Titanium dioxide nanoparticles (nanoTiO2) have been widely used as a photocatalyst in air and water cleaning. However, these nanoparticles inhalation can induce pulmonary toxicity and its mechanism is not fully understood. In this study we investigated the pulmonary toxicity of nanoTiO2 and its molecular pathogenesis. The adult male ICR mice were exposed to intratracheal single dose of 0.1 or 0.5 mg nanoTiO2 (19-21 nm) and lung tissues were collected at 3rd day, 1st wk, and 2nd wk for morphometric, microarray gene expression, and pathway analyses. NanoTiO2 can induce pulmonary emphysema, macrophages accumulation, extensive disruption of alveolar septa, type II pneumocyte hyperplasia, and epithelial cell apoptosis. NanoTiO2 induced differential expression of hundreds of genes include activation of pathways involved in cell cycle, apoptosis, chemokines, and complement cascades. In particular, nanoTiO2 up-regulates placenta growth factor (PlGF) and other chemokines (CXCL1, CXCL5, and CCL3) expressions that may cause pulmonary emphysema and alveolar epithelial cell apoptosis. Cultured human THP-1 cell-derived macrophages treated with nanoTiO2 in vitro also resulted in up-regulations of PlGF, CXCL1, CXCL5, and CCL3. These results indicated that nanoTiO2 can induce severe pulmonary emphysema, which may be caused by activation of PlGF and related inflammatory pathways.

Curcumin (diferuloylmethane) is an active component of the spice turmeric and has a diversity of antitumor activities. In this study, we found that curcumin can inhibit cancer cell invasion and metastasis through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). Human lung adenocarcinoma cells (CL1-5) treated with curcumin (1-20 Mmol/L) showed a concentration-dependent reduction in cell migration, invasion, and metastatic ability, and this was associated with increased HLJ1 expression. Knockdown of HLJ1 expression by siRNA was able to reverse the curcumininduced anti-invasive and antimetastasis effects in vitro and in vivo. The HLJ1 promoter and enhancer in a luciferase reporter assay revealed that curcumin transcriptionally upregulates HLJ1 expression through an activator protein (AP-1) site within the HLJ1 enhancer. JunD, one of the AP-1 components, was significantly up-regulated by curcumin (1-20 Mmol/L) in a concentration-and time-dependent manner. Knockdown of JunD expression could partially reduce the curcumin-induced HLJ1 activation and diminish the anti-invasive effect of curcumin, indicating that JunD would seem to be involved in curcumin-induced HLJ1 expression. Curcumin was able to induce c-Jun NH 2 -kinase (JNK) phosphorylation, whereas the JNK inhibitor (SP-600125) could attenuate curcumin-induced JunD and HLJ1 expression. Activation of HLJ1 by curcumin further leads to up-regulation of E-cadherin and a suppression of cancer cell invasion. Our results show that curcumin induces HLJ1, through activation of the JNK/JunD pathway, and inhibits lung cancer cell invasion and metastasis by modulating E-cadherin expression. This is a novel mechanism and supports the application of curcumin in anti-cancer metastasis therapy. [Cancer Res 2008;68(18):7428-38]

Many purine nucleosides and their analogs are actively transported in the kidney. Using homology cloning strategies and reverse transcriptase-polymerase chain reactions, we isolated a cDNA encoding a Na+-dependent nucleoside transporter, hSPNT1, from human kidney. Functional expression in Xenopus laevis oocytes identified hSPNT1 as a Na+-dependent nucleoside transporter that selectively transports purine nucleosides but also transports uridine. The Michaelis constant ( K m) of uridine (80 μM) in interacting with hSPNT1 was substantially higher than that of inosine (4.5 μM). hSPNT1 (658 amino acids) is 81% identical to the previously cloned rat Na+-nucleoside transporter, SPNT, but differs markedly from SPNT in terms of its primary structure in the NH2 terminus. In addition, an Alu repetitive element (∼282 bp) is present in the 3′-untranslated region of the hSPNT1 cDNA. Northern analysis revealed that multiple transcripts of hSPNT1 are widely distributed in human tissues including human kidney. In contrast, rat SPNT transcripts are absent in kidney and highly localized to liver and intestine. The hSPNT1 gene was localized to chromosome 15. This is the first demonstration of a purine nucleoside transporter in human kidney.

Background-The ischemic preconditioning response among elderly patients is known to be lower than in adult patients.Since mitochondrial ATP-sensitive potassium (K ATP ) channels exert preconditioning effects, we undertook this study to determine whether this attenuated activation of K ATP channels influences the reduced responsiveness of elderly patients to ischemic preconditioning. Methods and Results-Fifty-six patients undergoing angioplasty for a major epicardial coronary artery were randomly allocated to either an ischemic preconditioning group, a nicorandil (an agonist of K ATP channels) group, or a glibenclamide (an antagonist of K ATP channels), group based on their age: adult groups (nϭ26; age, Յ55 years; mean age, 45Ϯ5 years) and elderly groups (nϭ30; age, Ն65 years; mean age, 71Ϯ3 years). Ischemic preconditioning with a 120-second coronary occlusion significantly lowered the ischemic burden assessed by ST-segment shift, chest pain score, and myocardial lactate extraction ratios in the adult group. This did not occur in the elderly group. The impaired preconditioning responsiveness in the elderly patients was reversed by nicorandil administration or an ischemic period lengthened to 180 seconds. However, nicorandil-induced cardioprotection was abolished by administering glibenclamide in both the adult and elderly groups. Conclusions-The present study demonstrates that preconditioning significantly enhances the tolerance of the heart to subsequent ischemia in adults but not in senescent patients. Since prolonged ischemia and nicorandil are able to mimic preconditioning and can reverse impaired responsiveness, impaired preconditioning of the aged heart appears to be due to an attenuated activation of K ATP channels.