Disease relevance of AIDS-004145

• A strong and prolonged activation of NF-kappaB but not of AP-1 was observed in LN-induced hyperplasia [1].
• A single intravenous injection of lead nitrate at a dose of 10 mumoles/100 gm of body weight caused liver enlargement associated with hepatic cell proliferation [2].
• Teratogenicity, fetal toxicity, and placental transfer of lead nitrate in rats [3].
• Changes in the gene expressions of hepatic enzymes responsible for cholesterol homeostasis were examined during the process of lead nitrate (LN)-induced development of hypercholesterolemia in male rats [4].
• Actively-growing Bacillus subtilis 168 cells, exposed to lead nitrate, had only slightly decreased ability to bind the divalent cation magnesium [5].

High impact information on AIDS-004145

• LN also induced an increase in hepatic levels of TNF-alpha and iNOS mRNA [1].
• Therefore, we examined the liver and blood level of hepatocyte growth factor and tumor necrosis factor alpha (TNF-alpha) at various intervals to determine whether lead nitrate modifies hepatocyte proliferation by altering the production of these cytokines [6].
• Eight hours after an intravenous injection of lead nitrate 100 mumol/kg, DNA synthesis was detected in a few scattered hepatocytes and in nonparenchymal cells in portal connective tissue [7].
• Furthermore, gel mobility shift assays showed no enhanced nuclear factor-kappa B binding to its DNA consensus sequence after BR931 treatment, whereas control studies demonstrated a distinct increase in binding after partial hepatectomy or lead nitrate treatment [8].
• In the present study, the effect of 2/3 partial hepatectomy (PH) and that of a potent direct liver mitogen, lead nitrate, were compared in their ability to modulate the kinetics of liver repopulation [9].

Chemical compound and disease context of AIDS-004145

• Compensatory regeneration was induced in male Wistar rats by partial hepatectomy of two thirds (PH) or a necrogenic dose of CCl4 (2 mL/kg), whereas direct hyperplasia was induced by a single administration of the primary mitogens lead nitrate (LN, 100 micromol/kg), cyproterone acetate (CPA, 60 mg/kg), or nafenopin (NAF, 200 mg/kg) [1].
• Continuous exposure of the teleost fish Heteropneustes fossilis to sublethal concentrations of lead nitrate in water solution for short (35 days) and long (120 days) periods decreased both the soluble protein, RNA and glycogen contents in the liver and the body weight, but increased the cholesterol content [10].
• GABAergic alterations in brain stem during compensatory hyperplasia after partial hepatectomy (PH), lead nitrate (LN)-induced direct hyperplasia, and N-nitrosodiethylamine (NDEA)-induced neoplasia in liver were investigated [11].
• The pulmonary toxicity of two potential environmental pollutants was studied in rats 1, 7 and 30 days after a single intratracheal instillation of lead nitrate and Dithane M-45 (mancoceb), either individually or in various combinations [12].
• Differential diagnoses included hypocalcemia, hypomagnesemia, carbohydrate overload, and several toxicoses including mycotoxin, lead, nitrate, organophosphate, atropine or atropine-like alkaloid, and botulism [13].

Biological context of AIDS-004145

• However, a progressive reduction in the capacity of hepatic cells to divide was found in rats given repeated administrations of the metal, when compared with the extent of cell proliferation induced by a single dose of lead nitrate [14].
• The results suggest that lead nitrate leads to a loss of initiated hepatocytes, due to the apoptosis that occurs during regression of the LN-induced hyperplasia [15].
• CONCLUSIONS: These results indicate that direct mitogenic signals (such as those induced by lead nitrate), and compensatory signals (such as those elicited by PH), are not equally effective on kinetics of liver repopulation in this system [9].
• The results of this study suggest that a single dose of lead nitrate not only stimulates proliferation of hepatocytes but also induces considerable changes in rat liver carbohydrate metabolism, especially between 24 and 72 h after administration [16].
• CYP76C2 gene expression was moreover associated with various processes leading to cell death such as leaf senescence, ageing of cell cultures, wounding as well as with treatment with the necrotising heavy metal salt, lead nitrate [17].

Anatomical context of AIDS-004145

• Possible roles of nonparenchymal cells in hepatocyte proliferation induced by lead nitrate and by tumor necrosis factor alpha [18].
• Effect of various concentrations of lead nitrate on the induction of micronuclei in mouse bone marrow [19].
• In the present study we applied the Gomori lead nitrate method for ultrastructural examination of AP in rat gastrocnemius muscles and showed that the enzyme was linked to the sarcolemma of the striated muscle and to the membranes of endothelial cells in adjacent capillaries [20].
• The lead nitrate treatment resulted in a spurt in the erythropoiesis as is evidenced by a significant increase in the ratios of polychromatic to normochromatic erythrocytes (P/N ratio) compared to non-drug treated controls at 12, 24 and 36 h post-treatment [19].
• There was a dose-dependent effect of lead nitrate on microtubule motility [21].

Associations of AIDS-004145 with other chemical compounds

• Pretreatment of rats with a single dose of dexamethasone (2 mg/kg) 60 minutes before lead nitrate (100 mumol/kg) or ethylene dibromide completely abolished the increased levels of liver TNF-alpha mRNA induced by these agents [22].
• Transient inhibition by orotic acid does not abolish the in vivo response of rat hepatocytes to a direct mitogen, lead nitrate [23].
• While the rats were on these regimens they were given liver cell proliferative stimulus, either a compensatory type (two-thirds partial hepatectomy or a necrogenic dose of carbon tetrachloride) or a direct hyperplastic stimulus such as that induced by the primary mitogen, lead nitrate [24].
• Both insoluble lead sulfide and more soluble lead nitrate were mutagenic at the HPRT locus in V79 cells [25].
• A maximal decrease in PEMT activity (60%) and loss of PEMT2 protein (95%) coincided with maximal DNA synthesis and maximal cytidine triphosphate:phosphocholine cytidylyltransferase activity 36 h and 48 h after lead nitrate stimulation in male and female livers respectively [26].

Gene context of AIDS-004145

• RESULTS: No changes were observed in the liver levels of mRNAs for HGF, TGF-alpha, and TGF-beta 1 at various time intervals after a single injection of lead nitrate [27].
• We previously reported that lead nitrate (LN), an inducer of hepatic tumor necrosis factor-alpha (TNF-alpha), downregulated gene expression of cholesterol 7alpha-hydroxylase [28].
• In the present study, we assessed the temporal change in gene expression of neurotrophins, NGF, BDNF, and NT-3, and their receptors, low affinity neurotrophin receptor (p75NTR) and Trks A, B, and C, by RT-PCR technique in the liver of rats treated with lead nitrate (LN; 0.1 mmol/kg body weight), an inducer of liver hyperplasia [29].
• Lead is known to sensitize animals to lethal effects of bacterial lipopolysaccharides (LPS), suggesting that lead nitrate may modify the production of TNF-alpha in response to endogenous LPS of intestinal origin [27].
• CONCLUSIONS: Stimulation of hepatocyte proliferation induced by lead nitrate was not accompanied by changes in liver levels of HGF, TGF-alpha, or TGF-beta 1 mRNA [27].

Analytical, diagnostic and therapeutic context of AIDS-004145

• Hepatocyte proliferation occurred by 24 hours and reached a peak 48 hours after a single intravenous injection of lead nitrate (100 mumol/kg) [6].
• Immunoelectron microscopy identification of early proliferating cells in rat liver tissue during hyperplasia induced by lead nitrate [7].
• The cytological changes induced by lead nitrate were not reversible 2 weeks after treatment [30].
• A lysosomal system was demonstrated in hyphal tip cells of Sclerotium rolfsii by light and electron microscopy observations of the sites of acid phosphatase activity visualized by a modified Gomori lead nitrate method [31].
• EXPERIMENTAL DESIGN: We investigated first whether a single intravenous dose of lead nitrate (100 mumole/kg) to rats modifies the production of HGF, TGF-alpha, and TGF-beta 1, by examining the steady-state level of their mRNA in the liver by Northern blot analyses [27].

References