scholarly journals Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

2005 ◽  
Vol 26 (2) ◽  
pp. 171-202 ◽  
Author(s):  
M. J. Reed ◽  
A. Purohit ◽  
L. W. L. Woo ◽  
S. P. Newman ◽  
B. V. L. Potter
Keyword(s):  
Tumor Growth ◽  
Prognostic Significance ◽  
Dehydroepiandrosterone Sulfate ◽  
The Body ◽  
Biologically Active ◽  
Steroid Sulfatase ◽  
Estrone Sulfate ◽  
Estrogenic Properties ◽  
Hydrolysis Of

Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

scholarly journals Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

2011 ◽  
Vol 212 (2) ◽  
pp. 99-110 ◽  
Author(s):  
Atul Purohit ◽  
Paul A Foster
Keyword(s):  
Clinical Trials ◽  
Dehydroepiandrosterone Sulfate ◽  
Biologically Active ◽  
Steroid Sulfatase ◽  
Developmental History ◽  
Estrone Sulfate ◽  
Therapy Targets ◽  
History Of

Estrogens and androgens are instrumental in the maturation of many hormone-dependent cancers. Consequently, the enzymes involved in their synthesis are cancer therapy targets. One such enzyme, steroid sulfatase (STS), hydrolyses estrone sulfate, and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone respectively. These are the precursors to the formation of biologically active estradiol and androstenediol. This review focuses on three aspects of STS inhibitors: 1) chemical development, 2) biological activity, and 3) clinical trials. The aim is to discuss the importance of estrogens and androgens in many cancers, the developmental history of STS inhibitor synthesis, the potency of these compounds in vitro and in vivo and where we currently stand in regards to clinical trials for these drugs. STS inhibitors are likely to play an important future role in the treatment of hormone-dependent cancers. Novel in vivo models have been developed that allow pre-clinical testing of inhibitors and the identification of lead clinical candidates. Phase I/II clinical trials in postmenopausal women with breast cancer have been completed and other trials in patients with hormone-dependent prostate and endometrial cancer are currently active. Potent STS inhibitors should become therapeutically valuable in hormone-dependent cancers and other non-oncological conditions.

scholarly journals Steroid sulfatase deficiency causes cellular senescence and abnormal differentiation by inducing Yippee-like 3 expression in human keratinocytes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyoung-Seok Baek ◽  
Tae-Uk Kwon ◽  
Sangyun Shin ◽  
Yeo-Jung Kwon ◽  
Young-Jin Chun
Keyword(s):  
Cellular Senescence ◽  
Disease Model ◽  
Human Keratinocytes ◽  
Dehydroepiandrosterone Sulfate ◽  
Steroid Sulfatase ◽  
Cholesterol Sulfate ◽  
Knock Out ◽  
Estrone Sulfate ◽  
Breast And Prostate Cancer ◽  
Related Proteins

AbstractHuman steroid sulfatase (STS) is an enzyme that catalyzes the hydrolysis of dehydroepiandrosterone sulfate (DHEAS), estrone sulfate (E1S), and cholesterol sulfate. Abnormal expression of STS causes several diseases including colorectal, breast, and prostate cancer and refractory skin disease. In particular, accumulation of intracellular cholesterol sulfate by STS deficiency leads to a skin disorder with abnormal keratinization called X-linked ichthyosis (XLI). To determine the detailed mechanisms of XLI, we performed RNA sequencing (RNA-seq) analysis using human keratinocyte HaCaT cells treated with cholesterol and cholesterol sulfate. Of the genes with expression changes greater than 1.5-fold, Yippee-like 3 (YPEL3), a factor expected to affect cell differentiation, was found. Induction of YPEL3 causes permanent growth arrest, cellular senescence, and inhibition of metastasis in normal and tumor cells. In this study, we demonstrate that YPEL3 expression was induced by STS deficiency and, using the CRISPR/Cas9 system, a partial knock-out (STS+/−) cell line was constructed to establish a disease model for XLI studies. Furthermore, we show that increased expression of YPEL3 in STS-deficient cell lines promoted cellular senescence and expression of keratinization-related proteins such as involucrin and loricrin. Our results suggest that upregulation of YPEL3 expression by STS deficiency may play a crucial role in inducing cellular senescence and abnormal differentiation in human keratinocytes.

Matrix Metalloproteinases: Biologic Activity and Clinical Implications

2000 ◽  
Vol 18 (5) ◽  
pp. 1135-1135 ◽  
Author(s):  
Amy R. Nelson ◽  
Barbara Fingleton ◽  
Mace L. Rothenberg ◽  
Lynn M. Matrisian
Keyword(s):  
Matrix Metalloproteinases ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Metastatic Tumor ◽  
The Body ◽  
Genetic Changes ◽  
Biologic Activity ◽  
The Matrix ◽  
Degradative Enzymes

ABSTRACT: Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.

scholarly journals ОЦІНКА БІОЛОГІЧНОЇ ДІЇ ЕЛЕМЕНТВМІСНИХ ЛІПІДНИХ КОМПЛЕКСІВ З CHLORELLA VULGARIS НА ФУНКЦІОНАЛЬНИЙ СТАН ЗДОРОВИХ ЩУРІВ

2020 ◽  
Vol 80 (3-4) ◽  
pp. 50-62
Author(s):  
O. I. Bodnar ◽  
H. B. Kovalska ◽  
O. Ya. Lukashiv ◽  
V. V. Grubinko
Keyword(s):  
Trace Elements ◽  
Antioxidant System ◽  
Lipid Fraction ◽  
Dry Weight ◽  
The Body ◽  
Biologically Active ◽  
Spectrometric Analysis ◽  
Diene Conjugates ◽  
Complete Set

Chlorella is one of the most promising species of algae, which is widely cultivated for the industrial production of nutraceuticals in the form of tablets or powder. The value of Chlorella is primarily due to the high content of proteins and lipids (51–58 % and 20–23 % of dry weight respectively), carotenoids and an almost complete set of vitamins. At the same time, in the process of cultivation, a method was developed to enrich algobiomass and its individual components (primarily the lipid fraction) with selenium, zinc, chromium, as important regulatory trace elements. From chlorella, we obtained seleniumlipid, selenium-zinclipid and selenium-chromiumlipid complexes, and their constancy and structure were grounded by chromatographic and mass spectrometric analysis. After feeding healthy rats with a starch solution of selenium-zinclipid complex (1 ml of which contained 0.4 μg of selenium, 2.5 μg of zinc and 0.5 mg of lipids) and selenium-chromiumlipid complex (1 ml contained 1.85 μg of selenium, 1.1 μg of chromium, 0,45 mg of lipids), no signs of intoxication were found (total medium molecular peptides content was reduced to 1.5 times, the content of TBA-active products and diene conjugates were also decreased), antioxidant processes (increase of glutathione content and activity of glutathione peroxidase while reducing the functional role of catalase) were activated (by increasing of succinate dehydrogenase and cytochrome oxidase activity, glutamate dehydrogenase - the way of glutamate formation), which contributed to the successful functioning of the antioxidant system and maintenance of energy and metabolic homeostasis in the body. The obtained results enable the use of biologically active additives from chlorella, enriched with trace elements Se (IV), Zn (II) and Cr (III), as promising therapeutic and prophylactic substances, which will contribute to the successful functioning of the antioxidant system, maintain energy metabolism and metabolism correction of pathological processes, which is the basis for further studies of the biological activity of the complexes under study.

scholarly journals Integrated Bioinformatics Data Analysis and Experimental Studies Reveals Prognostic Significance of ALDH Family in Endometria Cancer

2021 ◽  
Author(s):  
Zhou-Tong Dai ◽  
Yuan Xiang ◽  
Xing-Hua Liao
Keyword(s):  
Cell Lines ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Experimental Studies ◽  
Female Reproductive Tract ◽  
The Body ◽  
Mouse Tumor ◽  
The Impact

Abstract Background Uterine Corpus Endometrial Cancer (UCEC) is one of the three common malignant tumors of the female reproductive tract. According to reports, the cure rate of early UCEC can reach 95%. Therefore, the development of prognostic markers will help UCEC patients to find the disease earlier and develop treatment earlier. The ALDH family was first discovered to be the essential gene of the ethanol metabolism pathway in the body. Recent studies have shown that ALDH can participate in the regulation of cancer. Methods We used the gene profile data of 33 cancers in the TCGA database to analyze the expression and survival of the ALDH family. GO, KEGG, PPI multiple functional analysis was used to predict the regulatory role of ALDH family in cancer. In addition, using CCK-8, colony formation, nude mouse tumor formation and other methods, the in vitro function of UCEC cancer cell lines was tested to further confirm the key role of ALDH2 expression in the proliferation of UCEC cell lines. Finally, Lasso and Cox regression methods were used to establish an overall survival prognosis model based on ALDH2 expression. Result In our research, we explored the expression of ALDH family in 33 cancers. It was found that ALDH2 was abnormally expressed in UCEC. Besides, in vivo and in vitro experiments were conducted to explore the effect of ALDH2 expression on the proliferation of UCEC cell lines. Meanwhile, the change of its expression is not due to gene mutations, but is regulated by miR-135-3p. At the same time, the impact of ALDH2 changes on the survival of UCEC patients is deeply discussed. Finally, a nomogram for predicting survival was constructed, with a C-index of 0.798 and AUC of 0.764. Conclusion This study suggests that ALDH2 may play a crucial role in UCEC progression and has the potential as a prognostic biomarker of UCEC.

ATEROSCLEROSIS AND INFLAMMATION: GENERAL PATHOGENETIC MECHANISMS

2019 ◽  
pp. 31-37
Author(s):  
S. H. Kotiuzhynska ◽  
D. O. Umanskyy
Keyword(s):  
Fatty Acids ◽  
Endothelial Dysfunction ◽  
Polyunsaturated Fatty Acids ◽  
Functional State ◽  
Transport System ◽  
Vascular Wall ◽  
The Body ◽  
Biologically Active ◽  
Lipid Transport

According to modern notions, atherosclerosis is a complex multifactorial process in which the mechanisms of development involved endothelial dysfunction, inflammation, dyslipidemia, disorders of the blood coagulation system, and the like. Polyunsaturated fatty acids are a source of biologically active substances that regulate metabolic processes in the body. It is known that during the development of inflammation, biologically active agents are synthesized and accumulated, which both provide a protective function, and play the role of triggers or lead to the development of additional alteration and the formation of pathological systems. Purpose of the study. The purpose of the work is to study the functional state of the lipid transport system and to ascertain the role of polyunsaturated fatty acids in the mechanisms of atherosclerosis. The analysis of the functional state of the lipid-transport system of 221 patients with diffuse cardiosclerosis with different nosological forms revealed a disturbance of direct and reverse transport of cholesterol, but with varying degrees of orientation. Significant increase in the content of saturated fatty acids by 7.51% and reduction of unsaturated. Reducing the level of polyunsaturated fatty acids is a consequence of increased formation of prostaglandins and leukotrienes in inflammatory processes of the vascular wall, and indicates a disbalance in the regulation of lipid homeostasis. The deficiency in polyunsaturated fatty acid cells for many years models the high potential of endothelial dysfunction, which can be a pathogenetic mechanism not only for atherosclerotic lesions, but also for inflammation of the vessels. Conclusion. The recognition of atherogenesis as an active process rather than a cholesterol storage disease has highlighted some key inflammatory mechanisms. In our opinion, the local violation of the transport of lipids in the tissue is at the heart of the atherosclerotic lesion of the vascular wall, which develops irrespective of inflammation in the vessel wall, but substantially potentiates them due to the action of inflammatory mediators.

Dual Aromatase-Sulphatase Inhibitors (DASIs) for the Treatment of Hormone Dependent Breast Cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Laxmi Banjare ◽  
Akhlesh Kumar Jain ◽  
Suresh Thareja
Keyword(s):  
Breast Cancer ◽  
Dehydroepiandrosterone Sulfate ◽  
Develop Breast Cancer ◽  
Estrone Sulfate ◽  
Cancer Tissues ◽  
Breast Cancer Inhibition ◽  
Estrogen Biosynthesis ◽  
Breast Tissues ◽  
Cancer Inhibition

: Breast cancer is the most frequent diagnosed cancer in women and the second most common form of cancer, causing death after lung cancer, all across the globe at an alarming rate. The level of estrogens, in breast cancer tissues of postmenopausal women is 10-40 folds higher than the non-carcinogenic breast tissues. As a result of this greater level of estrogen, breast tissue becomes more prone to develop breast cancer; mainly estradiol plays a significant role in the initiation and development of hormone dependent breast cancer. Androstenedione, Adrenal dehydroepiandrosterone sulfate and estrone-sulfate also plays an important role of precursor for estrogen biosynthesis. Estrogens deprivation exhibits an attractive phenomena in the advancement of most ideal therapeutics for the treatment of breast cancer. Inhibition of aromatase and sulphatase emerged as attractive therapy for the treatment of hormone dependent breast cancer via deprivation of estrogen by different pathways. The cocktail of aromatase and sulphatase inhibitors known as dual aromatase-sulphatase inhibitors (DASIs) emerged as an attractive approach for the effective estrogen deprivation. The present review article focused on the journey of dual aromatase-sulphatase inhibitors from the beginning to till date (2020). Keeping in view the key observations, this review may be helpful for medicinal chemists to design and develop new and efficient dual aromatase-sulphatase inhibitors for the possible treatment of hormone-related breast cancer.

Role of lysosomal acid lipase in the intracellular metabolism of LDL-transported dehydroepiandrosterone-fatty acyl esters

2008 ◽  
Vol 295 (6) ◽  
pp. E1455-E1461 ◽  
Author(s):  
Feng Wang ◽  
Wei Wang ◽  
Kristiina Wähälä ◽  
Herman Adlercreutz ◽  
Elina Ikonen ◽  
...  
Keyword(s):  
Hela Cells ◽  
Ldl Receptor ◽  
Fatty Acyl ◽  
Biologically Active ◽  
Acid Lipase ◽  
Lysosomal Acid ◽  
Lysosomal Acid Lipase ◽  
Cellular Fraction ◽  
Hydrolysis Of

Dehydroepiandrosterone-fatty acyl esters (DHEA-FAE) belong to a unique family of naturally occurring hydrophobic steroid hormone derivatives that are transported in circulating lipoproteins and may act as a source of dehydroepiendrosterone (DHEA) and other biologically active steroid hormones in cells. Here, we studied the metabolic fate of low-density lipoprotein-associated [3H]DHEA-FAE ([3H]DHEA-FAE-LDL) and the possible role of lysosomal acid lipase (LAL) in the hydrolysis of DHEA-FAE in cultured human cells. When HeLa cells were incubated with [3H]DHEA-FAE-LDL, the accumulation of label in the cellular fraction increased with incubation time and could be inhibited by excess unlabeled LDL, suggesting LDL receptor or LDL receptor-related receptor-dependent uptake. During 48 h of chase, decreasing amounts of [3H]DHEA-FAE were found in the cellular fraction, while in the medium increasing amounts of unesterified [3H]DHEA and its two metabolites, [3H]-5α-androstanedione (5α-adione) and [3H]androstenedione (4-adione), appeared. As LDL-cholesteryl ester hydrolysis is dependent on LAL activity, we depleted LAL from HeLa cells using small interfering RNAs and compared the hydrolysis of [3H]DHEA-FAE-LDL and [3H]cholesteryl-FAE-LDL. The results demonstrated a more modest but significant reducing effect on the hydrolysis of [3H]DHEA-FAE compared with [3H]cholesteryl-FAE. Moreover, experiments in LAL-deficient human fibroblasts (Wolman disease patient cells) showed that [3H]DHEA-FAE hydrolysis was not completely dependent on LAL activity. In summary, LDL-transported [3H]DHEA-FAE entered cells via LDL receptor or LDL receptor-related receptor-mediated uptake, followed by intracellular hydrolysis and further metabolism into 5α-adione and 4-adione that were excreted from cells. Although LAL contributed to the deesterification of DHEA-FAE, it was not solely responsible for the hydrolysis.

Circulating steroid hormones in prostate carcinogenesis. Part 2: Estrogens

2011 ◽  
Vol 6 (1) ◽  
Author(s):  
Jean Fiet ◽  
Frank Giton
Keyword(s):  
High Risk ◽  
Dna Adducts ◽  
Proliferative Activity ◽  
Estrone Sulfate ◽  
Hydroxylated Metabolites ◽  
Prostate Carcinogenesis ◽  
Carcinogenic Effects ◽  
Hydrolysis Of ◽  
Exhaustive List

AbstractThe aim of this review is to describe the associations between circulating plasma estrogens and prostate cancer (PCa). We recall the origins of estrogens, which derive from the aromatization of androgens, but also by sulfatase hydrolysis of estrone sulfate (E1-S), the main circulating plasma estrogen. We evoke that the carcinogenic effects of estrogens were demonstrated in the rat and murine prostate when estrogens and androgens were simultaneously administered to them. We also describe estrogen proliferative activity and the genotoxicity of estrogen-hydroxylated metabolites with the formation of DNA adducts. We report published aromatase and CYP1B1 polymorphisms found in men with PCa. We published a bibliography on the relation between PCa and prostate inflammation, as well as the possible role of obesity in the aggressiveness of PCa. In this review, we provide an exhaustive list of assays carried out in subjects at high risk for PCa compared with Caucasians, showing that higher estrogen levels were found in the plasma of these subjects at high risk for PCa. Plasma estrone was the estrogen for which plasma concentration was highest in subjects of African descent. We recall the links observed between plasma estrogens, particularly E1-S, and PCa aggressiveness. Finally, we describe assays for determining hydroxylated estrogens and DNA adducts in the urine of men with PCa. We insist on the importance of the technology employed in estrogen measurement and propose the use of mass spectrometry methods to carry out estrogen assays, in order to decrease variability in the results of plasma estrogen assays.

scholarly journals Role of Glucomannans in Immunology

2017 ◽  
Vol 20 ◽  
pp. 97 ◽  
Author(s):  
Richard Tester ◽  
Farage H Al-Ghazzewi
Keyword(s):  
Human Health ◽  
Dietary Fibre ◽  
The Body ◽  
Biologically Active ◽  
Surface Carbohydrates

Glucomannans play a much broader role in human health then providing dietary fibre. They are biologically active molecules and can when added to the body imitate innate molecules found in different organs including surface carbohydrates on cells. This review considers the immunological role of exogenous glucomannans within animals and man. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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