scholarly journals Production of an inhibitor of rat mesangial cell growth by the glomerulus and its alteration in puromycin nephrosis.

1993 ◽  
Vol 4 (2) ◽  
pp. 155-161
Author(s):  
G C Groggel ◽  
M L Hughes
Keyword(s):  
Cell Growth ◽  
Renal Disease ◽  
Growth Inhibition ◽  
Growth Regulation ◽  
Mesangial Cell ◽  
Growth Inhibitor ◽  
Puromycin Aminonucleoside ◽  
3T3 Fibroblasts ◽  
Growth Inhibitory Activity ◽  
Progressive Renal Disease

Mesangial cell proliferation is found in many forms of progressive renal disease. This proliferation may be due to dysregulation of mesangial cell growth. The studies presented here test the hypothesis that the normal glomerulus produces a regulator of mesangial cell growth. Conditioned media (CM) from primary glomerular cultures were able to inhibit rat mesangial cell growth in a dose- and time-dependent fashion, from 30.0 +/- 3.8 to 86.6 +/- 3.9% growth inhibition. The growth inhibitor in glomerular CM appears to have a molecular weight of less than 3,000. Glomerular CM caused significantly more growth inhibition than did 3T3 fibroblast CM, 77.9 +/- 2.8% growth inhibition by 10% glomerular CM versus 21.2 +/- 5.4% by 10% 3T3 CM (P < 0.001). The growth inhibition was completely reversible. Glomerular CM had no effect on the growth of 3T3 fibroblasts. Treatment of the glomerular CM with either trypsin or neutral protease had no effect on its growth inhibitory activity. Glomerular CM obtained from rats with puromycin aminonucleoside nephrosis caused significantly less growth inhibition than did control glomerular CM; at a concentration of 10% CM, control glomerular CM had 65.1 +/- 1.9% growth inhibition and puromycin had 45.4 +/- 2.1% (P < 0.001). Thus, the rat glomerulus produces a small, nonprotein inhibitor of rat mesangial cell growth and the activity of this inhibitor is reduced in puromycin nephrosis. Impairment of mesangial cell growth regulation may be important in the pathogenesis of progressive renal disease.

Inhibition of rat mesangial cell growth by heparan sulfate

1990 ◽  
Vol 258 (2) ◽  
pp. F259-F265
Author(s):  
G. C. Groggel ◽  
G. N. Marinides ◽  
P. Hovingh ◽  
E. Hammond ◽  
A. Linker
Keyword(s):  
Cell Growth ◽  
Heparan Sulfate ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Significant Inhibition ◽  
3T3 Fibroblasts ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent ◽  
Endogenous Component

The ability of heparan sulfate, an endogenous component of the glomerulus, to regulate the growth of cultured rat mesangial cells was investigated. Heparan sulfate caused a dose-dependent inhibition of rat mesangial cell growth, 85% inhibition compared with controls at the highest dose (1,000 micrograms/ml). Chondroitin sulfate produced no inhibition. The low-sulfated fraction of heparan sulfate (9%) produced more inhibition than the high-sulfated fraction (13%), 90 +/- 1 vs. 71 +/- 2% (P = 0.002). The effects of the heparan sulfate were completely reversible. Treatment of heparan sulfate with heparitinase increased the degree of inhibition, 71 +/- 1 vs. 84 +/- 1% (P less than 0.001). Four different oligosaccharides derived from heparan sulfate and heparin were tested for their ability to inhibit growth. One of the oligosaccharides, low-sulfated (10%), caused significant inhibition, 76 +/- 2%. Heparan sulfate was also able to inhibit the growth of Swiss 3T3 fibroblasts (63 +/- 5%). This inhibition was less marked than that seen with mesangial cells. Thus heparan sulfate was able to significantly inhibit rat mesangial cell growth in culture. Alterations in glomerular heparan sulfate may play an important role in alterations in mesangial cell growth.

Role of Mesangial Cell Damage in Progressive Renal Disease

1999 ◽  
Vol 22 (1-2) ◽  
pp. 5-12 ◽  
Author(s):  
F. Shimizu ◽  
H. Kawachi ◽  
M. Orikasa
Keyword(s):  
Renal Disease ◽  
Mesangial Cell ◽  
Cell Damage ◽  
Progressive Renal Disease

Involvement of MAP kinase phosphatase-1 in mesangial cell growth regulation

Nephrology ◽  
1997 ◽  
Vol 3 (6) ◽  
pp. 443-453 ◽  
Author(s):  
Toshiki MORIYAMA ◽  
Chen XIA ◽  
Akiko MIYAI ◽  
Yoshitaka AKAGI ◽  
Yoshitaka ISAKA ◽  
...  
Keyword(s):  
Cell Growth ◽  
Map Kinase ◽  
Growth Regulation ◽  
Mesangial Cell ◽  
Cell Growth Regulation ◽  
Map Kinase Phosphatase

Jab1-siRNA Induces Cell Growth Inhibition and Cell Cycle Arrest in Gall Bladder Cancer Cells via Targeting Jab1 Signalosome

2020 ◽  
Vol 19 (16) ◽  
pp. 2019-2033 ◽  
Author(s):  
Pratibha Pandey ◽  
Mohammad H. Siddiqui ◽  
Anu Behari ◽  
Vinay K. Kapoor ◽  
Kumudesh Mishra ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Cell Growth ◽  
Gall Bladder ◽  
Growth Inhibition ◽  
Cell Cycle Arrest ◽  
Gall Bladder Cancer ◽  
Cell Growth Inhibition ◽  
Cycle Arrest ◽  
Apoptotic Induction

Background: The aberrant alteration in Jab1 signalosome (COP9 Signalosome Complex Subunit 5) has been proven to be associated with the progression of several carcinomas. However the specific role and mechanism of action of Jab1 signalosome in carcinogenesis of gall bladder cancer (GBC) are poorly understood. Objective: The main objective of our study was to elucidate the role and mechanism of Jab1 signalosome in gall bladder cancer by employing siRNA. Methods: Jab1 overexpression was identified in gall bladder cancer tissue sample. The role of Jab1-siRNA approach in cell growth inhibition and apoptotic induction was then examined by RT-PCR, Western Blotting, MTT, ROS, Hoechst and FITC/Annexin-V staining. Results: In the current study, we have shown that overexpression of Jab1 stimulated the proliferation of GBC cells; whereas downregulation of Jab1 by using Jab1-siRNA approach resulted incell growth inhibition and apoptotic induction. Furthermore, we found that downregulation of Jab1 induces cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene. Moreover, Jab1-siRNA induces apoptosis by enhancing ROS generation and caspase-3 activation. In addition, combined treatment with Jab1-siRNA and gemicitabine demonstrated an enhanced decline in cell proliferation which further suggested increased efficacy of gemcitabine at a very lower dose (5μM) in combination with Jab1-siRNA. Conclusion: In conclusion, our study strongly suggests that targeting Jab1 signalosome could be a promising therapeutic target for the treatment of gall bladder cancer.

scholarly journals TAMI-38. CYSTEINE-PROMOTING COMPOUNDS INDUCE MITOCHONDRIAL TOXICITY IN GLIOBLASTOMA THROUGH ALTERED PYRUVATE AND SERINE METABOLISM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii221-ii221
Author(s):  
Evan Noch ◽  
Laura Palma ◽  
Isaiah Yim ◽  
Bhavneet Binder ◽  
Elisa Benedetti ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Glucose Deprivation ◽  
Tumor Metabolism ◽  
Metabolic Phenotype ◽  
Low Grade ◽  
Mitochondrial Toxicity ◽  
Human Cancers ◽  
Pathway Gene

Abstract Glioblastoma (GBM) remains a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for accelerated growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, little is known about the metabolic alterations that are specific to GBM and that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated the TCGA and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. From these analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine-related metabolites compared to low-grade gliomas. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with a variety of FDA-approved cyst(e)ine-promoting compounds in vitro, including N-acetylcysteine (NAC) and the cephalosporin antibiotic, Ceftriaxone (CTX), which induces cystine import through System Xc transporter upregulation. Cysteine-promoting compounds, including NAC and CTX, inhibit growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Metabolic tracing experiments with 13C6-glucose demonstrate that L-serine is rapidly depleted in GBM cells upon treatment with NAC and CTX, and exogenous serine rescues NAC- and CTX-mediated cell growth inhibition. In addition, these compounds reduce GBM mitochondrial pyruvate transport. We show that cysteine-promoting compounds reduce cell growth and induce mitochondrial toxicity in GBM, which may be due to rapid serine depletion and reduced mitochondrial pyruvate transport. This metabolic phenotype is exacerbated by glucose deprivation. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.

scholarly journals Semi-Synthesis of Small Molecules of Aminocarbazoles: Tumor Growth Inhibition and Potential Impact on p53

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1637
Author(s):  
Solida Long ◽  
Joana B. Loureiro ◽  
Carla Carvalho ◽  
Luís Gales ◽  
Lucília Saraiva ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Small Molecules ◽  
Tumor Cells ◽  
Mutant P53 ◽  
Wild Type ◽  
Naturally Occurring ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Amino Derivatives ◽  
Carbazole Alkaloids

The tumor suppressor p53 is inactivated by mutation in approximately 50% of human cancers. Small molecules that bind and stabilize those mutants may represent effective anticancer drugs. Herein, we report the tumor cell growth inhibitory activity of carbazole alkaloids and amino derivatives, as well as their potential activation of p53. Twelve aminocarbazole alkaloids were semi-synthesized from heptaphylline (1), 7-methoxy heptaphylline (2), and 7-methoxymukonal (3), isolated from Clausena harmandiana, using a reductive amination protocol. Naturally-occurring carbazoles 1–3 and their amino derivatives were evaluated for their potential effect on wild-type and mutant p53 activity using a yeast screening assay and on human tumor cell lines. Naturally-occurring carbazoles 1–3 showed the most potent growth inhibitory effects on wild-type p53-expressing cells, being heptaphylline (1) the most promising in all the investigated cell lines. However, compound 1 also showed growth inhibition against non-tumor cells. Conversely, semi-synthetic aminocarbazole 1d showed an interesting growth inhibitory activity in tumor cells expressing both wild-type and mutant p53, exhibiting low growth inhibition on non-tumor cells. The yeast assay showed a potential reactivation of mutant p53 by heptaphylline derivatives, including compound 1d. The results obtained indicate that carbazole alkaloids may represent a promising starting point to search for new mutp53-reactivating agents with promising applications in cancer therapy.

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