Once ingested, most of the alcohol is metabolized in the liver by alcohol dehydrogenase to acetaldehyde. Two additional pathways of acetaldehyde generation are by microsomal ethanol oxidizing system (cytochrome P450 2E1) and catalase. Acetaldehyde can form adducts which can interfere with cellular function, leading to alcohol-induced liver injury. The variants of alcohol metabolizing genes encode enzymes with varied kinetic properties and result in the different rate of alcohol elimination and acetaldehyde generation. Allelic variants of these genes with higher enzymatic activity are believed to be able to modify susceptibility to alcohol-induced liver injury; however, the human studies on the association of these variants and alcohol-associated liver disease are inconclusive. In addition to acetaldehyde, the shift in the redox state during alcohol elimination may also link to other pathways resulting in activation of downstream signaling leading to liver injury.
MicroRNAs are small non-coding RNAs that range in length from 18 to 24 nucleotides. As one of the most extensively studied microRNAs, microRNA-21 (miR-21) is highly expressed in many mammalian cell types. It regulates multiple biological functions such as proliferation, differentiation, migration, and apoptosis. In this review, we summarized the mechanism of miR-21 in the pathogenesis of various liver diseases. While it is clear that miR-21 plays an important role in different types of liver diseases, its use as a diagnostic marker for specific liver disease or its therapeutic implication are not ready for prime time due to significant variability and heterogeneity in the expression of miR-21 in different types of liver diseases depending on the studies. Additional studies to further define miR-21 functions and its mechanism in association with each type of chronic liver diseases are needed before we can translate the bedside observations into clinical settings.
Nicotinamide mononucleotide adenylyltransferease (NMNAT), a rate-limiting enzyme present in all organisms, reversibly catalyzes the important step in the biosynthesis of NAD from ATP and NMN. NAD and NADP are used reversibly in anabolic and catabolic reactions. NAD is necessary for cell survival in oxidative stress and DNA damage. Based on their localization, three different NMNAT's have been recognized, NMNAT-1 (homohexamer) in the nucleus (chromosome 1 p32-35), NMNAT-2 (homodimer) in the cytoplasm (chromosome 1q25) and NMNAT-3 (homotetramer) in the mitochondria. NMNAT also catalyzes the metabolic conversion of potent antitumor prodrugs like tiazofurin and benzamide riboside to their active forms which are analogs of NAD. NAD synthase-NMNAT acts as a chaperone to protect against neurodegeneration, injury-induced axonal degeneration and also correlates with DNA synthesis during cell cycle. Since its activity is rather low in tumor cells it can be exploited as a source for therapeutic targeting. Steps involved in NAD synthesis are being utilized as targets for chemoprevention, radiosensitization and therapy of wide range of diseases, such as cancer, multiple sclerosis, neurodegeneration and Huntington's disease.
DMAPT promotes cell death by both generating ROS and inhibition of NFkappaB. Its in vivo activity supports the conduct of clinical trials in patients with castrate-resistant disease.
Dimethylaminoparthenolide (DMAPT) is a water soluble parthenolide analog with preclinical activity in hematologic malignancies. Using non-small lung cancer (NSCLC) cell lines (A549 and H522) and an immortalized human bronchial epithelial cell line (BEAS2B) and TCC cell lines (UMUC-3, HT-1197 and HT-1376) and a bladder papilloma (RT-4), we aimed to characterize DMAPT's anticancer activity in tobacco-associated neoplasms. Flow cytometric, electrophoretic mobility gel shift assays (EMSA), and Western blot studies measured generation of reactive oxygen species (ROS), inhibition of NFjB DNA binding, and changes in cell cycle distribution and apoptotic proteins. DMAPT generated ROS with subsequent JNK activation and also decreased NFjB DNA binding and antiapoptotic proteins, TRAF-2 and XIAP. DMAPT-induced apoptotic cell death and altered cell cycle distribution with upregulation of p21 and p73 levels in a cell type-dependent manner. DMAPT suppressed cyclin D1 in BEAS2B. DMAPT retained NFjB and cell cycle inhibitory activity in the presence of the tobacco carcinogen nitrosamine ketone, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Using a BrdU accumulation assay, 5-20 lM of DMAPT was shown to inhibit cellular proliferation of all cell lines by more than 95%. Oral dosing of DMAPT suppressed in vivo A549 and UMUC-3 subcutaneous xenograft growth by 54% (p 5 0.015) and 63% (p < 0.01), respectively, and A549 lung metastatic volume by 28% (p 5 0.043). In total, this data demonstrates DMAPT's novel anticancer properties in both early and late stage tobacco-associated neoplasms as well as its significant in vivo activity. The data provides support for the conduct of clinical trials in TCC and NSCLC.In the United States in 2008, over 68,000 individuals were diagnosed with bladder cancer, and more than 14,000 patients died from their disease. Transitional cell carcinoma (TCC) is the dominant histology in over 95% of cases.1 There were also more than 200,000 patients diagnosed with lung cancer with 160,390 deaths and non-small lung cancer (NSCLC) makes up more than three quarters of these cases. Tobacco smoking is a major modifiable risk factor for both bladder and NSCLCs and significant achievements in decreasing this risk factor have been made in some countries. Despite this progress, these cancers are still a major cause of the current death rate from cancer.2 Modest advances have recently been made in the treatment of NSCLC with epidermal growth factor receptor and angiogenesis inhibition. 3,4 Therefore, novel strategies are needed to prevent the progression of epithelial cells which have entered the neoplastic
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