Home About us Contact
|
Home About us Contact | ||
|
|
||
Wasting Syndrome (wasting + syndrome)
Selected AbstractsStudies on the cell treatment conditions to elicit lipolytic responses from 3T3-L1 adipocytes to TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxinJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2007Wen Li Abstract Wasting syndrome is one of the hallmark symptoms of poisoning by TCDD (=dioxin), which is associated with the massive loss of adipose tissue and serum hyperlipidemia in vivo. Yet, the most widely used in vitro cell model 3T3-L1 adipocyte has not been useful for studying such an action of TCDD because of the difficulty of inducing their mature adipocytes to respond to TCDD to go through lipolysis. Here, we made efforts to find the right cell culture and treatment conditions to induce mature 3T3-L1 adipocytes to go through lipolysis, which is defined as events leading to reduction of lipids in adipocytes. The optimum condition was found to require 7-day differentiated adipocytes being subjected to DMEM medium containing TCDD (but without insulin) for 5 day incubation with two medium changes (the same composition) on incubation days 2 and 4. After 24 h, the early effect of TCDD on adipocytes was predominantly on inflammation, particularly induction of COX-2 and KC (IL-8), which is accompanied by upregulation of C/EBP, and ,. The sign of TCDD-induced lipolysis starts slowly and by incubation day 3, a few markers showed modestly significant changes. By day 5 of incubation, however, many markers show highly significant signs of lipolytic changes. Although this process could take place without exogenous macrophages or their cytokines, addition of exogenous TNF, considerably synergized this action of TCDD. In conclusion, under a right condition, 3T3-L1 adipocytes were found to respond to TCDD to go through lipolysis. The early trigger of such a response appears to be activation of COX-2, which is amplified by TNF,. J. Cell. Biochem. 102: 389,402, 2007. © 2007 Wiley-Liss, Inc. [source] Thalidomide as an anti-cancer agentJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 2 2002S. Kumar Abstract Thalidomide is a glutamic acid derivative initially introduced as a sedative hypnotic nearly forty years ago. It was withdrawn following numerous reports linking it to a characteristic pattern of congenital abnormalities in babies born to mothers who used the drug for morning sickness. It has gradually been re-introduced into clinical practice over the past two decades, albeit under strict regulation, since it was found to be useful in the management of erythema nodosum leprosum and HIV wasting syndrome. Recognition of its anti-angiogenic effect led to its evaluation in the treatment of various malignancies, where angiogenesis has been shown to play an important role. Numerous clinical trials done over the past four years have confirmed the significant anti-myeloma activity of this drug. It has also shown promise in preliminary trials in the treatment of a variety of different malignant diseases. The mechanisms of its antineoplastic effects continue to be the focus of ongoing research. It has become clear that even though its anti angiogenic effects play a significant role in the anti-tumor activity, there are other properties of this drug which are responsible as well. It also possesses anti-TNF alpha activity, which has led to its evaluation in several inflammatory states. In this concise review, we briefly describe the historical background and pharmacological aspects of this drug. We have concisely reviewed the current knowledge regarding mechanisms of its anti-neoplastic activity and the results of various clinical trials in oncology. [source] Genetic engineering to study testicular tumorigenesisAPMIS, Issue 1 2003WEI YAN In humans, Sertoli cell tumors account for approximately 4% of all testicular tumors, and 20% of these are malignant. The mechanisms underlying Sertoli cell tumorigenesis remain largely unknown. Using gene knockout technology, we previously generated mutant mice lacking the , subunit of inhibin dimers. The inhibin ,-null male mice develop testicular Sertoli cell tumors with 100% penetrance. These tumors develop as early as 4 weeks of age and cause a cachexia-like wasting syndrome. Castrated inhibin , knockout mice develop sex steroidogenic adrenal cortical tumors. These studies have identified inhibins as secreted tumor suppressors with specificity for the gonads and adrenal glands. It had been suggested that endocrine factors play roles in Sertoli cell tumorigenesis by altering cell cycle machinery of the Sertoli cells. To test the potential of these factors to function as modifiers of Sertoli cell tumorigenesis, we have employed a genetic intercross strategy, breeding inhibin , mutant mice with mutant mice deficient in endocrine signaling factors including gonadotropin releasing hormone (hypogonadal, hpg mice), follicle stimulating hormone, anti-Müllerian hormone (MH), activin receptor type II, or androgen receptor (testicular feminization, tfm mice), or mice overexpressing follistatin. We are also investigating the effects of loss of critical cell cycle regulators, such as cyclin dependent kinase inhibitor p27, on Sertoli cell tumorigenesis in inhibin , knockout males. These studies clearly demonstrate the roles of these factors as modifiers of the Sertoli cell tumorigenesis. Activin signaling through activin receptor type II is responsible for the cachexia-like syndrome observed in the inhibin , knockout mice with tumors. The gonadotropin hormones are essential for testicular tumor development, but elevated FSH levels are not sufficient to cause Sertoli cell tumors. Absence of FSH, lack of androgen receptor, or overexpression of follistatin slows the tumor growth and minimizes the cachexia symptoms, thus prolonging the life span of these double mutant mice. In contrast, absence of AMH or p27 causes earlier onset and more aggressive development of testicular tumor, with an earlier death of double mutant mice. We are currently investigating roles of estrogen signaling pathways, and other cell cycle regulators, in tumor development in the inhibin , knockout mice by generating mice with double or triple mutations. Genetic engineering in mouse models provides a powerful tool to study the mechanisms of testicular tumorigenesis and define the important genetic modifiers in vivo. [source] From Dioxin to Drug Lead,The Development of 2,3,7,8-TetrachlorophenothiazineCHEMMEDCHEM, Issue 6 2007Kristian Abstract Polychlorinated dibenzo-p-dioxins are persistent environmental pollutants. The most potent congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes a wasting syndrome and is a potent carcinogen and immunosuppressant in the rat at high doses. However, low doses cause opposite effects to some of those observed at higher doses, resulting in chemoprevention, stimulation of the immune system, and longevity in experimental animals. The new TCDD analogue, 2,3,7,8-tetrachlorophenothiazine (TCPT), was developed to take advantage of the low-dose effects of dioxins that have potential application as therapeutics. Its development marked a deviation from the traditional scope of phenothiazine drug design by deriving biological effects from aryl substituents. TCPT was synthesized in three steps. The key ring-closing step was performed utilizing a Buchwald-Hartwig amination to provide TCPT in 37,% yield. Its potency to induce CYP1A1 activity over 24,h was 370 times lower than that of TCDD in,vitro. The elimination half-life of the parent compound in serum was 5.4,h in the rat and 2.7,h in the guinea pig, compared to 11 and 30 days, respectively, for TCDD. These initial findings clearly differentiate TCPT from TCDD and provide the basis for further studies of its potential as a drug lead. [source] | ||||||||||