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Aromatase (estrogen synthase) is the cytochrome P450 enzyme complex that converts C19 androgens to C18 estrogens. Aromatase activity has been demonstrated in breast tissue in vitro, and expression of aromatase is highest in or near breast tumor sites. Thus, local regulation of aromatase by both endogenous factors as well as exogenous medicinal agents will influence the levels of estrogen available for breast cancer growth. The prostaglandin E2 (PGE2) increases intracellular cAMP levels and stimulates estrogen biosynthesis, and our recent studies have shown a strong linear association between CYP19 expression and the sum of COX-1 and COX-2 expression in breast cancer specimens. PGE2 can bind to four receptor subtypes, EP1–EP4, which are coupled to different intracellular signaling pathways. In primary human breast stromal cell cultures, aromatase activity was significantly induced by PGE2, dexamethasone, and agonists for the EP1 and EP2 receptor subtypes. An EP1 antagonist, SC-19220, inhibited the induction of enzyme activity by PGE2 or 17-phenyltrinor-PGE2, an EP1 agonist. Sulprostone, an EP3 agonist, did not alter aromatase activity levels. Investigations are also underway on the regulation of aromatase by exogenous medicinal agents. Selective steroidal and nonsteroidal agents are effective in inhibiting breast tissue aromatase. The benzopyranone ring system is a molecular scaffold of considerable interest, and this scaffold is found in certain flavonoid natural products that have weak aromatase inhibitory activity. Our novel synthetic route for benzopyranones utilizes readily available salicylic acids and terminal alkynes as starting materials. The synthesis of flavones with diversity on the benzopyranone moiety and at the C-2 position occurs with good to excellent yields using these reaction conditions, resulting in an initial benzopyranone library of thirty compounds exhibiting enhanced and differential aromatase inhibition. Current medicinal chemistry efforts focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aromatase inhibitors.  相似文献   

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Genetic epidemiology of multistage carcinogenesis   总被引:6,自引:0,他引:6  
It is commonly believed that cancer is a multistage, polygenic disease. Even though conceptually appealing, the evidence supporting the multistage theory remains limited. Most known tumor suppresser genes are associated with monogenic dominant cancers following a two-hit pathway. We review results from a recent twin study on 90000 individuals that give support to the multistage theory. Statistically significant heritability estimates were shown for cancers of the colorectum (35%), breast (27%), and prostate (42%). These estimates are much higher than those obtained from family studies in which parents and offspring, or sibs are compared. The difference can be accounted for by the involvement of many genes. A polygenic cancer would show small effects in family studies but large effects in twin studies. We present calculations on the decrease in familial risks when the number of genes involved increases or when the penetrance decreases. We test the apparent number of stages involved in the main cancers from the Swedish Family-Cancer Database. The logarithms of the slopes suggest large differences in the apparent numbers of mutations involved in different cancers. The number of mutations required appears to be less in familial breast cancer compared to sporadic breast cancer. Study designs for gene identification should be revised to accommodate polygenic cancers.  相似文献   

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Retroviruses are distinguished from other viruses by several features. Notably, some retroviruses are present as normal elements in the genomes of virtually all vertebrates (endogenous proviruses). Others are exogenous, i.e. horizontally transmitted agents, many of which cause fatal diseases. The endogenous retroviruses are genetically transmitted and to a large extent their significance is uncertain. However, there is evidence suggesting that they contribute to the development of diseases in several animal species. Most importantly, some endogenous retroviruses are capable of interacting with exogenous counterparts through a variety of different mechanisms with serious consequences to the host. Conversely, others are advantageous in that they protect against exogenous retroviruses. In this review various types of interactions between endogenous and exogenous retroviruses are discussed, including receptor interference, recombination, phenotypic mixing, immunological interactions and heterologoustrans-activation.  相似文献   

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Retrovirus genes have become inserted into the human genome for more than one million years. These retroviruses are now inactivated due to mutation, such as deletions or nonsense mutations. After mutation, retroviruses eventually become fixed in the genome in the endogenous form and exist as traces of ancient viruses. These retroviruses are called human endogenous retroviruses (HERVs). HERVs cannot make fully active viruses, but a number of viral proteins (or even virus particles) are expressed under various conditions. By comparison with ERVs, some exogenous retroviruses are still infectious and cause serious diseases threatening human life. Recent studies have shown that some elements of HERVs are closely related to other exogenous retroviruses, including human immunodeficiency virus (HIV). This review will describe the regulation and interaction between HERVs and other active viral infections. In addition, we introduce the development of vaccines and therapeutic agents against these viral infections through the use of HERV elements.  相似文献   

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This paper reviews the experimental results of our research in the past several years and other related papers that have been directed toward the occurrence, biotransformation and epidemiological significance of carcinogenic N-nitroso compounds in biosphere. Endogenous carcinogens are a group of cancer-causing compounds produced in vivo from harmless precursors. This category has been exemplified by the well-known carcinogens, N-nitroso compounds. The significance of naturally occurring amines and amides as precursors of carcinogenic N-nitroso compounds in vivo and their implication in the incidence of human cancer have been investigated and emphasized. Extremely high levels of trimethylamine-N-oxide and dimethylamine were detected in squids and other seafoods. More than 90% of trimethylamine-N-oxide were converted to dimethylamine and trimethylamine on pyrolysis. Low levels of dimethylamine and methylamine were also detected in the fermented soybean products, wines and sauces. Both dimethylamine and trimethylamine are excellent precursors of dimethylnitrosamine. Several naturally occurring aromatic amines especially 2-carboline derivatives such as harman, norharman, harmaline, harmalol, harmine and harmol are mutagenic and become more mutagenic to Salmonella typhimurium after nitrosation. Appreciable amounts of piperidine were detected in the popular spice white and black pepper powders. Under acidic condition, piperidine reacts readily with nitrite to form carcinogenic N-nitroso-piperidine. N-Nitrosophenacetin was formed from the reaction of nitrite with the amide drug phenacetin. This new compound showed strong mutagenicity to Salmonella typhimurium and Sarcina lutea and strong teratogenic activity to Leghorn chicken embryos. Studies have shown that the majority of N-nitroso compounds in the body come from in vivo conversion. Most investigators believe that this endogenous pool of N-nitroso compounds may prove to be a major exposure route in man. The presence of naturally occurring amines and amides in the diet then becomes one of the crucial limiting steps in the formation of endogenous N-nitroso compounds in vivo.  相似文献   

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Ethanolaminephosphotransferase (EC 2.7.8.1) activity was determined in lung microsomes using diacylglycerols generated endogenously from [14C]glycerol 3-phosphate and different mixtures of fatty acids. Ethanolaminephosphotransferase used endogenously generated dipalmitoylglycerol better than dioleoylglycerol. The apparent Km and the reaction rates for four different endogenously generated mixtures were the same (16 nmol/mg microsomal proteins). The apparent Km values for CDP-ethanolamine were the same (0.26 mm) for endogenously generated dipalmitoylglycerol and dioleoylglycerol. The amount of diacylglycerol generated in microsomes was 2-3-times the apparent Km for diacylglycerol. Dipalmitoylglycerol, supplied exogenously as a Tween 20/phosphatidylglycerol emulsion, was nearly twice as active as dioleoylglycerol. Both dipalmitoylglycerol and dioleoylglycerol were more active as substrates when emulsions were made with phosphatidylglycerol/Tween 20 than with Tween 20 alone. The results suggest that ethanolaminephosphotransferase in lung is relatively nonselective for molecular species of diacylglycerol. In addition, the results suggest that the concentration of diacylglycerol and the physical state in which it is presented to the enzyme can affect the apparent selectivity of ethanolaminephosphotransferase for diacylglycerols.  相似文献   

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Histologic examination of the spleens in RFM/Un mice killed 6 to 9 days after 350 to 800 R whole-body x-irradiation revealed hemopoietic colonies, the numbers of which decreased exponentially with increasing radiation dose. In such animals, myelocytic colonies were the predominant type on the sixth to the eighth day. However, they decreased in number with time, being fewer than erythropoietic colonies by the ninth day after irradiation. In C57BL mice, erythropoietic colonies were relatively more numerous, markedly predominating on both the eighth and the thirteenth days. RFM/Un mice injected with nonirradiated syngeneic bone marrow cells within 24 hours after 750 R developed colonies, predominantly of erythropoietic and undifferentiated types, the numbers of which were proportional to the numbers of marrow cells injected. The number of colonies formed from exogenous marrow cells increased slightly between the sixth and ninth days after inoculation, possibly because of a greater likelihood of counting them due to an increase in their size.  相似文献   

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肿瘤发生发展的分子机理(4)   总被引:1,自引:0,他引:1  
细胞由静息状态进入到细胞增殖期并不断进展是受到十分精确调控的,一旦细胞进入到G1后期这个“限制点”,将不可逆转地进入到S期,进行DNA复制。细胞周期蛋白、细胞周期蛋白依赖激酶(cyclindependent kinases,CDKs)和Rb蛋白都是调节细胞通过“限制点”的重要成分。这些蛋白可以通过控制细胞  相似文献   

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Betaretroviruses of sheep include two exogenous viruses, Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), and a group of endogenous viruses known as enJSRVs. The exogenous JSRV and ENTV are the etiological agents of ovine pulmonary adenocarcinoma (OPA) and enzootic nasal tumor (ENT), respectively. Sheep affected by OPA or ENT do not show an appreciable antibody response to JSRV or ENTV. Consequently, it is conceivable that enJSRV expression in the fetal lamb tolerizes sheep to the related exogenous viruses. In this study, possible mechanisms of interference between the sheep exogenous and endogenous betaretroviruses were investigated. In situ hybridization detected enJSRV RNAs in lymphoid cells associated with the lamina propria of the small intestine and in the thymus of sheep fetuses. Low-level expression of enJSRVs was also detected in the lungs. In addition, expression of enJSRVs was found to block entry of the exogenous JSRV, presumably via mechanisms of receptor interference. Indeed, enJSRVs, like JSRV and ENTV, were found to utilize hyaluronidase-2 as a cellular receptor.  相似文献   

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The expression of macrophage antitumor activity and the production of prostaglandins (PG) by operationally defined macrophage populations differed under varying culture conditions. Culture conditions that caused increased PGE2 production by activated macrophages resulted in an inhibition of their tumoricidal activity. In contrast, production of high levels of PGE2 by resident and elicited macrophages was associated with an increase in antitumor activity. The activation of resident or elicited cells by lipopolysaccharide (LPS) could be blocked by indomethacin. Treatment of these macrophages with PGE2 alone also resulted in their activation and subsequent tumor cell destruction. Activation of resident and elicited macrophages by LPS appears to be mediated by PGE2.  相似文献   

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Molecular epidemiology of cryptosporidiosis: An update   总被引:1,自引:0,他引:1  
Molecular tools have been developed to detect and differentiate Cryptosporidium at the species/genotype and subtype levels. These tools have been increasingly used in characterizing the transmission of Cryptosporidium spp. in humans and animals. Results of these molecular epidemiologic studies have led to better appreciation of the public health importance of Cryptosporidium species/genotypes in various animals and improved understanding of infection sources in humans. Geographic, seasonal and socioeconomic differences in the distribution of Cryptosporidium spp. in humans have been identified, and have been attributed to differences in infection sources and transmission routes. The transmission of C. parvum in humans is mostly anthroponotic in developing countries, with zoonotic infections play an important role in developed countries. Species of Cryptosporidium and subtype families of C. hominis have been shown to induce different clinical manifestations and have different potential to cause outbreaks. The wide use of a new generation of genotyping and subtyping tools in well designed epidemiologic studies should lead to a more in-depth understanding of the epidemiology of cryptosporidiosis in humans and animals.  相似文献   

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