 |
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
|
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
*C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel; and Departments of Nephrology and Pathology, Rabin Medical Center, Petah Tikva, Israel, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Correspondence to Prof. B. Sredni, C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, 52900 Israel. Phone: 972-3-5318250; Fax: 972-3-6356041;
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
B were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27kip1 expression, resulting in the increased formation of cyclin D1/cdk4 and cyclin E/cdk2 complexes, followed by hyperphosphorylation of retinoblastoma, a key event for G1 to S phase progression. IL-10 appears to be a more potent MC growth factor that negatively regulates GDNF expression. Indeed, its inhibition by the nontoxic tellurium anti-IL-10 compound, ammonium trichloro(dioxoethylene-o,o’) tellurate (AS101), extensively decreased MC clonogenicity despite GDNF upregulation. Identification of the mesangial GDNF and IL-10 pathways as critical mediators of mesangial cell proliferation may provide another target for therapeutic intervention in certain glomerular diseases. In vivo animal studies using AS101, currently undergoing phase II clinical trials on cancer patients, are warranted to determine its potential in the management of glomerular diseases associated with mesangial cell proliferation. E-mail: srednib@mail.biu.ac.il |
Introduction |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
(TGF-) superfamily (1). Unlike other members of the TGF- superfamily, which signal through the receptor serine-threonine kinase, GDNF family ligands activate intracellular signaling cascades via the receptor tyrosine kinase RET (2). These neurotrophic factors promote the survival of various neurons, including peripheral autonomic and sensory neurons, as well as central motor and dopamine neurons. GDNF also has distinct functions outside the nervous system, promoting ureteric branching in kidney development (3) and regulating spermatogenesis (4). Ret mutations cause several human diseases such as papillary thyroid carcinoma, multiple endocrine neoplasia, and Hirschsprung disease (5). Like other receptor tyrosine kinases, RET can activate various signaling pathways, including Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/AKT, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) pathways (6). IL-10, first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on a variety of cell types. The principal function of IL-10 appears to be limitation and ultimately termination of inflammatory responses. In addition, IL-10 regulates growth and/or differentiation of many cell types (7). The best-characterized IL-10 signaling pathway is the Jak/stat system. The IL-10/IL-10R interaction engages the Jak family tyrosine kinases Jak1 and Tyk2 and induces tyrosine phosphorylation and activation of the latent transcription factors stat3, stat1, and stat5 (8).
Increased proliferation of glomerular mesangial cells, leading to mesangial hyperplasia, is a hallmark of many forms of glomerulonephritis (9). Persistent mesangial cell hyperplasia is pathologically linked to progressive and irreversible glomerular scarring. Several studies on experimental glomerular disease demonstrated that strategies to inhibit mesangial cells proliferation could indeed preserve glomerular function by preventing glomerulosclerosis (10,11). Glomerular cell cycle progression is controlled by cyclin-dependent kinases (cdk), the catalytic activity of which is modulated by association with different cyclins, functioning as regulatory subunits. Cyclin D activates cdk4 to form active cyclin-cdk complexes during early G1 phase (12). This is followed by increased cyclin E levels (late G1 phase), which increase CDK2 activity. The major function of cyclin D/CDK4 during G1 is the phosphorylation of the retinoblastoma tumor suppressor protein (pRb) (13). This results in the inactivation of pRb and plays an essential role in the progression of cells from G1 to S, mainly through regulation of the E2F family of transcription factors. Cyclin kinase inhibitors (CKI) such as p21waf or p27kip-1 negatively regulate the cell cycle by inhibiting the formation or activation of cyclin-cdk complexes (14). Agents that upregulate mesangial p27kip-1 and p21waf expression have been reported to decrease cyclin D1/CDK4 and cyclin E/CDK2 activities, resulting in inhibition of mesangial cell proliferation (15,16).
Recently mRNAs for GDNF and its receptors have been detected in human renal cortex and medulla and in human mesangial cells (17). In addition, increased plasma GDNF levels in patients with chronic renal diseases have been recently reported (18), suggesting GDNF may be implicated to play a role in the genesis of progressive renal damage. Moreover, IL-10 has been previously implicated as a mesangial autocrine growth factor (19).
The nontoxic immunomodulator ammonium trichloro(dioxoethylene-o,o’)tellurate (AS101) first developed by us, has been shown to have beneficial effects in diverse preclinical and clinical studies. Most of its activities have been primarily attributed to the direct inhibition of the antiinflammatory cytokine IL-10, followed by the simultaneous increase of specific cytokines. These include IL-1
, TNF, IFN
, IL-2, IL-12, and GM-CSF (20–22). These immunomodulatory properties were found to be crucial for the clinical activities of AS101, demonstrating the protective effects of AS101 in parasite and viral infected mice models (23), in autoimmune diseases (24), in septic mice (25), and in a variety of tumor models in mice and humans, where AS101 had a clear anti-tumoral effect (26–28).
In the present study, we explored the ability of rat glomerular mesangial cells to secrete GDNF in an autocrine manner and gained insight into the signaling pathways involved in GDNF-induced MC proliferation. In addition, the interrelationship between GDNF and IL-10 was studied. Moreover, the regulation of GDNF and IL-10 production by AS101 was explored.
|
Material and Methods |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
B, anti-P-Rb (Santa Cruz, Santa Cruz, CA); anti-active MAPK (Sigma Aldrich, Rehovot, Israel); rat GDNF, rat IL-10 (R&D Systems); Farnesyltransferase inhibitor II (Fti) (Calbiochem, La Jolla, CA); PD 98059 (Sigma Aldrich); Geldanamycin (GA) was obtained as a gift from the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, NCI (Bethesda, MD). LY294002 (Calbiochem); N--tosyl-L-lysine chloromethyl ketone (TLCK; Roche; Indiapolis, IN); Pyrrolidine dithiocarbamate (PDTC;Sigma Aldrich); AS101 was supplied by Prof. M. Albeck from the chemistry department in Bar-Ilan University, in a solution of PBS, pH 7.4, and maintained at 4°C.
Animals
Male Wistar rats (8 to 10 wk old, 150 to 170 g) were purchased from Harlan Laboratories, Israel. Animal experiments were performed in accordance with approved institutional protocols and approved by the Institutional Animal Care and Use Committee.
Isolation of Glomeruli
Glomeruli were isolated from the renal cortex of rats using the differential thieving method. The purity of glomeruli was >95%.
MC Isolation and Culture
Two sources of rat glomerular MC were used:
Clonogenic Assay
After 24 h of serum starvation, cells were disrupted by repeated aspiration through a 26-gauge needle, counted, and plated at 1000 cells/plate in DMEM supplemented with 0.5% FCS and 10 µg/ml lipopolysacharide (LPS) and/or various doses of rat GDNF or IL-10, and incubated for macroscopic colony formation. After 4 to 5 d of incubation, colonies were fixed with methanol, stained with Giemsa, and counted.
3H-Thymidine Uptake
RMC were cultured in flat-bottomed 96-well plates at 1.105 cells/well in medium containing 10% FCS. After 24 h, cells were growth-arrested for 48 h in medium containing 0.5% FCS. MC were then exposed for 24 h to fresh medium without or with 2% FCS in the presence of specific components. Cells were pulsed with 1 µCi/ml of 3H-Thymidine for the last 24 h.
Cell-Cycle Distribution Studies
After 24 h of serum starvation, cells were passed through a 26-gauge needle, counted, and plated at 1.106 cells/plate in DMEM supplemented with 0.5% FCS for 72 h with or without GDNF or IL-10. Cells were trypsinized and suspended for 30 min in buffer containing propidium iodide. Propidium iodide fluorescence was measured using a FACStar plus (Becton Dickinson, San Jose, CA) flow cytometer equipped with an air-cooled argon laser delivering 15 mW of light at 488 nm. The fluorescence from 1.104 cells from each sample was collected through a 610-nm bandpass filter.
Quantitation of IL-10 and GDNF
Mesangial cells were cultured at 0.5 x 106/ml for different time points with or without LPS (10 µg/ml) or AS101. For quantitation of IL-10, supernatants were collected and evaluated by Elisa kits (R&D). For GDNF, cells were pelleted, resuspended in lysis buffer (20 mM HEPES, 1 mM EDTA, 5 mM MgAc, 1 mM DTT, 10% glycerol, 0.5% NP-40) with protease inhibitors. The resulting supernatants after centrifugation were analyzed by Elisa kits (Promega, Madison, WI).
Immunoprecipitation and Western Blot Analyses
Total cell extracts and immunoprecipitation were performed as described (27).
Transfection of Antisense ODN
Phosphothioate-modified, antisense, or mismatch control ODN were purchased from MWG-Biotech AG (Ebersberg, Germany) and dissolved in water. The ODN had the following sequences and positions, as derived from the rat P27kip1 and p21cip1/waf1:
For assessment of transfection efficiency cell lyzates have been prepared and analyzed by Western blot analysis for p27kip1 and p21cip1/waf1 protein expression. Polycationic transfection reagent (Lipofectamine; Invitrogen; Carlsbad, CA) was used to facilitate uptake of ODN, according to the protocol recommended by the manufacturers.
RT-PCR Analysis
Total RNA was isolated using the RNAqueous-4PCR kit (Ambion; Austin, Texas). Reverse transcription of RNA to cDNA was carried out using RETROscript kit (Ambion). The cDNA synthesized was subjected to PCR amplification with GDNF primer set in the presence of 18S Primers Pair/Competimers mix (Ambion) at 2/8 ratio mix. The GDNF primer set had the following sequences: 5'- TCA CCA GAT AAA CAA GCG GC-3' (sense) and 5'-TAC ATC CAC ACC GTT TAG CG-3' (anti sense). PCR products were analyzed by TBE-agarose gel electrophoresis and stained with ethidium bromide.
Immunocytochemistry
For cyclin D1 staining, serum-starved MC were grown on eight-well glass chamber slides with or without 50 ng/ml GDNF for 24 h. Cells were fixed in 3% paraformaldehyde/PBS and permeabilized for 10 min at 4°C with 1% Triton X-100 in PBS. Staining was performed using the ABC staining kit (Santa Cruz) using the primary antibody against cyclin D1 overnight. As a negative control, equal concentrations of rabbit IgG were used.
Statistical Analyses
Data are presented as mean ± SEM. The Mann-Whitney U test was used for comparisons between groups. Two-tail P < 0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
|
|
Cell Cycle Analyses of Mesangial Cells Treated with GDNF
Cell cycle distribution was assessed in mesangial cells exposed to GDNF at various concentrations. As summarized in Table 1, 61.7 ± 1.5% of serum-starved mesangial cells accumulated in G0/G1. Treatment of cells with increasing doses of GDNF caused a gradual and significant reduction in the proportion of cells in G0/G1 phase. This decrease was significant at 20 to 50 ng/ml GDNF. At 50 ng/ml, the % of cells in this phase amounted to only 35.9 ± 1.2% (P < 0.01). Moreover, GDNF at increasing doses enhanced the accumulation of cells in S phase, the volume of which amounted to 58.0 ± 0.3% at 50 ng/ml of GDNF (P < 0.01) (Table 1).
|
|
|
B in GDNF-Induced Mesangial Cells ProliferationB is a known downstream mediator of the PI3K pathway. In the present study, we show that GDNF increased the degradation of IB, the protein inhibitor of NF-B activation, in a time-dependent manner (Figure 3C). Simultaneously, the translocation of the p65 subunit of NF-B from the cytosol to the nucleus of mesangial cells occured in a time-dependent manner (Figure 3D). In addition, introduction of TLCK or PDTC, inhibitors of IB degradation, indeed prevented the degradation of this protein in GDNF-stimulated mesangial cells (Figure 3C) and concomitantly inhibited NF-B activation in these cells (Figure 3D). Moreover, addition of these inhibitors to GDNF-stimulated cultures abrogated the increased proliferation induced by GDNF (Figure 5A). This effect was significant (P < 0.01). Most importantly, inhibition of PI3K by LY294002, shown to inhibit mesangial cells proliferation (Figure 4, A and B) or by transfection of anti-sense PI3K to MC, Figure 4C also inhibited activation of NF-B (Figure 3, D and E). These results imply the PI3K pathway and its downstream mediator NF-B to play a significant role in the mitogenic activity of GDNF on mesangial cells.
|
|
|
The mitogenic activity of IL-10 could be also deduced from the results presented in Table 1 in which the introduction of increasing doses of IL-10 to the cultures resulted in the decreased proportion of cells in G0/G1, with 25.7 ± 1% at the highest dose (P < 0.01). Concomitantly, this dose of IL-10 increased the proportion of cells in S phase to 66.7 ± 1.2% (P < 0.01; Table 1).
The Immunomodulator AS101 Reduces Clonogenicity of Mesangial Cells via Inhibition of IL-10
We used AS101, as an anti–IL-10 compound, to find if this property will enable it to inhibit the proliferation of MC and to determine the role of IL-10 inhibition on GDNF production. Figure 8A shows that AS101 decreases IL-10 production in a dose-dependent manner by both LPS-stimulated RMCL and RMC. This decrease is significant starting from 0.5 to 2.5 µg/ml (P < 0.01). Incubation of RMCL and RMC in the presence of AS101 gradually and significantly decreases mesangial cell proliferation (Figure 8, B and C). This activity of AS101 was not apparent when MC transfected with anti sense IL-10 were used (Figure 8D), suggesting that inhibition of proliferation by AS101 may be due to the inhibition of IL-10.
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
The finding that rat glomerular mesangial cells express GDNF at the mRNA level appears to be consistent with previous observations of Orth et al. (17), which show mRNA expression of GDNF in human mesangial cells. However, this is the first report showing both mRNA expression and production of pronounced amounts of GDNF by glomerular mesangial cells from adult rats.
The fact that GDNF is a mesangial autocrine growth factor is also consistent with the role of GDNF in nephrogenesis and its association with kidney diseases. GDNF, like other members of the TGF- superfamily, has distinct functions outside the nervous system. Indeed, Ret, GDNF, and GFR 1-deficient mice do not develop kidneys (29). Transgenic and organ culture experiments have shown that GDNF is the mesenchyme-derived morphogenetic signal for kidney ureteric budding and branching (30). A potential role of GDNF in the genesis of progressive renal damage was recently suggested by studies reporting increased plasma GDNF levels in patients with chronic renal diseases (18).
Activation of c-Ret in neurons initiates the Ras/Raf pathway, which leads to the activation of the mitogen-activated protein kinases Erk1 and Erk2, and the PI3K pathway, which leads to activation of the serine-threonine kinase Akt, resulting in neuronal proliferation and survival. We therefore studied the role of these pathways in GDNF-induced MC proliferation. The ras, raf, ERK cascade is known to be activated in numerous cultured cell lines after mitogenic stimulation. Nevertheless, we show that, although GDNF promptly elevates the expression of both activated raf-1 and ERK, consistent with its activity in neurons, the ras cascade components do not play an important role in GDNF-induced mesangial proliferation, because the latter was not significantly affected by their inhibition. Rather, we show that the PI3K pathway plays a dominant role in GDNF-induced mesangial mitogenesis because the latter was promptly and significantly abolished by the specific PI3K inhibitor LY294002 and by transfection of PI3K anti-sense oligonucleotides. Moreover, the role of this pathway in GDNF-induced MC proliferation is further emphasized by GDNF-induced activation of NF-B, a known downstream mediator of the PI3K pathway. Importantly, introduction of NF-B inhibitors to GDNF-stimulated mesangial cells abrogated their increased proliferation and concomitantly inhibited GDNF-induced NF-B activation in these cells. Moreover, GDNF-induced NF-B nuclear translocation was abolished by both LY294002 and transfection of anti-sense PI3K. These results imply the PI3K pathway and its downstream mediator NF-B to play a significant role in the mitogenic activity of GDNF in mesangial cells. These results are in line with those of Choudhury et al. (31), who had recently reported that inhibition of mesangial MAPK only partially attenuated PDGF-induced DNA synthesis, while PI3K plays the predominant role in PDGF-induced mitogenesis.
CDK inhibitors are critical determinants for the onset and magnitude of renal cell proliferation. The CKI p27kip1 is a nuclear protein that binds to and inhibits both G1 and S phase cyclin-CDK complexes, which are required for DNA synthesis. MC proliferation requires a decrease in p27kip1 levels, and the inhibitory threshold to growth factor-induced proliferation is determined by p27kip1. With this respect, the reduction in p27kip1 levels by GDNF may account for the increased MC proliferation. Furthermore, although the activity of cdks was not evaluated in this study, GDNF-induced MC proliferation was associated with a dissociation of p27kip1 from both the cyclinD1/cdk4 and cyclinE/cdk2 complexes followed consequently by pRb hyperphosphorylation — one of the key events for G1 to S phase progression. Moreover, we show that GDNF-induced decrease in p27kip1 is regulated by PI3K. Previous studies showed that PI3K activity is important for G1 to S transition (32). Moreover p27kip1 has been recently described to be regulated by PI3K in mouse embryo fibroblasts (33). Furthermore, Akt has been previously shown to regulate PDGF-induced decrease in p27kip1 (31). Thus GDNF appears to be a novel and potent autocrine mesangial growth factor that allows cells to progress through the cell cycle in association with decreased p27kip1 levels, dissociating it from cyclin-CDK complexes resulting in pRb hyperphosphorylation. The production of GDNF by MC is reminiscent of the expression of this and other neurotrophic factors in bone marrow stromal cells and in human macrophages and B cells (34).
This study describes another mesangial autocrine growth factor-IL-10. Although IL-10 has been previously reported to promote proliferation of mesangial cells, to the best of our knowledge, this is the first report showing the regulation of GDNF production by IL-10. We show that IL-10 negatively regulates GDNF production by mesangial cells. This may explain the different kinetics of production of each growth factor. The optimal time of GDNF production (24 h) occurs at the time when negligible amounts of IL-10 are produced. Alternatively, low GDNF production occurs at the time when IL-10 production is optimal (48 h). Furthermore, neutralizing IL-10 increases GDNF at time points where increased levels of IL-10 are produced. We do not know if this regulation is cell type–specific; nevertheless, it may explain the elevated expression of IL-10 in most major diseases in the CNS, whereas, at least in neurodegenerative diseases, deprivation of neurotrophic factors occurs.
Following these results, we used the tellurium anti IL-10 compound, AS101, and studied its effects on MC proliferation. AS101, currently used in clinical studies on cancer patients, has been previously shown to directly inhibit the transcription of monocyte IL-10 (21). AS101 is shown in this study to decrease mesangial IL-10 production, which leads to decreased MC proliferation. Inhibition of IL-10 by AS101 results in increased GDNF production at the posttranscriptional level. Interestingly, although AS101 increases production of a mesangial growth factor (GDNF), it negatively affects MC proliferation. This may be explained by the fact that GDNF is less potent than IL-10; thus inhibition by AS101 of a more effective growth factor (IL-10) results in a net inhibitory effect. The specificity of AS101’s activity to IL-10 inhibition could be deduced from the lack of AS101’s effect on MC transfected with anti-sense IL-10.
It is intriguing to note that neutralization of GDNF or IL-10 extensively inhibited glomerular MC proliferation despite the existence of many other potent growth factors known to stimulate MC proliferation. Furthermore, disruption of either one of the other growth factor–mediated pathways also abrogated MC hyperplasia (10,35). Even more appealing is the fact that at least some of these growth factors share overlapping modes of resolution of cell proliferation. Growth factor-induced mesangial cell proliferation is associated with decreased levels of p27kip1. The inhibitory threshold to growth factor–induced proliferation is determined by p27kip1. We show that in the presence of GDNF, p27kip1 expression by MC promptly decreased as reported on PDGF-treated MC. Furthermore, IL-10–induced B cell proliferation has been also reported to be mediated by decreased p27kip1 (36). One might therefore expect that lowering p27kip1 levels via neutralization of any one of the mesangial growth factors will result in resolution of MC proliferation. Nevertheless, we show in this study that the decrease in p27kip1 by transfection of anti-sense oligonucleotides, at least in vitro, is necessary albeit not sufficient for MC proliferation. However, once decreased, GDNF increases cell proliferation more efficiently as compared with control cells. Similar data have been reported on PDGF (37). The insufficiency of decreased p27kip1 for MC proliferation is also reflected by the fact that the loss of p27kip1 alone was not sufficient to induce detectable proliferation or structural changes in mature p27-/- kidneys (38). Thus, besides lowering p27kip1, growth factors probably contribute further elements needed for MC proliferation. It may be conceivable that these growth factors act in concert, and that, despite their apparent redundancy, they all must be present for supporting maximal mesangial proliferation. Such an interdependence between cytokines has been described previously in various physiologic states. Alternatively, growth factors may modulate the expression of each other. For example, the mesangial mitogenic factor EGF induces the expression of PDGF, while blocking PDGF with anti-PDGF antibody abrogates the mitogenic effect of EGF-induced MC proliferation (39). Similarly, Gas6 induces MC proliferation via activation of STAT3 (40), and STAT3 was recently shown to activate the IL-10 promoter in macrophages (41).
Apart from the known ability of AS101 to inhibit IL-10, the beneficial pre-clinical effects of the compound have been attributed to this property. More importantly, AS101 was previously shown to delay the onset of autoimmune manifestations in a murine model of lupus erythematosus, reduce the level of immune complex deposition in the glomeruli, reduce proteinuria, prevent glomerular hypercellularity and mesangial expansion, and reduce the mean glomerular volume of treated mice (24). Furthermore, in a murine model of septic peritonitis, AS101 was recently shown to prevent kidney damage of septic mice (25). The above-mentioned effects of AS101 were attributed to the decreased levels of IL-10 in AS101-treated mice. These results imply that inhibition of IL-10 by compounds such as AS101 might be beneficial in the resolution of MC proliferation in vivo. This hypothesis is in line with data reported by Chadban et al. (19), which show that IL-10 stimulates proliferation of glomerular MC in normal rats, and also by reports showing that IL-10 is expressed in proliferative lesions at day 6 of anti Thy1 GN (42).
In vivo animal studies using the nontoxic compound AS101, currently undergoing phase II clinical trials on cancer patients, are warranted to determine its potential in the management of glomerular diseases associated with mesangial cell proliferation. Identification of the mesangial GDNF and IL-10 pathways as critical mediators of mesangial cell proliferation may provide another target for the treatment of glomerular diseases.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
and STAT3 complexes in human T cells and monocytes. J Immunol 155: 1079–1079, 1995[Abstract]
release by mouse and human mononuclear phagocytes. Cell Immunol 176: 180–185, 1997[CrossRef][Medline]
levels. J Immunol 159: 2658–2667, 1997[Abstract]
(p85-p110) in fibroblasts during mitogenesis: Requirement for insulin and lysophosphatidic acid-mediated signal transduction. Mol Cell Biol 18: 7119–7129, 1998This article has been cited by other articles:
 |
|
 |
|
  B. Sredni, R. Geffen-Aricha, W. Duan, M. Albeck, F. Shalit, H. M. Lander, N. Kinor, O. Sagi, A. Albeck, S. Yosef, et al. Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson's disease models FASEB J, June 1, 2007; 21(8): 1870 - 1883. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Tsui, S. J. Shankland, and B. A. Pierchala Glial Cell Line-Derived Neurotrophic Factor and Its Receptor Ret Is a Novel Ligand-Receptor Complex Critical for Survival Response during Podocyte Injury J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1543 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kalechman, U. Gafter, T. Weinstein, A. Chagnac, I. Freidkin, A. Tobar, M. Albeck, and B. Sredni Inhibition of Interleukin-10 by the Immunomodulator AS101 Reduces Mesangial Cell Proliferation in Experimental Mesangioproliferative Glomerulonephritis: ASSOCIATION WITH DEPHOSPHORYLATION OF STAT3 J. Biol. Chem., June 4, 2004; 279(23): 24724 - 24732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sredni, M. Weil, G. Khomenok, I. Lebenthal, S. Teitz, Y. Mardor, Z. Ram, A. Orenstein, A. Kershenovich, S. Michowiz, et al. Ammonium Trichloro(dioxoethylene-o,o')tellurate (AS101) Sensitizes Tumors to Chemotherapy by Inhibiting the Tumor Interleukin 10 Autocrine Loop Cancer Res., March 1, 2004; 64(5): 1843 - 1852. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
HOME
CURRENT ISSUE
ARCHIVES
JASN Express
ONLINE SUBMISSION
AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP |
