Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0002871 (anemia)
52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lentinan; i.e., polysaccharides extracted from a kind of black mushroom shiitake, has been clinically applied as an antitumor and antimetastatic drug, and has been reported to prevent both chemical and viral carcinogenesis. It is known that lentinan affects the tumorous vascular system resulting in the induction of hemorrhagic necrosis which is dependent on T-cells in the tumor. Repeated mucosal necrosis-regeneration sequence in chronic ulcerative colitis induced with 3% dextran sulfate sodium led to colorectal carcinogenesis in azoxymethane-pretreated mice. In the present study, the additive treatment with lentinan in the azoxymethane-dextran sulfate sodium treated mice enhanced the colorectal high-grade dysplasia, though not significantly, and the splenic weight. This may show the proliferation of pathogenic splenic T cells resulting in a change for the worse of ulcerative colitis, anemia induced with hemorrhage and colorectal carcinogenesis; i.e., high-grade dysplasia of the mucosa and/or invasive adenocarcinomas of the colorectum. The present results may recommend chemoimmunotherapy while using lentinan, but not immunotherapy using lentinan alone, is indicated for the management of cancer patients.
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PMID:Effects of lentinan on colorectal carcinogenesis in mice with ulcerative colitis. 1076 75

Sulphasalazine has been used in the treatment of ulcerative colitis and is known to be a prodrug and split into sulphapyridine and 5-aminosalicylic acid by bacteria in the colon. An increased incidence of colorectal carcinoma is known to occur in patients with ulcerative colitis, which displays a recurrence-remission cycle on colorectal mucosa, i.e., the ulceration and regeneration periods of the colorectal mucosa. Repeated mucosal necrosis-regeneration sequence in chronic ulcerative colitis induced with 3% dextran sulfate sodium led to colorectal carcinogenesis in azoxymethane-pretreated mice. Additive treatment with sulphasalazine normalized the enlarged organs, i.e. liver, spleen and kidney and anemia and leucocytosis induced with 3% dextran sulfate sodium resulted in the reduction of tumorous regions with high-grade dysplasia.
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PMID:Preventive effects of sulphasalazine on colorectal carcinogenesis in mice with ulcerative colitis. 1090 83

Fanconi anemia (FA) is a human autosomal disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinking agents such as mitomycin C and diepoxybutane. Six FA genes have been cloned including a gene designated XRCC9 (for X-ray Repair Cross Complementing), isolated using a mitomycin C-hypersensitive Chinese hamster cell mutant termed UV40, and subsequently found to be identical to FANCG. A nuclear complex containing the FANCA, FANCC, FANCE, FANCF and FANCG proteins is needed for the activation of a sixth FA protein FANCD2. When monoubiquitinated, the FANCD2 protein co-localizes with the breast cancer susceptibility protein BRCA1 in DNA damage induced foci. In this study, we have assigned NM3, a nitrogen mustard-hypersensitive Chinese hamster mutant to the same genetic complementation group as UV40. NM3, like human FA cell lines (but unlike UV40) exhibits a normal spontaneous level of sister chromatid exchange. We show that both NM3 and UV40 are also hypersensitive to other DNA crosslinking agents (including diepoxybutane and chlorambucil) and to non-crosslinking DNA damaging agents (including bleomycin, streptonigrin and EMS), and that all these sensitivities are all corrected upon transfection of the human FANCG/XRCC9 cDNA. Using immunoblotting, NM3 and UV40 were found not to express the active monoubiquitinated isoform of the FANCD2 protein, although expression of the FANCD-L isoform was restored in the FANCG cDNA transformants, correlating with the correction of mutagen-sensitivity. These data indicate that cellular resistance to these DNA damaging agents requires FANCG and that the FA gene pathway, via its activation of FANCD2 and that protein's subsequent interaction with BRCA1, is involved in maintaining genomic stability in response not only to DNA interstrand crosslinks but also a range of other DNA damages including DNA strand breaks. NM3 and other "FA-like" Chinese hamster mutants should provide an important resource for the study of these processes in mammalian cells.
Carcinogenesis 2001 Dec
PMID:The Chinese hamster FANCG/XRCC9 mutant NM3 fails to express the monoubiquitinated form of the FANCD2 protein, is hypersensitive to a range of DNA damaging agents and exhibits a normal level of spontaneous sister chromatid exchange. 1175 23

Fanconi anemia (FA) is a genetic disorder that leads to aplastic anemia and birth defects and predisposes to cancer. FA cells exhibit characteristic hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and FANCG is one of six known FA gene products. By immunocytochemical analysis of transfected cells, we discovered that although FANCG localized to both the nucleus and cytoplasm, there was an increase in cells with predominantly cytoplasmic staining after treatment with MMC. Concurrently, while searching by two-hybrid analysis for proteins that associate with FANCG, we identified a novel interaction between FANCG and cytochrome P450 2E1 (CYP2E1). A member of the P450 superfamily, CYP2E1 is associated with the production of reactive oxygen intermediates and the bioactivation of carcinogens. High constitutive levels of CYP2E1 were found in a FA-G lymphoblast cell line, whereas complementation of the FA-G line with wild-type FANCG was associated with decreased CYP2E1. These findings suggested that the interaction of FANCG with CYP2E1 might alter redox metabolism and increase DNA oxidation. Using a fluorescent assay, we found a dose-dependent increase in the oxidized DNA base, 8-oxoguanine (8-oxoG), after treatment of mutant FA-G cells with H(2)O(2) or MMC. Conversely, significantly lower levels of 8-oxoG were detected in FANCG-complemented FA-G cells. We conclude that the unknown function of FANCG involves at least transient interaction with cytoplasmic components, possibly including CYP2E1, and propose a role for FANCG in protection against oxidative DNA damage.
Carcinogenesis 2002 Jan
PMID:The FANCG Fanconi anemia protein interacts with CYP2E1: possible role in protection against oxidative DNA damage. 1175 25

Chronic ulcerative colitis (UC) patients frequently require iron supplementation to remedy anemia due to blood loss. However, the effect of iron supplementation on UC-associated carcinogenesis is unknown. In this study, the effect of an iron-enriched diet on dextran sulfate sodium-induced acute and chronic colitis in mice was assessed. In a short-term study, mice administered 1% DSS in the drinking fluid and an AIN76A diet containing increasing levels of iron exhibited dose-dependent increases in the severity of acute UC as compared to mice fed a control diet. A marked increase in iron deposition on the epithelial surface of the colon and in the inflamed areas and immunostaining for iNOS and nitrotyrosine were observed in the animals supplemented with diets containing different levels of iron. In a long-term carcinogenesis experiment, a twofold iron-enriched diet significantly increased colorectal tumor incidence (14/16, 88%) as compared with animals fed the control diet (3/16, 19%; P < 0.001). The present findings have implications for the management of human UC and suggest that dietary iron can enhance UC and its associated carcinogenesis by augmenting oxidative and nitrosative stress.
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PMID:Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. 1206 1

The role of the Fanconi anaemia genes in DNA repair was examined by a quantitative analysis of nuclear DNA repair foci in FA primary fibroblasts after ionising irradiation using antibodies directed against RAD51, MRE11 and BRCA1 for visualisation. IR induced foci detected with anti-RAD51, but not those detected with anti-MRE11, are reduced in fibroblasts of all eight FA complementation groups in comparison to control cells. Correction of FA-A, FA-C and FA-G cells by retroviral cDNA transfer specifically corrected the RAD51-foci response but did not affect formation of foci containing BRCA1 or MRE11. Since all FA cells, except FA-D1, lack the monoubiquitinated FANCD2-L protein, this isoform is likely to be involved in the formation of nuclear foci containing RAD51 in diploid FA cells. FA-D1 cells show the same attenuation in RAD51 foci formation, suggesting that the unknown FANCD1 protein is similarly involved in RAD51 foci formation, either independently or as a subsequent step in the FANCD2 pathway. These findings indicate that Fanconi anaemia cells have an impairment in the RAD51-dependent homologous recombination pathway for DNA repair, explaining their chromosomal instability and extreme sensitivity to DNA cross-linking agents.
Carcinogenesis 2002 Jul
PMID:Attenuation of the formation of DNA-repair foci containing RAD51 in Fanconi anaemia. 1211 68

Fanconi anaemia (FA) is a rare genetic syndrome of cancer susceptibility characterized by spontaneous and induced chromosome fragility, especially after treatment with cross-linking agents. Recent investigations showed interactions between FA proteins and chromatin remodelling factors. To investigate a potential uneven distribution of the FA pathway through the human genome depending on chromatin conformation, we have analysed chromosome breakage in the largest constitutively heterochromatic region in the human genome, the 1q12 band, in lymphocytes from FA patients, carriers and healthy controls after treatment with the cross-linking agents mitomycin-C (MMC) and diepoxybutane (DEB). As expected, a higher level of MMC-induced cytotoxicity and chromosome breakage was observed in cells from FA patients when compared with normal controls and carriers. However, the increase in 1q12 breakage after increasing concentrations of MMC was of a similar magnitude in FA patients, carriers and controls. Similarly, DEB induced a high level of overall genome chromosome fragility in cells from FA patients when compared with controls with no parallel increase in chromosome breaks specifically involving the heterochromatic band 1q12. We therefore conclude that, unlike the overall genome, the sensitivity of chromosome 1 constitutive heterochromatin to the chromosome breaking activity of cross-linking agents is independent of a functional FA pathway, indicating that the action of the FA pathway is unevenly distributed through the human genome.
Carcinogenesis 2002 Aug
PMID:The clastogenic response of the 1q12 heterochromatic region to DNA cross-linking agents is independent of the Fanconi anaemia pathway. 1215 43

Chromium exists mostly in two valence states in nature: hexavalent chromium [chromium(VI)] and trivalent chromium [chromium(III)]. Chromium(VI) is commonly used in industrial chrome plating, welding, painting, metal finishes, steel manufacturing, alloy, cast iron and wood treatment, and is a proven toxin, mutagen and carcinogen. The mechanistic cytotoxicity of chromium(VI) is not completely understood, however, a large number of studies demonstrated that chromium(VI) induces oxidative stress, DNA damage, apoptotic cell death and altered gene expression. Conversely, chromium(III) is essential for proper insulin function and is required for normal protein, fat and carbohydrate metabolism, and is acknowledged as a dietary supplement. In this paper, comparative concentration- and time-dependent effects of chromium(VI) and chromium(III) were demonstrated on increased production of reactive oxygen species (ROS) and lipid peroxidation, enhanced excretion of urinary lipid metabolites, DNA fragmentation and apoptotic cell death in both in vitro and in vivo models. Chromium(VI) demonstrated significantly higher toxicity as compared with chromium(III). To evaluate the role of p53 gene, the dose-dependent effects of chromium(VI) were assessed in female C57BL/6Ntac and p53-deficient C57BL/6TSG p53 mice on enhanced production of ROS, lipid peroxidation and DNA fragmentation in hepatic and brain tissues. Chromium(VI) induced more pronounced oxidative damage in multiple target organs in p53 deficient mice. Comparative studies of chromium(III) picolinate and niacin-bound chromium(III), two popular dietary supplements, reveal that chromium(III) picolinate produces significantly more oxidative stress and DNA damage. Studies have implicated the toxicity of chromium picolinate in renal impairment, skin blisters and pustules, anemia, hemolysis, tissue edema, liver dysfunction; neuronal cell injury, impaired cognitive, perceptual and motor activity; enhanced production of hydroxyl radicals, chromosomal aberration, depletion of antioxidant enzymes, and DNA damage. Recently, chromium picolinate has been shown to be mutagenic and picolinic acid moiety appears to be responsible as studies show that picolinic acid alone is clastogenic. Niacin-bound chromium(III) has been demonstrated to be more bioavailable and efficacious and no toxicity has been reported. In summary, these studies demonstrate that a cascade of cellular events including oxidative stress, genomic DNA damage and modulation of apoptotic regulatory gene p53 are involved in chromium(VI)-induced toxicity and carcinogenesis. The safety of chromium(III) is largely dependent on the ligand, and adequate clinical studies are warranted to demonstrate the safety and efficacy of chromium(III) for human consumption.
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PMID:Cytotoxicity and oxidative mechanisms of different forms of chromium. 1260 81

We review the genes and proteins related to the homologous recombinational repair (HRR) pathway that are implicated in cancer through either genetic disorders that predispose to cancer through chromosome instability or the occurrence of somatic mutations that contribute to carcinogenesis. Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. The Werner syndrome gene (WRN) helicase, another member of the RecQ family like BLM, has very recently been found to help mediate homologous recombination. Fanconi anemia (FA) is a genetically complex chromosomal instability disorder involving seven or more genes, one of which is BRCA2. FA may be at least partially caused by the aberrant production of reactive oxidative species. The breast cancer-associated BRCA1 and BRCA2 proteins are strongly implicated in HRR; BRCA2 associates with Rad51 and appears to regulate its activity. We discuss in detail the phenotypes of the various mutant cell lines and the signaling pathways mediated by the ATM kinase. ATM's phosphorylation targets can be grouped into oxidative stress-mediated transcriptional changes, cell cycle checkpoints, and recombinational repair. We present the DNA damage response pathways by using the DSB as the prototype lesion, whose incorrect repair can initiate and augment karyotypic abnormalities.
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PMID:Recombinational DNA repair and human disease. 1242 31

D&C Yellow No. 11 is used to color topical drug preparations and cosmetics. It is also used in spirit lacquers, polystyrenes, polycarbonates, polyamides, acrylic resins, colored smokes, and hydrocarbon solvents. D&C Yellow No. 11 was nominated to the NTP for toxicity and carcinogenesis studies as part of a larger regulatory effort mandated by Congress and undertaken by the Food and Drug Administration to determine the safety of a number of provisionally listed dyes. D&C Yellow No. 11 is currently regulated for external use. The recommendation to study D&C Yellow No. 11 by dietary exposure was based on the fact that it is a contaminant of D&C Yellow No. 10, a candidate for permanent listing as a chemical for which there is a potential for ingestion. First-generation (F(0)) male and female F344/N rats were given D&C Yellow No. 11 (approximately 99% pure) in feed for up to 19 weeks and then mated, and exposure of second-generation (F(1)) males and females began in utero and continued for 2 years after weaning at 28 days of age. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood. REPRODUCTIVE TOXICITY STUDY: Groups of 60 male and 60 female F(0) rats were given 0, 500, 1,700, or 5,000 ppm D&C Yellow No. 11 in feed for up to 19 weeks, which resulted in average daily doses of 35, 120, or 350 mg D&C Yellow No. 11/kg body weight to males and 35, 120, or 370 mg/kg to females. All F(0) males and females survived until the end of the study. Prior to cohabitation, mean body weight gains of males given 500, 1,700, or 5,000 ppm and of females given 5,000 ppm were significantly lower than those of the controls. The mean body weight gains of exposed females during gestation and lactation were generally similar to those of the controls. Feed consumption by exposed groups of rats was generally similar to that by the control groups prior to cohabitation. The duration of gestation, the average litter size, the number of live pups on days 4 (precull) and 21, and the percentage of male pups for each exposure group were similar to those of the controls. The mean body weights of exposed litters were significantly less than those of the control litters on days 14 and 21; this effect was considered to be related to D&C Yellow No. 11 exposure. 2-YEAR STUDY: Groups of 60 male and 60 female F(1) rats were given 0, 500, 1,700, or 5,000 ppm D&C Yellow No. 11 in feed for 105 (males) or 106 (females) weeks after weaning (day 28); 6 to 10 rats per group were evaluated at 12 months. These exposure concentrations resulted in average daily doses of approximately 25, 85, or 250 mg D&C Yellow No. 11/kg body weight to males and 25, 100, or 280 mg/kg to females. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of males given 1,700 or 5,000 ppm was significantly less than that of the controls, and survival of 1,700 ppm females was significantly greater than that of the controls. Mean body weights of 1,700 and 5,000 ppm males and females were generally lower than those of the controls throughout the study. Feed consumption by exposed groups was similar to that by the controls. Chemical-related clinical findings included yellow discoloration of the entire body in all exposed males and females from day 1 and head swelling and edema in 1,700 and 5,000 ppm males. One 1,700 ppm and five 5,000 ppm males were moribund and were killed between weeks 49 and 81; these deaths were attributed to extensive edema. Hematology: A few minimal hematology changes occurred in male rats at the 12-month interim evaluation. There was evidence of minimal anemia in exposed males; this anemia was characterized by decreased hematocrit values, hemoglobin concentrations, and erythrocyte counts. The minimal anemia was characterized as normocytic, normochromic, and nonresponsive. There were no biologically or statistically significant differences in hematology parameters between control and exposed females. Pathology Findings: Absolute and relative liver weights of all exposed groups of md relative liver weights of all exposed groups of males and females were significantly greater than those of the controls at 12 months. At 2 years, the incidences of hepatocellular adenoma in 5,000 ppm males and of hepatocellular adenoma or carcinoma (combined) in 5,000 ppm females were significantly greater than those in the controls. At 12 months, the incidences of clear cell foci in 1,700 and 5,000 ppm females were significantly greater than that in the controls. At 2 years, the incidences of mixed cell foci in exposed males and of clear cell foci in exposed males (except 500 ppm) and females were significantly greater than those in the controls. Incidences of cytologic alterations (basophilia and granularity) of hepatocytes, and pigmentation in bile duct epithelium, hepatocytes, and Kupffer cells in exposed males and females were greater than those in the controls at both 12 months and 2 years. Renal tubule adenomas were observed in two 5,000 ppm males, and one renal tubule carcinoma was observed in a 1,700 ppm male. During an extended evaluation, renal tubule adenomas were observed in two additional 5,000 ppm males, four 1,700 ppm males, and two 500 ppm males. Renal tubule hyperplasia was observed in exposed groups of males but not in controls, and the incidences in 1,700 ppm males from both standard and extended evaluations were significantly greater than those in the controls. Necrosis and regeneration of the renal tubule epithelium were observed in all control and exposed male rats and in most female rats at 12 months and 2 years. The severity of nephropathy in exposed males and females was significantly greater than that in the controls. In exposed males and 1,700 ppm females at 2 years, the incidences of hyperplasia of the transitional epithelium in the kidney, which commonly accompanies advanced nephropathy, were greater than those of the controls, and the severity of this lesion in exposed males and females was greater than that in the controls. The incidences of renal tubule pigmentation in all exposed groups of males and females at 12 months and 2 years were significantly greater than those in the controls. Squamous cell carcinomas of the tongue were observed in one 500 ppm male at 12 months and one 5,000 ppm female at 2 years, and one squamous cell carcinoma of the oral mucosa was observed in each group of exposed males and in one 5,000 ppm female at 2 years. At 2 years, squamous cell papillomas were observed in the oral cavity (oral mucosa or tongue) of one control, one 500 ppm, two 1,700 ppm, and four 5,000 ppm males; this lesion was also observed in one control and one 500 ppm female. GENETIC TOXICOLOGY: Results of mutagenicity tests with D&amp;C Yellow No. 11 in Salmonella typhimurium were equivocal in one study, based on responses observed in strain TA100 with induced rat liver S9, and weakly positive in a second study, based on responses observed in strains TA98 and TA100 with induced rat or hamster liver S9. D&amp;C Yellow No. 11 induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. No increase in the frequency of micronucleated normochromatic erythrocytes was observed in peripheral blood samples from male and female B6C3F(1) mice administered D&amp;C Yellow No. 11 in feed for 13 weeks. CONCLUSIONS: Under the conditions of this perinatal exposure followed by a 2-year dosed feed study, there was some evidence of carcinogenic activity of D&amp;C Yellow No. 11 in male F344/N rats based on increased incidences of hepatocellular adenoma, renal tubule neoplasms, and squamous cell neoplasms of the oral cavity. There was some evidence of carcinogenic activity in female F344/N rats based on increased inci dences of hepatocellular neoplasms. Incidences of uncommon squamous cell carcinoma of the oral cavity in females may have been related to chemical treatment. Exposure of rats to D&amp;C Yellow No. 11 in feed for 2 years resulted in increased incidences of nonneoplastic liver lesions including clear cell foci, increased basophilia and granularity in the cytoplasm of hepatocytes, and bile duct, hepatocyte, and Kupffer cell pigmentation in males and females and mixed cell foci in males. In the kidney, there were increased incidences of renal tubule pigmentation and transitional epithelial hyperplasia in males and females and renal tubule hyperplasia in males. The severity of nephropathy was increased in exposed males and females. Synonyms: 2-(2-Quinolinyl)-1H-indene-1,3-(2H)-dione; 2-(2-quinolyl)-1,3-indandione Trade names: Arlosol Yellow S, Chinoline Yellow D (soluble in spirits), Chinoline Yellow ZSS, C.I. 47000, C.I. Solvent Yellow 33, Nitro Fast Yellow SL, Oil Yellow SIS, Petrol Yellow C, Quinoline Yellow A Spirit Soluble, Quinoline Yellow Base, Quinoline Yellow Spirit Soluble, Quinoline Yellow SS, Solvent Yellow 33, Waxoline Yellow T
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PMID:NTP Toxicology and Carcinogenesis Studies of D&C Yellow No. 11 (CAS No. 8003-22-3) in F344/N Rats (Feed Studies). 1258 13


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