. Melatonin exerts its oncostatic effects through the estrogen receptor (ER) pathway in cancer cells, however its action in CSCs is unclear. Here, we evaluated the effect of melatonin on the regulation of the transcription factor OCT4 (Octamer Binding 4) by estrogen receptor alpha (ERα) in breast cancer stem cells (BCSCs). The cells were grown as a cell suspension or as anchorage independent growth, for the mammospheres growth, representing the CSCs population and treated with 10 nM estrogen (E2) or 10 μM of the environmental estrogen Bisphenol A (BPA) and 1 mM of melatonin. At the end, the cell growth as well as OCT4 and ERα expression and the binding activity of ERα to the OCT4 was assessed. The increase in number and size of mammospheres induced by E2 or BPA was reduced by melatonin treatment. Furthermore, binding of the ERα to OCT4 was reduced, ac...
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Van Rensselaer Potter II, age 90, died September 6, 2001, after a brief illness. Dr. Potter was a biochemist who devoted his scientific career to cancer research and pioneered efforts to develop the field of Bioethics, which he named. He... more
Van Rensselaer Potter II, age 90, died September 6, 2001, after a brief illness. Dr. Potter was a biochemist who devoted his scientific career to cancer research and pioneered efforts to develop the field of Bioethics, which he named. He was a Professor of Oncology at the McArdle Laboratory for
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ABSTRACT
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Research Interests: Pesticide and Carcinogen
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Chinese hamster ovary cells were initially selected for resistance to aphidicolin at 0.3 microgram/ml. Serial cultivation with aphidicolin at concentrations up to 5.0 micrograms/ml yielded a series of mutants with increasing resistance.... more
Chinese hamster ovary cells were initially selected for resistance to aphidicolin at 0.3 microgram/ml. Serial cultivation with aphidicolin at concentrations up to 5.0 micrograms/ml yielded a series of mutants with increasing resistance. The most resistant mutant isolated was 44 times more resistant to aphidicolin than the parental CHO. The alpha-polymerases, assayed in the cytoplasmic extracts of the mutants, did not increase in specific activity or differ from the parental CHO in their sensitivity to aphidicolin. When cultured in the presence of deoxythymidine, deoxyadenosine, and 1-beta-D-arabinofuranosyl cytosine (araC) the mutants showed considerably more resistance to these inhibitors than did the parental CHO. The intracellular pools of all four deoxynucleoside triphosphates (dNTPs) in the mutants increased with increasing resistance to aphidicolin. The elevated dNTP pools in the mutant most resistant to aphidicolin appear to be the result of a 4- to 8-fold increase in the level of ribonucleotide reductase (2'-deoxyribonucleoside diphosphate:oxidized thioredoxin 2'-oxidoreductase, EC 1.17.4.1).
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Although considerable attention has been directed in the field of gene therapy toward elucidating the mechanism by which a transduced cell could kill a bystander cell, little is known about how bystander cells may affect transduced cells.... more
Although considerable attention has been directed in the field of gene therapy toward elucidating the mechanism by which a transduced cell could kill a bystander cell, little is known about how bystander cells may affect transduced cells. We hypothesized that bystander cells, particularly if they were capable of gap junctional communication, could protect cells transduced with the herpes simplex virus thymidine kinase (HSV-TK) from ganciclovir (GCV)-induced cytotoxicity. To test this hypothesis, we used a rat hepatocyte cell line (WB) that can carry out efficient gap junctional communication, a WB clone transduced with HSV-TK (WB-TK), and a communication-incompetent subclone of WB cells (aB1). We cocultured WB-TK cells with either WB or aB1 cells, treated them with GCV, and then plated the cells into selective media that permitted us to quantify independently the surviving fraction of WB-TK cells or bystander cells. We found that WB bystander cells conferred up to a 1000-fold protec...
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The discovery of the gap junction structure, its functions and the family of the "connexin" genes, has been basically ignored by the major biological disciplines. These connexin genes code for proteins that organize to form... more
The discovery of the gap junction structure, its functions and the family of the "connexin" genes, has been basically ignored by the major biological disciplines. These connexin genes code for proteins that organize to form membrane-associated hemi-channels, "connexons", co-join with the connexons of neighboring cells to form gap junctions. Gap junctions appeared in the early evolution of the metazoan. Their fundamental functions, (e.g., to synchronize electrotonic and metabolic functions of societies of cells, and to regulate cell proliferation, cell differentiation, and apoptosis), were accomplished via integrating the extra-cellular triggering of intra-cellular signaling, and therefore, regulating gene expression. These functions have been documented by genetic mutations of the connexin genes and by chemical modulation of gap junctions. Via genetic alteration of connexins in knock-out and transgenic mice, as well as inherited connexin mutations in various huma...
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Inflammation, induced by microbial agents, radiation, endogenous or exogenous chemicals, has been associated with chronic diseases, including cancer. Since carcinogenesis has been characterized as consisting of the 'initiation',... more
Inflammation, induced by microbial agents, radiation, endogenous or exogenous chemicals, has been associated with chronic diseases, including cancer. Since carcinogenesis has been characterized as consisting of the 'initiation', 'promotion' and 'progression' phases, the inflammatory process could affect any or all three phases. The stem cell theory of carcinogenesis has been given a revival, in that isolated human adult stem cells have been isolated and shown to be 'targets' for neoplastic transformation. Oct4, a transcription factor, has been associated with adult stem cells, as well as their immortalized and tumorigenic derivatives, but not with the normal differentiated daughters. These data are consistent with the stem cell theory of carcinogenesis. In addition, Gap Junctional Intercellular Communication (GJIC) seems to play a major role in cell growth. Inhibition of GJIC by non-genotoxic chemicals or various oncogenes seems to be the mechanism fo...
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TCDD administered to NIH 3T3 fibroblast cells transfected with a plasmid containing MMTV-LTR and mouse ras DNAs caused an increased level of p21ras protein and down-regulation of EGF receptor. This effect occurred only in the cells with... more
TCDD administered to NIH 3T3 fibroblast cells transfected with a plasmid containing MMTV-LTR and mouse ras DNAs caused an increased level of p21ras protein and down-regulation of EGF receptor. This effect occurred only in the cells with introduced N-ras or Ha-ras under transcriptional control of glucocorticoid-sensitive MMTV-LTR but not ones without these DNAs. The MMTV-LTR ras-incorporated cells treated with either dexamethasone or TCDD grew in soft agar to form colonies (anchorage independent growth), while nontreated cells did not, indicating profound cellular changes due to activation of N-ras by these two agents.
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ABSTRACT The convergence of new experimental findings, such as human adult stem cells as potential target cells for cancer and the epigenetic effects of oxidative stress-inducing agents, and of old concepts, such as the multi-stage,... more
ABSTRACT The convergence of new experimental findings, such as human adult stem cells as potential target cells for cancer and the epigenetic effects of oxidative stress-inducing agents, and of old concepts, such as the multi-stage, multimechanism process of carcinogenesis and the stem cell theory of cancer, has called into question the linear, no-threshold hypothesis of radiation-induced health effects. Specifically, the integration of the multistage, multiple mechanism concept of carcinogenesis, the stem cell theory of cancer, the Barker effect on prenatal/postnatal development, which affects disease risks later in life, and epigenetic effects induced by low-level exposure to oxidative stress-inducing agents, such as ionizing radiation, the effect of intercellular communication on modifying the effects of ionizing radiation in tissues, and the effect of caloric restriction on reducing risks to chronic diseases, should be all considered in interpreting the risk to exposure to low-level ionizing radiation. All these concepts might help to explain radiation-induced observations of the adaptive response, bystander effects, genomic instability, and the Barker hypothesis.
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During the evolution of multicellular organisms, survival in an aerobic environment came about by adaptive responses, both to the endogenous oxidative metabolism within the cells of the organism as well as the chemicals and low-level... more
During the evolution of multicellular organisms, survival in an aerobic environment came about by adaptive responses, both to the endogenous oxidative metabolism within the cells of the organism as well as the chemicals and low-level radiation to which they are exposed. In addition to defense mechanisms shared with single-cell organisms, multicellular organisms are equipped with gap junctions which allow electrotonic and/or metabolic synchronization of processes between coupled cells. The connexin genes, which code for the proteins comprising the gap junctions, provide homeostatic regulation of cell proliferation, differentiation, and adaptive responses of individual cells through a mechanism of "gap junctional intercellular communication." The biological consequences of the response of a multicellular organism to low-level radiation exceeding the background level of oxidative damage to a cell in a tissue could be apoptosis, cell proliferation, or cell differentiation.
Research Interests: Intercellular Communication, Gap Junctions, Biology, Cell Biology, Oxidative Stress, and 15 moreMedicine, Cell Division, Signal Transduction, Biological Sciences, Cell Differentiation, Humans, Animals, Cell, Life Expectancy, Organism, Homeostasis, Cell communication, Intracellular, Connexins, and Medical and Health Sciences
Based principally on the cancer incidence found in survivors of the atomic bombs dropped in Hiroshima and Nagasaki, the International Commission on Radiation Protection (ICRP) and the United States National Council on Radiation Protection... more
Based principally on the cancer incidence found in survivors of the atomic bombs dropped in Hiroshima and Nagasaki, the International Commission on Radiation Protection (ICRP) and the United States National Council on Radiation Protection and Measurements (NCRP) have recommended that estimates of cancer risk for low dose exposure be extrapolated from higher doses by using a linear, no-threshold model. This recommendation is based on the dogma that the DNA of the nucleus is the main target for radiation-induced genotoxicity and, as fewer cells are directly damaged, the deleterious effects of radiation proportionally decline. In this paper, we used a precision microbeam to target an exact fraction (either 100% or ≤20%) of the cells in a confluent population and irradiated their nuclei with exactly one α particle each. We found that the frequencies of induced mutations and chromosomal changes in populations where some known fractions of nuclei were hit are consistent with non-hit cells...
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By using antiserum against pyrimidine dimers and argon-laser imaging microspectrofluorometry, we established a new method to determine UV-induced pyrimidine dimers and their repair in individual human cells. The method was sensitive... more
By using antiserum against pyrimidine dimers and argon-laser imaging microspectrofluorometry, we established a new method to determine UV-induced pyrimidine dimers and their repair in individual human cells. The method was sensitive enough to determine dimers induced by UV dose as low as 2 J/m2. Normal human cells repaired 50 and 60% of total damage within 8 and 24 h after UV irradiation (20 J/m2), but Xeroderma pigmentosum cells (complementation group A) were unable to repair any within the same period. Therefore, the method proved to be a quick, easy, sensitive and accurate means to determine pyrimidine dimers in situ.
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We purified compounds from the husks of psyllium seeds (Plantago ovata Forsk; desert Indian wheat), beginning with an ethanol extraction then followed by HP-20 and silica gel chromatography, which restored gap junctional intercellular... more
We purified compounds from the husks of psyllium seeds (Plantago ovata Forsk; desert Indian wheat), beginning with an ethanol extraction then followed by HP-20 and silica gel chromatography, which restored gap junctional intercellular communication (GJIC) in v-Ha-ras transfected rat liver epithelial WB-F344 cell line (WB-Ha-ras). GJIC was assessed by a scrape loading dye transfer assay. The active compound was identified as beta-sitosterol based on gas chromatography retention times and electron ionization mass spectroscopy (EI-MS) spectrum of authentic beta-sitosterol. Authentic beta-sitosterol restored GJIC in the tumorigenic WB-Ha-ras GJIC-deficient cells at a dose of 2.4 microM. In addition, a similar phytosterol, stigmasterol, also restored GJIC, albeit at a lower activity. beta-sitosterol and stigmasterol increased the level of connexin43 protein (Cx43) and restored phosphorylation of Cx43 to levels similar to the parental nontransfected cell line. We concluded that the restoration of intercellular communication in the GJIC-deficient, tumorigenic WB-Ha-ras cell line by the ethanol soluble fraction of psyllium seed husks is largely due to the presence of the phytosterol, beta-sitosterol. We discuss implications for dietary modulation of cancer by beta-sitosterol.
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Gap-junctional intercellular communication (GJIC) is involved in cellular growth control and is often reduced in neoplastic cells. In this study, four GJIC-deficient rat liver epithelial cell lines (WB-aB1, WB-bA2, WB-cD6, and WB-dA2)... more
Gap-junctional intercellular communication (GJIC) is involved in cellular growth control and is often reduced in neoplastic cells. In this study, four GJIC-deficient rat liver epithelial cell lines (WB-aB1, WB-bA2, WB-cD6, and WB-dA2) were examined for altered growth and tumorigenicity in comparison with their GJIC-competent parental cell line, WB-F344. WB-aB1 cells were also forced to express connexin 32 (Cx32) by transduction with a Cx32 cDNA retroviral expression vector to help determine whether the restoration of GJIC could reverse their neoplastic phenotype. WB-aB1 and WB-bA2 cells had faster population doubling times (PDTs) and higher saturation densities (SDs) than did WB-F344 cells. In contrast, the growth of WB-cD6 and WB-dA2 cells was not significantly different from that of WB-F344 cells. WB-aB1 and WB-bA2 cells formed tumors in male F344 rats, but WB-cD6 and WB-dA2 cells did not. After transduction of WB-aB1 cells with Cx32, four stable clones (WB-a/32-3, -8, -9, and -10) were isolated that had GJIC levels of 5.2%, 44.5%, 69.8%, and 90.5%, respectively. The growth of poorly coupled clones 3 and 8 was similar to that of parental WB-aB1 cells, but the growth of well-coupled clones 9 and 10 was similar to that of WB-F344 cells. The tumorigenicity of WB-a/32-9 and WB-a/32-10 cells was also significantly lower than that of WB-aB1 cells. Our results suggest that reduced GJIC contributes to neoplastic transformation of WB cells, that additional changes are necessary, and that restoration of GJIC by forced Cx32 protein expression can suppress the neoplastic phenotype of these cells.
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Many tumor promoters suppress the immune system; however, the direct effect of immunosuppressants on the tumorigenic pathways of nonimmune cells in solid tissue has not been well documented. Cannabinoids were chosen to explore this... more
Many tumor promoters suppress the immune system; however, the direct effect of immunosuppressants on the tumorigenic pathways of nonimmune cells in solid tissue has not been well documented. Cannabinoids were chosen to explore this question further. Cannabinoids are immune modulators that affect specific intracellular signaling pathways in leukocytes. Since these compounds are nongenotoxic, any tumorigenic effect that might be associated with these compounds would need to occur through an epigenetic mechanism. Therefore, we determined the effect of Delta(9)-THC and CBN, 2 plant-derived cannabinoids, on 2 key epigenetic markers of tumor promotion: inhibition of GJIC, which is essential in removing a cell from growth suppression, and activation of the ERK-MAPK pathway, which is crucial in activating the appropriate genes for mitogenesis. Both Delta(9)-THC and CBN reversibly inhibited GJIC at noncytotoxic doses (15 microM) in a normal diploid WB rat liver epithelial oval cell line within 20 min and activated ERK1 and ERK2 within 5 min. Inhibition of MEK with PD98059 prevented the inhibition of GJIC by either cannabinoid, suggesting that inhibition of GJIC was MEK-dependent. Based on RT-PCR analysis and employment of an antagonist of CB1 and CB2, the effects on GJIC and MAPK were independent of both cannabinoid receptors. Cannabinoids affected crucial epigenetic pathways associated with cell proliferation in a rodent liver epithelial cell model system.
Research Interests: Gap Junctions, Cancer, Biology, Enzyme Inhibitors, Cell Biology, and 15 moreFlavonoids, Medicine, Cell line, Liver, cyclic AMP, Animals, Phosphorylation, Mitogen Activated Protein Kinase, Epithelial cells, Cell communication, Cannabinoid, Cannabinoid Receptor, Intracellular, Cannabinol, and Dronabinol
BIOTECHNOLOGY P-3001 Pollen Viability and Longevity of Switchgrass (Panicum virgatum L.) Y. Ge, The Samuel Roberts Noble Foundation, C. Fu, H. Bhandari, J. Bouton, C. Brummer, and Z.-Y. Wang P-3002 Degradation of Aflatoxin B1 and... more
BIOTECHNOLOGY P-3001 Pollen Viability and Longevity of Switchgrass (Panicum virgatum L.) Y. Ge, The Samuel Roberts Noble Foundation, C. Fu, H. Bhandari, J. Bouton, C. Brummer, and Z.-Y. Wang P-3002 Degradation of Aflatoxin B1 and Biological Control of Aspergillus flavus Using Soil Microbial Diversity Rajesh Kumar, University of Delhi, and Ved Pal Singh P-3003 New Gene Delivery System for Mitochondria and Chloroplast Trevor Macmillan, Agriculture and Agri-Food Canada, François Eudes, and Igor Kovalchuk P-3004 Effect of 2, 4-D on In Vitro Regeneration of Callus in Sugarcane Kalpana Sengar, Sardar Vallabh Bhai Patel University of Agriculture & Technology, and R. S. Sengar P-3005 Evaluation of Biolistic and Agrobacterium-mediated Sugarcane Gene Transfer Methods H. Wu, University of Florida IFAS, F. S. Awan, Q. Zeng, T. Phipps, A. Vilarinho, J. McCuiston, W. Wang, K. Caffall, and F. Altpeter
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Research Interests: Biology, Cancer Research, Epigenetics, Medicine, Cell Division, and 13 moreSignal Transduction, Cell Differentiation, Humans, Female, Male, Carcinogenesis, Health physics, Public health systems and services research, Radiation Injuries, Ionizing Radiation, Cell communication, Nuclear Warfare, and Neoplastic Stem Cells
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The effect of phorbol esters on ganglioside metabolism in contact-inhibited Chinese hamster V79 cells was examined. Three phorbol esters of varying structure and tumor-promoting activity were used. Treatment of cells with tumor-promoting... more
The effect of phorbol esters on ganglioside metabolism in contact-inhibited Chinese hamster V79 cells was examined. Three phorbol esters of varying structure and tumor-promoting activity were used. Treatment of cells with tumor-promoting phorbol esters resulted in accumulation of gangliosides and increased incorporation of [1-14C]palmitate and [9-3H]sialic acid into gangliosides. Moreover, the phorbol esters were found to increase the activity of CMP-sialic acid: lactosylceramide sialyltransferase, the enzyme catalysing the first step in ganglioside biosynthesis. The magnitude of phorbol ester effects on V79 cell ganglioside metabolism correlated with the in vivo phorbol ester tumor-promoting activity.