Medical Sciences | Open Access Articles | Digital Commons Network™

Identification Of Hydroxyxanthones As Na/K-Atpase Ligands, Zhongbing Zhang, Zhichuan Li, Jiang Tian, Wei Jiang, Yin Wang, Xiaojin Zhang, Zhuorong Li, Qidong You, Joseph Shapiro, Shuyi Si, Zijian Xie

Zijian Xie

We have screened a chemical library and identified several novel structures of Na/K-ATPase inhibitors. One group of these inhibitors belongs to polyphenolic xanthone derivatives. Functional characterization reveals the following properties of this group of inhibitors. First, like ouabain, they are potent inhibitors of the purified Na/K-ATPase. Second, their effects on the Na/K-ATPase depend on the number and position of phenolic groups. Methylation of these phenolic groups reduces the inhibitory effect. Third, further characterization of the most potent xanthone derivative, MB7 (3,4,5,6-tetrahydroxyxanthone), reveals that it does not change either Na⁺ or ATP affinity of the enzyme. Finally, unlike that of …

Go to article

Marinobufagenin Stimulates Fibroblast Collagen Production And Causes Fibrosis In Experimental Uremic Cardiomyopathy, Jihad Elkareh, David Kennedy, Belvadi Yashaswi, Sandeep Vetteth, Amjad Shidyak, Eric Kim, Sleiman Smaili, Sankaridrug Periyasamy, Imad Hariri, Larisa Fedorova, Jiang Liu, Liang Wu, M. Kahaleh, Zijian Xie, Deepak Malhotra, Olga Fedorova, Vladimir Kashkin, Alexei Bagrov, Joseph Shapiro

Jiang Liu

We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased …

Go to article

Marinobufagenin Stimulates Fibroblast Collagen Production And Causes Fibrosis In Experimental Uremic Cardiomyopathy, Jihad Elkareh, David Kennedy, Belvadi Yashaswi, Sandeep Vetteth, Amjad Shidyak, Eric Kim, Sleiman Smaili, Sankaridrug Periyasamy, Imad Hariri, Larisa Fedorova, Jiang Liu, Liang Wu, M. Kahaleh, Zijian Xie, Deepak Malhotra, Olga Fedorova, Vladimir Kashkin, Alexei Bagrov, Joseph Shapiro

Zijian Xie

We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased …

Go to article

Spironolactone Attenuates Experimental Uremic Cardiomyopathy By Antagonizing Marinobufagenin, Jiang Tian, Amjad Shidyak, Sankaridrug Periyasamy, Steven Haller, Mohamed Taleb, Nasser El-Okdi, Jihad Elkareh, Shalini Gupta, Sabry Gohara, Olga Fedorova, Christopher Cooper, Zijian Xie, Deepak Malhorta, Alexei Bagrov, Joseph Shapiro

Zijian Xie

Spironolactone has been noted to attenuate cardiac fibrosis. We have observed that the cardiotonic steroid marinobufagenin plays an important role in the diastolic dysfunction and cardiac fibrosis seen with experimental renal failure. We performed the following studies to determine whether and how spironolactone might ameliorate these changes. First, we studied rats subjected to partial nephrectomy or administration of exogenous marinobufagenin. We found that spironolactone (20 mg/kg per day) attenuated the diastolic dysfunction as assessed by ventricular pressure-volume loops and essentially eliminated cardiac fibrosis as assessed by trichrome staining and Western blot. Next, we examined the effects of spironolactone and its …

Go to article

Marinobufagenin Induces Increases In Procollagen Expression In A Process Involving Protein Kinase C And Fli-1: Implications For Uremic Cardiomyopathy, Jihad Elkareh, Sankaridrug Periyasamy, Amjad Shidyak, Sandeep Vetteth, Jeremy Schroeder, Vanamala Raju, Imad Hariri, Nasser El-Okdi, Shalini Gupta, Larisa Fedorova, Jiang Liu, Olga Fedorova, M. Kahaleh, Zijian Xie, Deepak Malhotra, Dennis Watson, Alexei Bagrov, Joseph Shapiro

Zijian Xie

The cardiotonic steroid marinobufagenin (MBG) has been implicated in the pathogenesis of experimental uremic cardiomyopathy, which is characterized by progressive cardiac fibrosis. We examined whether the transcription factor Friend leukemia integration-1 (Fli-1) might be involved in this process. Fli-1-knockdown mice demonstrated greater cardiac collagen-1 expression and fibrosis compared with wild-type mice; both developed increased cardiac collagen expression and fibrosis after 5/6 nephrectomy. There was a strong inverse relationship between the expressions of Fli-1 and procollagen in primary culture of rat cardiac and human dermal fibroblasts as well as a cell line derived from renal fibroblasts and MBG-induced decreases in nuclear …

Go to article

Prieurianin Causes Weight Loss In Diet-Induced Obese Mice And Inhibits Adipogenesis In Cultured Preadipocytes, Ahmed Kablan, Rudel A. Saunders, Maria Szkudlarek-Mikho, Andrew J.B. Chin, Raul M. Bosio, Kazuyuki Fujii, Joseph I. Shapiro M.D., Khew-Voon Chin

Joseph I Shapiro MD

The global increase in the incidence of obesity has emerged as one of the most serious public health risks in recent years. Despite the enormity of the obesity pandemic, there are currently only two FDA-approved therapies for its treatment and these drugs exhibit modest effi cacy and have limiting side effects. Prieurianin is a plant limonoid product that deters feeding in insect larvae. We investigated in this study the effects of prieurianin on weight loss and adipogenesis. Our results showed that prieurianin causes weight loss by reducing energy intake in obese mice on highcalorie diet. We also found that prieurianin …

Go to article

Down-Regulation Of The Transcription Factor Snail In The Placentas Of Patients With Preeclampsia And In A Rat Model Of Preeclampsia, Larissa Federova, Cara Gatto-Weis, Sleiman Smaili, Nauman Khurshid, Joseph I. Shapiro M.D., Deepak Malhorta, Terrence Horrigan

Joseph I Shapiro MD

Background: Placental malfunction in preeclampsia is believed to be a consequence of aberrant differentiation of trophoblast lineages and changes in utero-placental oxygenation. The transcription factor Snail, a master regulator molecule of epithelial-mesenchymal transition in embryonic development and in cancer, is shown to be involved in trophoblast differentiation as well. Moreover, Snail can be controlled by oxidative stress and hypoxia. Therefore, we examined the expression of Snail and its downstream target, e-cadherin, in human normal term, preterm and preeclamptic placentas, and in pregnant rats that developed preeclampsia-like symptoms in the response to a 20- fold increase in sodium intake. Methods: Western …

Go to article

Stem Cell Transplantation Increases Antioxidant Effects In Diabetic Mice, Ming Li, Luca Vanella, Yuming Zhang, Ming Shi, Takashi Takaki, Joseph I. Shapiro M.D., Susuma Ikehera

Joseph I Shapiro MD

Intra bone marrow-bone marrow transplantation (IBM- BMT) + thymus transplantation (TT) has been shown to reduce the incidence of graft versus host disease (GVHD) and restore donor-derived T cell function. In addition, an increase in insulin sensitivity occurred in db/db mice after IBM-BMT+TT treatment. Heme oxygenase (HO)-1 is a stress inducible enzyme which exert antioxidant, antiapoptotic, and immune-modulating properties. We examined whether IBM-BMT+TT could modulate the expression of HO-1 in the kidneys of db/db mice. Six-week-old db/db mice with blood glucose levels higher than 250 mg/dl were treated with IBM-BMT+TT. Six weeks later, the db/db mice showed decreased body weight, …

Go to article

Ouabain Decreases Sarco(Endo)Plasmic Reticulum Calcium Atpase Activity In Rat Hearts By A Process Involving Protein Oxidation, David Kennedy, Sandeep Vetteth, Miaorong Xie, Sankaridrug Periyasamy, Jingwei Xie, Chi Han, Venkatesha Basrur, Krishna Mutgi, Vladimir Fedorov, Deepak Malhotra, Joseph Shapiro

Jingwei Xie

The effect of cardiac glycosides to increase cardiac inotropy by altering Ca2+ cycling is well known but still poorly understood. The studies described in this report focus on defining the effects of ouabain signaling on sarcoplasmic reticulum Ca2+-ATPase function. Rat cardiac myocytes treated with 50 μM ouabain demonstrated substantial increases in systolic and diastolic Ca2+ concentrations. The recovery time constant for the Ca2+ transient, τ, was significantly prolonged by ouabain. Exposure to 10 μM H2O2, which causes an increase in intracellular reactive oxygen species similar to that of 50 μM ouabain, caused a similar increase in τ. Concurrent exposure to …

Go to article

Effects Of Cardiotonic Steroids On Dermal Collagen Synthesis And Wound Healing, Nasser El-Okdi, Sleiman Smaili, Vanamala Raju, Amjad Shidyak, Shalini Gupta, Larisa Fedorova, Jihad Elkareh, Sankaridrug Periyasamy, Anna Shapiro, M. Kahaleh, Deepak Malhotra, Jingwei Xie, Khew Chin, Joseph Shapiro

Jingwei Xie

We previously reported that cardiotonic steroids stimulate collagen synthesis by cardiac fibroblasts in a process that involves signaling through the Na-K-ATPase pathway (Elkareh et al. Hypertension 49: 215–224, 2007). In this study, we examined the effect of cardiotonic steroids on dermal fibroblasts collagen synthesis and on wound healing. Increased collagen expression by human dermal fibroblasts was noted in response to the cardiotonic steroid marinobufagenin in a dose- and time-dependent fashion. An eightfold increase in collagen synthesis was noted when cells were exposed to 10 nM marinobufagenin for 24 h (P < 0.01). Similar increases in proline incorporation were seen following treatment with digoxin, ouabain, and marinobufagenin (10 nM × 24 h, all results P < 0.01 vs. control). The coadministration of the Src inhibitor PP2 or N-acetylcysteine completely prevented collagen stimulation by marinobufagenin. …

Go to article

Using Lectinmicroarrays To Identify Regulatory Mechanisms For Mammalian Glycosylation, John F. Rakus

John F. Rakus

Glycosylation involves the post-translational addition of carbohydrates to protein molecules and is an intricate and indispensable biochemical process. Study of this complicated network of interactions is hindered by the lack of a coding template analogous to the genetic code, and by the vast structural complexity inherent to carbohydrate polymers. We use lectins (non-enzymatic carbohydrate-binding proteins of non-immunological origin) as microarray probes to identify carbohydrate features expressed on cellular surfaces. Specifically, we utilized lectin microarray technology to investigate the differences in carbohydrates expressed by the cell lines of the Nation Cancer Institute’s NCI-60 panel. Our investigation identified tissue-specific expression differences in …

Go to article

Iron Alters Cell Survival In A Mitochondria-Dependent Pathway In Ovarian Cancer Cells., Edward Haller

Edward Haller

ABSTRACT The role of iron in the development of cancer remains unclear. We previously reported that iron reduces cell survival in a Ras/mitogen-activated protein kinase (MAPK)-dependent manner in ovarian cells; however, the underlying downstream pathway leading to reduced survival was unclear. Although levels of intracellular iron, ferritin/CD71 protein and reactive oxygen species did not correlate with iron-induced cell survival changes, we identified mitochondrial damage (via TEM) and reduced expression of outer mitochondrial membrane proteins (translocase of outer membrane: TOM20 and TOM70) in cell lines sensitive to iron. Interestingly, Ru360 (an inhibitor of the mitochondrial calcium uniporter) reversed mitochondrial changes and …

Go to article

Medical Sciences Commons^™

Full-Text Articles in Medical Sciences

Identification Of Hydroxyxanthones As Na/K-Atpase Ligands, Zhongbing Zhang, Zhichuan Li, Jiang Tian, Wei Jiang, Yin Wang, Xiaojin Zhang, Zhuorong Li, Qidong You, Joseph Shapiro, Shuyi Si, Zijian Xie

Zijian Xie

Jiang Liu

Zijian Xie

Zijian Xie

Zijian Xie

Prieurianin Causes Weight Loss In Diet-Induced Obese Mice And Inhibits Adipogenesis In Cultured Preadipocytes, Ahmed Kablan, Rudel A. Saunders, Maria Szkudlarek-Mikho, Andrew J.B. Chin, Raul M. Bosio, Kazuyuki Fujii, Joseph I. Shapiro M.D., Khew-Voon Chin

Joseph I Shapiro MD

Down-Regulation Of The Transcription Factor Snail In The Placentas Of Patients With Preeclampsia And In A Rat Model Of Preeclampsia, Larissa Federova, Cara Gatto-Weis, Sleiman Smaili, Nauman Khurshid, Joseph I. Shapiro M.D., Deepak Malhorta, Terrence Horrigan

Joseph I Shapiro MD

Stem Cell Transplantation Increases Antioxidant Effects In Diabetic Mice, Ming Li, Luca Vanella, Yuming Zhang, Ming Shi, Takashi Takaki, Joseph I. Shapiro M.D., Susuma Ikehera

Joseph I Shapiro MD

Jingwei Xie

Effects Of Cardiotonic Steroids On Dermal Collagen Synthesis And Wound Healing, Nasser El-Okdi, Sleiman Smaili, Vanamala Raju, Amjad Shidyak, Shalini Gupta, Larisa Fedorova, Jihad Elkareh, Sankaridrug Periyasamy, Anna Shapiro, M. Kahaleh, Deepak Malhotra, Jingwei Xie, Khew Chin, Joseph Shapiro

Jingwei Xie

Using Lectinmicroarrays To Identify Regulatory Mechanisms For Mammalian Glycosylation, John F. Rakus

John F. Rakus

Iron Alters Cell Survival In A Mitochondria-Dependent Pathway In Ovarian Cancer Cells., Edward Haller

Edward Haller