Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To gain a better understanding of the mechanism of action of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer.
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PMID:Motexafin gadolinium disrupts zinc metabolism in human cancer cell lines. 1586 82

We have investigated metallothionein (MT) I and II mRNA and protein in B-cell lymphomas with particular reference to diffuse large B-cell lymphoma (DLBCL). The mRNA profiling was performed on Affymetrix arrays and showed up-regulated MT mRNA in 15 of 48 DLBCLs, including 12 of 23 activated B-cell (ABC) and 3 of 9 type-3 lesions. In contrast, MT mRNA was low to undetectable in 16 germinal center B-cell (GCB)-type DLBCLs. Only 1 of 15 patients with up-regulated MT mRNA achieved a sustained remission, suggesting that up-regulated MT mRNA constitutes a significant risk factor for treatment failure. This was confirmed in 2 independent series, which showed significantly shorter 5-year survival in DLBCL with high versus low MT-IIa levels. By immunohistology, MT was shown to be present in both macrophages and lymphoma cells. The proportion of MT-positive macrophages did not correlate with the survival. In contrast, in 115 DLBCLs, MT labeling of more than 20% lymphoma cells was associated with a significantly poorer 5-year survival, independent of the age, stage, or International Prognostic Index. Taken together, it is suggested that both increased MT mRNA and MT protein expression by more than 20% lymphoma cells constitute independent risk factors in DLBCL.
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PMID:Prognostic significance of metallothionein in B-cell lymphomas. 1686 54

Primary central nervous system lymphoma (PCNSL) in immunocompetent patients is highly malignant and has a poor prognosis. The PCNSL molecular features are reminiscent to some degree of diffuse large B-cell lymphoma (DLBCL), yet PCNSL shows unique molecular profiles and a distinct clinical behavior. This article characterizes the histopathology and expression profiles of metallothionein-I + II (MT-I + II) and their receptor megalin along with proliferation, oxidative stress, and apoptosis in PCNSL and in central nervous system (CNS) lymphomas due to relapse from DLBCL (collectively referred to as CNS lymphoma). We show for the first time that MT-I + II and megalin are significantly altered in CNS lymphoma relative to controls (reactive lymph nodes and non-lymphoma brain tissue with neuropathology). MT-I + II are secreted in the CNS and are found mainly in the lymphomatous cells, while their receptor megalin is increased in cerebral cells. This morphology likely reflects the CNS lymphoma microenvironment and molecular interactions between lymphomatous and neuronal cells.
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PMID:Metallothionein-I + II and receptor megalin are altered in relation to oxidative stress in cerebral lymphomas. 2003 20

The aim of the present study was to investigate the prognostic role of metallothionein-2A (MT-2A), E-cadherin, interleukin-6 (IL-6), cyclin-E, proliferating cell nuclear antigen (PCNA) and B cell lymphoma (Bcl)-2 in the biochemical recurrence of prostate cancer (PCa) using tissue microarray immunostaining. Tissue specimens from 128 PCa patients who underwent radical prostatectomy were processed and transferred onto tissue microarrays. The clinicopathological parameters of PCa patients were also recorded. Following immunohistochemical examination of MT-2A, E-cadherin, IL-6, cyclin-E, PCNA and Bcl-2 expression in PCa specimens, association analysis of biomarkers expression with the biochemical recurrence of PCa was performed. The results revealed that the overall rate of biochemical recurrence was 30.5% (39/128) and the median biochemical recurrence-free time was 19 months (range, 6-35 months). The biochemical recurrence rates in low-, intermediate- and high-risk PCa classification were 14.8 (8/54), 38.7 (24/62) and 58.3% (7/12), respectively. Survival analysis demonstrated that a decreased biochemical recurrence-free survival rate was noted in PCa cases with positive MT-2A and cyclin E expression as well as those with negative E-cadherin expression (P=0.022, 0.028 and 0.011, respectively). Subsequent multivariate Cox analysis revealed that MT-2A [hazard ratio (HR)=2.01; 95% confidence interval (CI)=1.08-3.15; P=0.005], E-cadherin (HR=1.79; 95% CI=1.08-2.21; P=0.042) and cyclin E (HR=1.92; 95% CI=1.22-2.45; P=0.020) were independent predictors of the biochemical recurrence of PCa. In conclusion, the present study provided clinical evidence that evaluation of molecular biomarkers expression may improve clinical prognostic accuracy for the biochemical recurrence of PCa. Of note, the expression of MT-2A, cyclin E and E-cadherin may serve as independent predictors for biochemical recurrence of PCa.
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PMID:Association of molecular biomarkers expression with biochemical recurrence in prostate cancer through tissue microarray immunostaining. 2662 16

Obesity often leads to obesity-related cardiac hypertrophy (ORCH), which is suppressed by zinc-induced inactivation of p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated the mechanisms by which zinc inactivates p38 MAPK to prevent ORCH. Mice (4-week old) were fed either high fat diet (HFD, 60% kcal fat) or normal diet (ND, 10% kcal fat) containing variable amounts of zinc (deficiency, normal and supplement) for 3 and 6 months. P38 MAPK siRNA and the p38 MAPK inhibitor SB203580 were used to suppress p38 MAPK activity in vitro and in vivo, respectively. HFD activated p38 MAPK and increased expression of B-cell lymphoma/CLL 10 (BCL10) and caspase recruitment domain family member 9 (CARD9). These responses were enhanced by zinc deficiency and attenuated by zinc supplement. Administration of SB203580 to HFD mice or specific siRNA in palmitate-treated cardiomyocytes eliminated the HFD and zinc deficiency activation of p38 MAPK, but did not significantly impact the expression of BCL10 and CARD9. In cultured cardiomyocytes, inhibition of BCL10 expression by siRNA prevented palmitate-induced increased p38 MAPK activation and atrial natriuretic peptide (ANP) expression. In contrast, inhibition of p38 MAPK prevented ANP expression, but did not affect BCL10 expression. Deletion of metallothionein abolished the protective effect of zinc on palmitate-induced up-regulation of BCL10 and phospho-p38 MAPK. HFD and zinc deficiency synergistically induce ORCH by increasing oxidative stress-mediated activation of BCL10/CARD9/p38 MAPK signalling. Zinc supplement ameliorates ORCH through activation of metallothionein to repress oxidative stress-activated BCL10 expression and p38 MAPK activation.
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PMID:Zinc rescues obesity-induced cardiac hypertrophy via stimulating metallothionein to suppress oxidative stress-activated BCL10/CARD9/p38 MAPK pathway. 2815 19

Emerging evidence suggests that zinc (Zn) deficiency is associated with depression and anxiety in both human and animal studies. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of Zn distribution. The work has focused on one case study, the association between an animal model of posttraumatic stress disorder (PTSD) and the Zn distribution in the rat hippocampus. Behaviors were assessed with the elevated plus-maze and acoustic startle response tests 7 days later. Preset cut-off criteria classified exposed animals according to their individual behavioral responses. To further characterize the distribution of Zn that occurs in the hippocampus 8 days after the exposure, laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging was used. It has been found that Zn distribution in the dentate gyrus (DG) sub-region in the hippocampus is clearly more widely spread for rats that belong to the extreme behavioral response (EBR) group as compared to the control group. Comparison of the Zn concentration changes in the cornu ammonis 1 (CA1) and the DG sub-regions of the hippocampus shows that the concentration changes are statistically significantly higher in the EBR rats compared to the rats in the control and minimal behavioral response (MBR) groups. In order to understand the mechanism of stress-induced hippocampal Zn dyshomeostasis, relative quantitative analyses of metallothionein (MT), B-cell lymphoma 2 (Bcl-2) and caspase 3 immunoreactivity were performed. Significant differences in the number of caspase-ir and Bcl-2 cells were found in the hippocampal DG sub-region between the EBR group and the control and MBR groups. The results of this study demonstrate a statistically significant association between the degree of behavioral disruption resulting from stress exposure and the patterns of Zn distribution and concentration changes in the various hippocampal regions. Taken together, these findings indicate that Zn distribution patterns play an active role in the neurobiological response to predator scent stress.
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PMID:Distinctive hippocampal zinc distribution patterns following stress exposure in an animal model of PTSD. 2848 98

Obesity often leads to cardiovascular diseases, such as obesity-related cardiac hypertrophy (ORCH), due to chronic cardiac inflammation. Zinc is structurally and functionally essential for many transcription factors, therefore it not only has anti-inflammatory and anti-oxidative stress functions, but also has insulin-like function, however, its role in the development of obesity-associated cardiac pathogenesis and the potentially underlying mechanism(s) remains unclear. This review aims to summarize the available evidence on the role of zinc homeostasis in the prevention of ORCH. It was recently reported that when four-week old mice were fed either high fat diet (HFD) or normal diet containing deficient, adequate or supplemented zinc, HFD induced obesity and ORCH along with increased phosphorylation of p38 MAPK and increased expression of B-cell lymphoma/ leukemia 10 (BCL10) and caspase recruitment domain family member 9 (CARD9). These effects were further aggravated by zinc deficiency and significantly alleviated by zinc supplementation. Mechanistically administration of a p38 MAPK specific inhibitor in HFD-fed mice for 3 months did not affect HFD-induced obesity and increased expression of BCL10 and CARD9, but completely abolished HFD/obesity-induced cardiac hypertrophy and inflammation. In cultured cardiomyocytes, inhibition of BCL10 expression by siRNA prevented palmitate-induced increased p38 MAPK activation and atrial natriuretic peptide expression. Deletion of metallothionein abolished the protective effect of zinc on palmitate-induced up-regulation of BCL10 and phospho-p38 MAPK. Taken together with other recent studies, we concluded that HFD and zinc deficiency synergistically induce ORCH by increasing oxidative stress-mediated activation of BCL10/CARD9/p38 MAPK signaling. Zinc supplementation ameliorates ORCH through activation of metallothionein to repress oxidative stress-activated BCL10 expression and p38 MAPK activation.
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PMID:Zinc homeostasis plays an important role in the prevention of obesity-induced cardiac inflammation, remodeling and dysfunction. 3268 30