Research Interests:
Research Interests:
Research Interests:
There is an urgent need to define mechanisms underlying pancreatic adenocarcinoma (PDA) development. Our studies of ubiquitin ligases that may underlie PDA development led us to identify and characterize RNF125. We show that RNF125... more
There is an urgent need to define mechanisms underlying pancreatic adenocarcinoma (PDA) development. Our studies of ubiquitin ligases that may underlie PDA development led us to identify and characterize RNF125. We show that RNF125 exhibits nuclear expression in acinar cells, with reduced and largely cytosolic expression in ductal cells, PanIN and PDA specimens. We find that RNF125 interacts with histone deacetylase 2 (HDAC2) and promotes its non-canonical K63-linked ubiquitination. Inhibition of HDAC2 activity by RNF125 resulted in elevated expression of the pancreatic and duodenal homeobox 1 (PDX1). Correspondingly, inhibition of RNF125 expression enhanced organoid growth in culture and orthotopic tumor development. Conversely, restoration of PDX1 levels in human or mouse PDA cells and organoids depleted of RNF125, inhibited cell proliferation and growth, while expression of HDAC2 enhanced it. Notably, higher expression of RNF125 and PDX1 coincided with differentiated tumor phenot...
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Research Interests:
Research Interests:
Cigarette smoking is linked to various human disorders. Active and passive smokers suffer from inflammatory diseases of lungs and airways. Smoking-dependent airway inflammation is related to the cytotoxic effects of cigarette smoke (CS)... more
Cigarette smoking is linked to various human disorders. Active and passive smokers suffer from inflammatory diseases of lungs and airways. Smoking-dependent airway inflammation is related to the cytotoxic effects of cigarette smoke (CS) and chronic recruitment of neutrophils and macrophages. NF-kappaB is a key inflammatory, redox-sensitive transcription factor. Its role in CS-induced airway inflammation is unclear. This study investigated CS-induced NF-kappaB activation in human lymphocytes and the possible involvement of oxidative insult in this activation. A method for accurate and reproducible exposure of lymphocytes to CS was developed. The intensity of CS exposure was linearly correlated with nitrite concentration originating from reactive oxygen species in CS. Mild, but not high exposure to CS, induced NF-kappaB in lymphocytes through the increase in oxidative stress and the reduction in the intracellular glutathione levels. These findings may have implications to active as we...
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Research Interests:
Research Interests:
Using the electromobility shift assay (EMSA) in the rat myoblast system, the activation of transcription factor NF-kappaB by reactive nitrogen species was evaluated. Two distinct patterns of activation were demonstrated. Whereas NO donor,... more
Using the electromobility shift assay (EMSA) in the rat myoblast system, the activation of transcription factor NF-kappaB by reactive nitrogen species was evaluated. Two distinct patterns of activation were demonstrated. Whereas NO donor, SNAP, activated NF-kappaB in the classical pathway, which led to a transient response, NF-kappaB activation by peroxynitrite donor, SIN-1, was mediated by an alternative pathway, which has been demonstrated in previous works to involve tyrosine nitration of the NF-kappaB inhibitory protein I-kappaB alpha. This led to a constitutive non-transient activation of NF-kappaB and a prolonged inflammatory reaction. Lymphocytes exposed to mild intensity of cigarette smoke for 8 h, which activated NF-kappaB, exhibited a decrease in the fraction of apoptotic cells from 27% to 19% compared with lymphocytes exposed to atmospheric air, using the FACS Annexin V assay. This also has been shown in previous works to be mediated by peroxynitrite. Thus, mild exposure ...
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Although the free radical theory of aging is widely accepted among scientists, the possibility of using antioxidants to delay the aging processes seems to encounter considerable skeptism among clinicians. This may be due, at least in... more
Although the free radical theory of aging is widely accepted among scientists, the possibility of using antioxidants to delay the aging processes seems to encounter considerable skeptism among clinicians. This may be due, at least in part, to lack of knowledge about the basic chemistry and biological behavior of oxidative stress, antioxidants, and the complex interactions between them. However, one cannot ignore the explosive growth of information concerning the mechanisms underlying the processes of aging, their consequences, and the use of antioxidants in suppressing such effects. In order to provide patients with the most accurate information regarding the use of antioxidant supplementation in their diet, it is important to obtain basic data regarding oxidative stress and antioxidants. This article explores the role of oxidative stress in the aging phenomena, recent evidence supporting supplementation of antioxidants for aged people, the ability of antioxidants to prevent or reta...