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At least 1,171 records · Page 65Linked to original sources
PubMed1986

Determinants of tissue oestradiol levels in human breast cancer.

A variety of clinical and experimental evidence indicates that the oestrogens are the major hormones affecting human breast cancer growth. The goal of recent treatment strategies is to reduce the amount of oestradiol acting locally on the tumour. For this reason, it is relevant to examine what determines tumour tissue oestradiol concentrations. Various steps are potentially important and include glandular or extraglandular production of oestradiol, tissue uptake, binding to receptors and the rate of local tissue oestradiol synthesis. In premenopausal women, glandular secretion of oestradiol by the ovary provides the major source of tissue oestradiol. In postmenopausal women, the extraglandular conversion of androstenedione to oestrone and then oestradiol in peripheral tissues accounts for 90% of circulating oestradiol. However, plasma levels of oestradiol in postmenopausal women are only 4 to 40% of those found in premenopausal patients and yet breast cancer tissue levels are similar. This observation suggests the possibility of local oestradiol synthesis by breast tumours in postmenopausal women. We examined two pathways which could be involved in local oestradiol synthesis: the androstenedione to oestrone (aromatase) pathway and the oestrone-sulphate to oestrone (sulphatase) system. Seventy-nine of 128 tumours contained aromatase with activity ranging from 5-80 pmol/g protein/hr. This enzyme was of high affinity with a Km of 0.027 microM. Sulphatase, on the other hand, was present in all tumours with activity ranging from 0.8-125 microM. Its affinity was appreciably lower with a Km of 27 microM. Comparing both activities at substrate concentrations approaching physiological levels, we detected 10-fold higher activity with sulphatase than with aromatase. Further studies revealed the presence of 17 beta-hydroxysteroid dehydrogenase in all tumors studied. Whereas 50% of tissues contained both a high and a low affinity type of activity, the remainder had only the low activity form. Since our data favoured the oestrone-sulphate to oestrone to oestradiol pathway as biologically relevant, we sought to determine whether oestrone-sulphate could act as an oestrogen after conversion to oestradiol. Using an NMU rat mammary tumour soft agar colony forming assay, we found that oestrone-sulphate stimulated colony growth in a manner consistent with its 1% conversion to oestradiol by cells in the agar dishes. Furthermore, preliminary data indicate that oestrone-sulphate can stimulate NMU tumour growth in vivo in rats. The metabolism of oestradiol in tissue can also determine its biological effects and its tissue levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Aromatase↗
PubMed1984

[Metabolism of arachidonic acid of the skin and its significance in the pathophysiology of inflammatory dermatosis].

Arachidonic acid can be converted via the cyclo-oxygenase and lipoxygenase pathways to biologically extremely potent products. The arachidonic acid metabolites - prostaglandins, prostacyclin, thromboxane, leukotrienes and hydroxy-fatty acids - are assumed to play a major role in the pathophysiology of inflammation. The skin shows an active arachidonic acid metabolism which is believed to be involved in the pathogenesis of psoriasis and different forms of dermatitis. Research into the biochemical basis of inflammation should lead to the introduction of new, pathogenetically oriented pharmacological principles in the treatment of these dermatoses.

Arachidonic Acids↗
PubMed1995

[The adipose Bichat bolla flaps in repair of oroantral fistulas].

The Authors review Literature concerning surgical treatment of oro-antral fistulas. After a brief discussion concerning the anatomy of the Bichat bulla, the Authors present two clinical cases of oro-antral fistulas with purulent sinusitis. The lesions were repaired using an adipose flap of the Bichat bulla which was sandwiched between the mucous flap and the bony defect. The partial introduction of the adipose flap in to the maxillary sinus through the bony defect, enabled the osteomyelitis bony edges to revascularize and created a pathway and biological substratum for re-epithelialization of the maxillary sinus. Clinical and radiological follow-up 24 months after treatment revealed stable closure of the fistula and normal ventilation of the maxillary sinus. On the basis of these results and those reported in Literature, the Authors advise employment of this technique, particularly in extensive oro-antral fistulas which do recur with other techniques and which, furthermore are complicated by local infectious processes.

Adipose Tissue↗
PubMed1997

Morphological aspects of the median eminence--place of accumulation and secretion of regulatory neurohormones and neuropeptides.

The median eminence (ME) is a small brain area forming both the structural and functional bridge between the hypothalamus and the hypophysis. It is supplied by a variety of neurohormones and neuropeptides which are delivered to the ME by different hypothalamic and extrahypothalamic pathways. These biologically active substances may act in the ME locally influencing the activity of secretion of the neighbouring terminals or, after being released from the neuronal endings into the network of fenestrated capillaries and transported to the hypophysis, they may be involved in the regulation of secretion of adenohypophyseal hormones. Recent demonstrations of extensive colocalizations of these biologically active substances in individual axonal endings in the ME with wide spectrum of biological actions further emphasizes the ME as an important place involved in the neuroendocrine regulatory processes.

Animals↗
PubMed1998

Cell biology of the 5-lipoxygenase pathway.

The initial enzymatic steps in leukotriene synthesis occur at the nuclear envelope. Cytosolic phospholipase A2 translocates from the cytoplasm to selectively hydrolyze nuclear envelope phospholipids, releasing free arachidonate. 5-Lipoxygenase-activating protein, an arachidonate transfer protein, then binds arachidonate and presents it to 5-lipoxygenase (5-LO), which catalyzes a two-step reaction to produce leukotriene A4. In resting human and rat peripheral blood neutrophils, 5-LO is localized to the cytoplasm; in rat basophilic leukemia cells and human alveolar macrophages, however, it is found predominantly in the nucleus. Immunofluorescence microscopy studies demonstrate that both cytoplasmic and nuclear 5-LO move to the nuclear envelope following cell activation. Many questions remain unanswered regarding the significance of nuclear 5-LO, potential autocrine actions of leukotrienes, and intracellular trafficking of these enzymes and their products.

Animals↗
PubMedDate not supplied

Mechanisms of action and cross-talk between estrogen receptor and progesterone receptor pathways.

The intriguing biology of estrogens and progestins in their diverse target cells is determined by the structure of the hormonal ligand, the receptor subtype or isoform involved, the nature of the hormone-responsive gene promoter, and the character and balance of coactivators and corepressors that modulate the cellular response to the receptor-ligand complex. Estrogens regulate the growth, differentiation, and functioning of diverse target tissues, both within and outside of the reproductive system. Most of the actions of estrogens appear to be exerted through the estrogen receptor (ER) of target cells, an intracellular receptor that is a member of a large superfamily of proteins, which function as ligand-activated transcription factors, regulating the synthesis of specific RNAs and proteins. To understand how the ER discriminates between estrogen ligands, which activate the ER, and antiestrogen ligands, which fail to effectively activate the ER, we have generated and analyzed human ERs with mutations or other alterations in portions of the receptor. These studies provide evidence for the promoter-specific and cell-specific actions of the estrogen-occupied and antiestrogen-occupied ER, highlight a regional dissociation of the hormone-binding and transcription activation functions in domain E of the receptor, and indicate that some of the contact sites of estrogens and antiestrogens in the ER are likely different. In addition, multiple interactions among different cellular signaling pathways are involved in the regulation of gene expression and cell proliferation by the ER. In several cell types, protein kinase activators and some growth factors enhance the transcriptional activity of the ER. Cyclic AMP also alters the agonist/antagonist balance of some antiestrogens. Estrogens, and antiestrogens to a lesser extent, as well as protein kinase activators and growth factors, increase phosphorylation of the ER and possibly other proteins involved in the ER-specific response pathway, suggesting that changes in cellular phosphorylation state will be important in determining the biologic activity of the ER and the effectiveness of antiestrogens as estrogen antagonists. The ER also has important interrelationships with the progesterone receptor (PR) system in modulation of biologic responses. Liganded PR-A and PR-B can each suppress estradiol-stimulated ER activity, with the magnitude of repression dependent on the PR isoform, progestin ligand, promoter, and cell type. These findings underscore the mounting evidence for the importance of interactions between members of the steroid hormone receptor family.

Animals↗
PubMed1999

4HPR triggers apoptosis but not differentiation in retinoid sensitive and resistant human embryonal carcinoma cells through an RARgamma independent pathway.

Retinoids signal biological effects through retinoic acid receptors (RAR) and retinoid X receptors (RXR) and their co-regulators. We previously reported that all-trans retinoic acid (RA) triggers terminal differentiation in the human embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1), through an RARgamma dependent pathway. RARgamma repression in NT2/D1-R1 cells accounts for RA resistance in this line. This report finds RARgamma repression is due to selective repression of RARgamma but not RARbeta transcription in NT2/D1-R1 cells. The repression is neither due to mutations in RARgamma nor its promoter containing the RA response element. Prior work was confirmed and extended by demonstrating that an RARgamma selective agonist preferentially signals differentiation of NT2/D1 cells, while RARalpha/beta, RARbeta, RXR agonists and an RAR pan-antagonist do not even when NT2/D1 cells are treated with these retinoids at 10 microM dosages. None of these examined retinoids induced differentiation of the RA resistant NT2/D1-R1 cells. In contrast, N-(4-hydroxyphenyl)retinamide (4HPR), a reported transcriptional activator of RARgamma was shown to potently induce growth inhibition and apoptosis in both NT2/D1 and NT2/D1-R1 cells. 4HPR-induced apoptosis was unaffected by co-treatment of both cell lines with equimolar RAR antagonist. Semi-quantitative reverse transcription-polymerase chain reaction (RT - PCR) assays of total RNA from 4HPR-treated NT2/D1 and NT2/D1-R1 cells did not reveal RARgamma induction. Since 4HPR signals in RA-resistant NT2/D1-R1 cells having an RARgamma transcriptional block, these results indicate that 4HPR triggers apoptosis but not differentiation through an RARgamma independent pathway. Taken together, these findings implicate a therapeutic role for 4HPR mediated apoptosis in germ cell tumors even when a maturation block is present.

Anticarcinogenic Agents↗
PubMed2005

Yellow pigments used in rapid identification of aflatoxin-producing Aspergillus strains are anthraquinones associated with the aflatoxin biosynthetic pathway.

Studies on biological control of aflatoxin production in crops by pre-infection with non-toxigenic Aspergillus flavus strains have created a need for improved methods to screen isolates for aflatoxigenicity. We have evaluated two empirical aflatoxigenicity tests: (i) yellow pigment production, and (ii) the appearance of a plum-red color in colonies exposed to ammonium hydroxide vapor. Yellow pigments from aflatoxigenic A. flavus were shown to function as pH indicator dyes. Seven pigments representing most of the pigmentation in extracts have been isolated using color changes when chromatography spots were exposed to ammonium hydroxide vapor to guide fractionation. Their structures have been shown to be norsolorinic acid, averantin, averufin, versicolorin C, versicolorin A, versicolorin A hemiacetal and nidurufin, all of which are known anthraquinone pigments on, or associated with, the aflatoxin biosynthetic pathway in Aspergillus spp. Thus, the basis of both empirical tests for aflatoxigenicity is detecting production of excess aflatoxin biosynthetic intermediates.

Aflatoxins↗
PubMed2005

mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival.

mSin3A is a core component of a large multiprotein corepressor complex with associated histone deacetylase (HDAC) enzymatic activity. Physical interactions of mSin3A with many sequence-specific transcription factors has linked the mSin3A corepressor complex to the regulation of diverse signaling pathways and associated biological processes. To dissect the complex nature of mSin3A's actions, we monitored the impact of conditional mSin3A deletion on the developmental, cell biological, and transcriptional levels. mSin3A was shown to play an essential role in early embryonic development and in the proliferation and survival of primary, immortalized, and transformed cells. Genetic and biochemical analyses established a role for mSin3A/HDAC in p53 deacetylation and activation, although genetic deletion of p53 was not sufficient to attenuate the mSin3A null cell lethal phenotype. Consistent with mSin3A's broad biological activities beyond regulation of the p53 pathway, time-course gene expression profiling following mSin3A deletion revealed deregulation of genes involved in cell cycle regulation, DNA replication, DNA repair, apoptosis, chromatin modifications, and mitochondrial metabolism. Computational analysis of the mSin3A transcriptome using a knowledge-based database revealed several nodal points through which mSin3A influences gene expression, including the Myc-Mad, E2F, and p53 transcriptional networks. Further validation of these nodes derived from in silico promoter analysis showing enrichment for Myc-Mad, E2F, and p53 cis-regulatory elements in regulatory regions of up-regulated genes following mSin3A depletion. Significantly, in silico promoter analyses also revealed specific cis-regulatory elements binding the transcriptional activator Stat and the ISWI ATP-dependent nucleosome remodeling factor Falz, thereby expanding further the mSin3A network of regulatory factors. Together, these integrated genetic, biochemical, and computational studies demonstrate the involvement of mSin3A in the regulation of diverse pathways governing many aspects of normal and neoplastic growth and survival and provide an experimental framework for the analysis of essential genes with diverse biological functions.

Animals↗
PubMed2025

A machine learning model and identification of immune infiltration for chronic obstructive pulmonary disease based on disulfidptosis-related genes.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic and progressive lung disease. Disulfidptosis-related genes (DRGs) may be involved in the pathogenesis of COPD. From the perspective of predictive, preventive, and personalized medicine (PPPM), clarifying the role of disulfidptosis in the development of COPD could provide a opportunity for primary prediction, targeted prevention, and personalized treatment of the disease. METHODS: We analyzed the expression profiles of DRGs and immune cell infiltration in COPD patients by using the GSE38974 dataset. According to the DRGs, molecular clusters and related immune cell infiltration levels were explored in individuals with COPD. Next, co-expression modules and cluster-specific differentially expressed genes were identified by the Weighted Gene Co-expression Network Analysis (WGCNA). Comparing the performance of the random forest (RF), support vector machine (SVM), generalized linear model (GLM), and eXtreme Gradient Boosting (XGB), we constructed the ptimal machine learning model. RESULTS: DE-DRGs, differential immune cells and two clusters were identified. Notable difference in DRGs, immune cell populations, biological processes, and pathway behaviors were noted among the two clusters. Besides, significant differences in DRGs, immune cells, biological functions, and pathway activities were observed between the two clusters.A nomogram was created to aid in the practical application of clinical procedures. The SVM model achieved the best results in differentiating COPD patients across various clusters. Following that, we identified the top five genes as predictor genes via SVM model. These five genes related to the model were strongly linked to traits of the individuals with COPD. CONCLUSION: Our study demonstrated the relationship between disulfidptosis and COPD and established an optimal machine-learning model to evaluate the subtypes and traits of COPD. DRGs serve as a target for future predictive diagnostics, targeted prevention, and individualized therapy in COPD, facilitating the transition from reactive medical services to PPPM in the management of the disease.

Pulmonary Disease, Chronic Obstructive↗
PubMed2006

New drugs for the treatment of advanced-stage diffuse large cell lymphomas.

The rapid pace of discovering new signaling pathways that influence the growth and survival of different types of cancer cells has produced a daunting array of potentially new, "drugable" targets for the treatment of cancer. This has been particularly true for the lymphomas. The empiric observation that many kinds of "novel targeted" drugs appear to exhibit relatively selective patterns of activity is testament to the concept that the lymphomas represent an incredibly diverse group of human cancers. Targeting one pathway in a subtype of lymphoma may not be universally effective against all subtypes of lymphoma, even closely related ones. These observations suggest that pharmacologically driven "target identification" plays an important role in the continued development of new therapeutic agents, and underscores the need for more research into the biologic basis for different subtypes of lymphoma. Over the past 10 years, there has been an explosion of new drugs making their way through preclinical laboratories and early clinical studies. These experiences have taught us some frustrating lessons. Sometimes, the strongest biologic rationale is associated with the poorest clinical results. Sometimes, where no rationale exists, golden therapeutic opportunities emerge. In either case, both experiences typically end up teaching us something about the disease we didn't historically appreciate. In this review, we will take a close look at some of the more intriguing targets in aggressive large B-cell lymphomas, all of which now have small molecules that can profoundly affect their activity, activity we hope will lead to new treatment opportunities. We will focus on the biologic rationale for targeting novel pathways regulated by Bcl-6, Bcl-2, BLysS, and APRIL for example. In addition, we will review how new concepts in structural biology and chemical design can help produce new generation compounds with novel activity, as is the case for pralatrexate and targeting the reduced folate carrier-type-1. Clearly, given the breadth and depth of information emerging on these and other relevant biologic pathways, we are limited to discussing only a few illustrative examples, which should in no way detract from the importance of other critical signaling and survival pathways now being exploited in the treatment of lymphoma.

Antibodies, Monoclonal↗
PubMed2004

Ethylene modulates development and toxin biosynthesis in aspergillus possibly via an ethylene sensor-mediated signaling pathway.

Ethylene, a biologically active natural compound, inhibited aflatoxin accumulation by Aspergillus parasiticus on a solid growth medium in a dose-dependent manner at concentrations of 0.1 to 150 ppm. The activity of the nor-1 promoter (an early aflatoxin gene) was reduced to nondetectable levels by similar quantities of ethylene, suggesting that the inhibitory effect on toxin synthesis occurred, at least in part, at the level of transcription. The inhibitory effect of ethylene on aflatoxin accumulation was also observed when A. parasiticus was grown on raw peanuts. Under similar growth conditions and doses, ethylene strongly inhibited development of asci and ascospores in Aspergillus nidulans, with no detectable effect on Hülle cell formation, conidiation, or sterigmatocystin accumulation. During early growth, A. parasiticus and A. nidulans produced ethylene with approximately twofold higher quantities measured in continuous light than in the dark. 1-Methylcyclopropene (an inhibitor of ethylene receptors in plants), light, CO2, temperature, and growth medium composition altered the effect of ethylene on A. nidulans and A. parasiticus. These observations are consistent with the existence of an ethylene sensor molecule that mediates the function of an ethylene-responsive signaling pathway(s) in Aspergillus.

Aflatoxins↗
PubMed2001

Functional modules in biological signalling networks.

Signalling pathways carry information from the outside of the cell to cellular machinery capable of producing biochemical or physiological responses. Although linear signalling plays an important role in biological regulation, signalling pathways are often interconnected to form networks. We have used computational analysis to study emergent properties of simple networks that consist of up to four pathways, We find that when one pathway gates signal flow through other pathways which produce physiological responses, gating results in signal prolongation such that the signal may be consolidated into a physiological response. When two pathways combine to form a feedback loop such feedback loops can exhibit bistability. Negative regulators of the loop can serve as the locus for flexibility whereby the system has the capability of switching states or functioning as a proportional read-out system. Networks where bistable feedback loops are connected to gates can lead to persistent signal activation at distal locations. These emergent properties indicate system analysis of signalling networks may be useful in understanding higher-order biological functions.

Animals↗