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Author: Daniel Bassi Publisher: Biota Publishing ISBN: 1615045090 Category : Medical Languages : en Pages : 60
Book Description
Many proprotein convertases (PC), especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases. In this chapter, we review mostly our work using animal models of squamous cancers that have been induced by chemical or UV carcinogenesis protocols to highlight the role of PCs in the development and progression of experimental tumors. After demonstrating in wild type mice the role of PACE4 in tumor progression as well as detecting the expression of PACE4 and furin in human non-melanoma skin cancers, we developed transgenic mice that over-express either PACE4 or furin in squamous epithelia, including the epidermis. This was accomplished by targeting the expression of the corresponding PC by using the promoter of the bovine keratin 5. Both K5-PACE4 and K5-Furin transgenic mice showed increased susceptibility to a two-stage carcinogenesis protocol of chemical carcinogenesis. Similar studies conducted in K5-PACE4 mice also showed an increased sensitivity to ultraviolet B radiation carcinogenesis. In most of these experiments, we were able to demonstrate that compared to the control wild type mice, the over-expression of the transgene in the epidermis increased the number of benign and malignant skin tumors and also had an effect on tumor progression as evidenced by the presence of less differentiated tumors and more frequent local and distant metastases in many of the transgenic lines. Interestingly, double transgenic mice in which PACE4 and furin are targeted to the epidermis did not show any additive effect, pointing to a probable in vivo overlap of functions at least in cutaneous tissues. The tumor-enhancing effects of PACE4 and furin further support their possible role as therapeutic targets. Furthermore, a proof of principle for PC inhibition as a therapeutic tool has been substantiated by an in vivo experiment in which the PC-inhibitor, decanoyl-RVKRchloromethylketone, was topically administrated to the skin of wild type and transgenic mice treated with chemical carcinogenesis protocols, resulting in a significant decrease of tumor development and progression.
Author: Daniel Bassi Publisher: Biota Publishing ISBN: 1615045090 Category : Medical Languages : en Pages : 60
Book Description
Many proprotein convertases (PC), especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases. In this chapter, we review mostly our work using animal models of squamous cancers that have been induced by chemical or UV carcinogenesis protocols to highlight the role of PCs in the development and progression of experimental tumors. After demonstrating in wild type mice the role of PACE4 in tumor progression as well as detecting the expression of PACE4 and furin in human non-melanoma skin cancers, we developed transgenic mice that over-express either PACE4 or furin in squamous epithelia, including the epidermis. This was accomplished by targeting the expression of the corresponding PC by using the promoter of the bovine keratin 5. Both K5-PACE4 and K5-Furin transgenic mice showed increased susceptibility to a two-stage carcinogenesis protocol of chemical carcinogenesis. Similar studies conducted in K5-PACE4 mice also showed an increased sensitivity to ultraviolet B radiation carcinogenesis. In most of these experiments, we were able to demonstrate that compared to the control wild type mice, the over-expression of the transgene in the epidermis increased the number of benign and malignant skin tumors and also had an effect on tumor progression as evidenced by the presence of less differentiated tumors and more frequent local and distant metastases in many of the transgenic lines. Interestingly, double transgenic mice in which PACE4 and furin are targeted to the epidermis did not show any additive effect, pointing to a probable in vivo overlap of functions at least in cutaneous tissues. The tumor-enhancing effects of PACE4 and furin further support their possible role as therapeutic targets. Furthermore, a proof of principle for PC inhibition as a therapeutic tool has been substantiated by an in vivo experiment in which the PC-inhibitor, decanoyl-RVKRchloromethylketone, was topically administrated to the skin of wild type and transgenic mice treated with chemical carcinogenesis protocols, resulting in a significant decrease of tumor development and progression.
Author: Daniel Bassi Publisher: Morgan & Claypool Publishers ISBN: 1615045082 Category : Medical Languages : en Pages : 61
Book Description
Many proprotein convertases (PC), especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases. In this chapter, we review mostly our work using animal models of squamous cancers that have been induced by chemical or UV carcinogenesis protocols to highlight the role of PCs in the development and progression of experimental tumors. After demonstrating in wild type mice the role of PACE4 in tumor progression as well as detecting the expression of PACE4 and furin in human non-melanoma skin cancers, we developed transgenic mice that over-express either PACE4 or furin in squamous epithelia, including the epidermis. This was accomplished by targeting the expression of the corresponding PC by using the promoter of the bovine keratin 5. Both K5-PACE4 and K5-Furin transgenic mice showed increased susceptibility to a two-stage carcinogenesis protocol of chemical carcinogenesis. Similar studies conducted in K5-PACE4 mice also showed an increased sensitivity to ultraviolet B radiation carcinogenesis. In most of these experiments, we were able to demonstrate that compared to the control wild type mice, the over-expression of the transgene in the epidermis increased the number of benign and malignant skin tumors and also had an effect on tumor progression as evidenced by the presence of less differentiated tumors and more frequent local and distant metastases in many of the transgenic lines. Interestingly, double transgenic mice in which PACE4 and furin are targeted to the epidermis did not show any additive effect, pointing to a probable in vivo overlap of functions at least in cutaneous tissues. The tumor-enhancing effects of PACE4 and furin further support their possible role as therapeutic targets. Furthermore, a proof of principle for PC inhibition as a therapeutic tool has been substantiated by an in vivo experiment in which the PC-inhibitor, decanoyl-RVKRchloromethylketone, was topically administrated to the skin of wild type and transgenic mice treated with chemical carcinogenesis protocols, resulting in a significant decrease of tumor development and progression.
Author: Abdel-Majid Khatib Publisher: Morgan & Claypool Publishers ISBN: 1615045368 Category : Medical Languages : en Pages : 89
Book Description
Proprotein convertases (PCs) are a family of proteases including PC1, PC2, Furin, PC4, PACE4, PC5, and PC7. These enzymes are involved in the maturation of many precursor proteins involved in the process of tumorigenesis and metastasis. Since their discovery, PCs were suggested as potential targets for anti-cancer therapy, and their activity was found to directly affect tumor cell proliferation, migration invasion, and the malignant phenotypes of tumor cells. Here, we discuss a number of previous and recent findings on the PCs features, their implication in the regulation of multiple cellular functions that impact on the invasive/metastatic potential of cancer cells, and their clinical relevance in cancer patients. Among the substrates of the proprotein convertases, various growth factors, their receptors, adhesion molecules, and proteases were identified. The PCs are inhibited by endogenous and exogenous inhibitors. To date, only pro7B2, a specific chaperone of PC2, and the granine-like precursor of neuroendocrine protein proSAAS, a selective ligand of PC1, have been identified as endogenous inhibitors of the PCs found in the regulated pathway. However, only PCs prosegments, several bioengineered inhibitors, peptides, and non-peptide compounds were found to inhibit the activity of the PCs found in the secretory pathway.
Author: Andres J.P. Klein-Szanto Publisher: Biota Publishing ISBN: 1615044655 Category : Science Languages : en Pages : 50
Book Description
Gynecological cancers include neoplasias of internal female genital organs, mainly ovarian, endometrial and cervical tumors, and cancers of the external female genital structures. Current scientific evidence indicates that both up- and down-regulation of the expression of PCs are part of the multiple changes occurring in these gynecological tumors. Nevertheless, the physiological significance of this puzzling pattern of PC expression remains elusive. The fact that PCs can activate both pro- and anticarcinogenic substrates may indicate that the nature of the overexpressed substrates in certain cancer types could determine the final outcome; i.e., slowing or accelerating cancer development. The expression of PCs in gynecological cancers and the correlation of this expression with other markers may facilitate preventive and therapeutic interventions in at-risk populations. Several studies single out furin as the main PC overexpressed in ovarian and endometrial cancers. For instance, furin expression has been associated with five-year survival in ovarian cancer, and measurements of furin activity in cells obtained by lavage constitute a non-invasive diagnostic tool for endometrial cancer. The other ubiquitously expressed PCs, PC5, PACE4, and PC7 do not show any changes with respect to normal controls or are decisively silenced, as indicated by studies on PACE4 expression and regulation in both ovarian and endometrial tumors. PCs activate crucial substrates implicated in the progression of gynecological cancers, including adhesion molecules, metalloproteinases, and viral proteins. In the first place, furin, and possibly the other PCs, process both E- and N-cadherin. Processing of these molecules results in variations of cell adhesiveness. The pattern of expression of N- and especially E-cadherin varies during tumor development, as well as in the stages of either epithelial to mesenchymal or mesenchymal to epithelial transitions. E-cadherin is up-regulated during initial steps in ovarian tumor development, whereas N-cadherin follows a more complex expression pattern. Nevertheless, cadherin processing requires fully functional PC activity, a feature that may be explored for future therapeutics applications. Furthermore, PCs drive the activation of metalloproteinases, especially the membrane-type metalloproteases MMP-14 and MMP-15, and also possibly MMP-9. The activity of these metalloproteases promotes the invasion into the omentum and other peritoneal structures, facilitating the degradation of collagens and other extracellular components. Finally, the role of furin in enabling papilloma virus infection, one of the main etiological factors in the development of exocervical cancer, and possibly vaginal and vulvar carcinoma, cannot be overemphasized. These experimental evidences suggest that careful targeting of PCs in gynecological cancer may represent a feasible strategy to deter tumor progression.
Author: Eva Böttcher-Friebertshäuser Publisher: Springer ISBN: 3319754742 Category : Medical Languages : en Pages : 335
Book Description
This book will give an overview on viruses undergoing proteolytic activation through host proteases. The chapters will be organized in three themed parts, the first part describing respective viruses and their characteristics in detail. In the second part the molecular and cellular biology of the proteases involved as well as their physiological functions will be further explored. The third part will contain a chapter on protease inhibitors that are promising tools for antiviral therapy. This book will engage scholars in virology and medical microbiology as well as researchers with an interest in enzymology and protein structure and function relationship.
Author: Gerald Litwack Publisher: Academic Press ISBN: 0128138157 Category : Medical Languages : en Pages : 738
Book Description
Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology covers the endocrine secretions produced by every organ. This extensive collection of knowledge is organized by tissue, addressing how certain hormones are synthesized in multiple tissues, along with their structure, function and pathways, which are very applicable for researchers in drug design who need to focus on a specific step along the pathway. This is a must have reference for researchers in endocrinology and practicing endocrinologists, but it is also ideal for biochemists, pharmacologists, biologists and students. Serves as a valuable desk reference for researchers Provides information on the structure of a given hormone, its receptor(s), and the pathways that become activated Includes extensive citations to the literature that will enable the reader to dig more deeply into the effects of a given hormone
Author: David Lyden Publisher: Cambridge University Press ISBN: 1139498754 Category : Science Languages : en Pages : 661
Book Description
Metastasis is responsible for a large burden of morbidity and mortality among cancer patients, and currently few therapies specifically target metastatic disease. Further scientific dissection of the underlying pathways is required to pave the way for new therapeutic targets. This groundbreaking new text comprehensively covers the processes underlying cancer metastasis and the clinical treatment of metastatic disease. Whereas previous volumes have been compendia of laboratory research articles, the internationally renowned authors of this volume have summarized the state-of-the-art research in the metastasis field. A major section covers the cellular and molecular pathways of metastasis and experimental techniques and the systems and models applied in this field. Subsequently, the clinical aspects of the major cancer types are considered, focusing on disease-specific research and therapeutic approaches to metastatic disease. The focus is on novel pathophysiological insights and emerging therapies; future directions for research and unmet clinical needs are also discussed.
Author: Ronald Ross Watson Publisher: Elsevier ISBN: 0124079342 Category : Medical Languages : en Pages : 559
Book Description
Nutrition in the Prevention and Treatment of Abdominal Obesity focuses on the important roles that exercise, dietary changes, and foods play in promoting as well as reducing visceral fat. Nutritionists, dieticians, and healthcare providers seeking to address the abdominal obesity epidemic will use this comprehensive resource as a tool in their long-term goal of preventing chronic diseases, especially heart, vascular, and diabetic diseases. Experts from a broad range of disciplines are involved in dealing with the consequences of excessive abdominal fat: cardiology, diabetes research, studies of lipids, endocrinology and metabolism, nutrition, obesity, and exercise physiology. They have contributed chapters that define a range of dietary approaches to reducing risk and associated chronic diseases. They begin by defining visceral obesity and its major outcomes; they also discuss the importance and the challenges of dietary approaches to reduce abdominal obesity, as compared to clinical approaches, with major costs and risks. Offers detailed, well-documented reviews outlining the various dietary approaches to visceral obesity with their benefits and failures Includes chapters on types of foods, exercise, and supplements in reducing obesity and its chronic clinical companions, especially diabetes and cardiovascular disease Helps nutritionists, dieticians, and healthcare providers approach patients in making decision about nutritional therapies and clinical treatments for abdominal obesity, from an evidence-based perspective
Author: Daniel Bassi
Author: Daniel Bassi
Author: Daniel Bassi
Author: Abdel-Majid Khatib
Author: Andres J.P. Klein-Szanto
Author: Eva Böttcher-Friebertshäuser
Author: Gerald Litwack
Author: 
Author: 
Author: David Lyden
Author: Ronald Ross Watson