A force field, developed and designated here as DNA/Pt, was optimized for modeling Pt ammine/amine complexes of guanine derivatives (G) bound via N7. DNA/Pt was based on the all-atom type force field of Weiner et al. (Weiner, S. J.; Kollman, P. A.; Nguyen, D. T.; Case, D. A. J. Comput. Chem. 1986, 7, 230) as modified by Veal and Wilson (Veal, J. M.; Wilson, D. W. J. Biomol. Struct. Dyn. 1991, 8, 1119. New atom types were created for Pt, N7 of G, and the amine/a"ine N and H atoms. Force field parameters for these new atom types were developed by comparing force field parameters found in the literature with the structural features of published crystal structures. Pt out-of-plane bending was treated by a single improper torsion barrier, C8-N7-C5-Pt.The force constant parameter for the improper torsional deformation barrier was determined in this study by fitting the resulting out-of-plane bending potential curve onto the corresponding profile from ab initio calculations on [Pt(NH3)3(Ade)12+ (Kozelka, J.; Savinelli, R.; Berthier, G.; Flament, J.-P.; Lavery, R. J. Comput. Chem. 1993, 14, 45). The DNA/Pt force field also includes parameters for the van der Waals radius of the Pt atom and for 06-HN(amine/a"ine) H-bonding. An empirical charge distribution method was used to modify the atomic point charges on the cis-[PtA2Gz] moiety, where A = amine or l/2 of a diamine. In general, widely used procedures were adopted. For example, a distance-dependent dielectric constant of E = 4ru and partially neutralized phosphates were used to represent solvent and counterion. The validity of this new DNA/Pt force field was evaluated by a number of test cases. Conformational features determined by either X-ray crystallographic or NMR techniques were reproduced well by the calculations. The rotational barriers for a number of complexes were calculated and were found to agree with NMR data quite well. The calculated relative stabilities of head-to-head and head-totail conformers of some complexes are also in good agreement with experimental results. Finally, an initial attempt to model lattice effects was found to improve the fit between calculated and crystal structures of the cis-[PtA2G2] species.

Triple-helical structures involving the interaction of an oligonucleotide third strand with a duplex nucleic acid sequence have recently gained attention as a therapeutic strategy in the "antigene" approach [cf. Helene, C. (1991) Eur. J. Cancer 27, 1466-1471]. This method utilizes the triple helix formed from the cellular duplex and an added third strand to directly regulate the activity of a selected gene. The limited stability of nucleic acid triple-helical interactions, particularly if the third strand has backbone modifications such as methylphosphonate or phosphorothioate substitutions, is a limiting condition for the use of this approach. We have designed and synthesized compounds, on the basis of the following three criteria, that we feel should provide selective interactions and significant stabilization of triplexes: appropriate aromatic surface area for stacking with triplex bases in an intercalation complex, positive charge, and limited torsional freedom in the aromatic system to match the propeller twist of the triple-base interactions in the triplex. A series of quinoline derivatives with an alkylamine side chain at the 4-position and with different aryl substituents at the 2-position has been synthesized as our first compounds. A 2-naphthyl derivative provides significant and selective stabilization of the triplex. In a 0.2 M NaCl buffer, the naphthyl derivative increased the Tm for the triplex (triplex to duplex and third strand transition) by approximately 30 degrees C more than the Tm increase for the duplex (duplex to single strands transition). Spectral changes and energy-transfer results indicate that the naphthyl compound and related derivatives bind to the triplex by intercalation.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal ischemia/reperfusion injury (IRI) is a significant challenge in perioperative medicine and is related to oxidative programmed cell death. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been evaluated widely. Pannexin 1 (PANX1), an ATP-releasing pathway family protein, has pro-apoptotic effects during kidney injury. Here, we demonstrate that PANX1 deletion protects against renal IRI by regulating ferroptotic cell death. Panx1 knockout mice subjected to renal IRI had decreased plasma creatinine, malondialdehyde (MDA) levels in kidney tissues, and tubular cell death (visible as decreased TUNEL-positive renal tubular cells) compared with WT mice. In cultured human kidney 2 (HK-2) cells, silenced Panx1 expression significantly attenuated ferroptotic lipid peroxidation and iron accumulation induced by the ferroptosis inducer erastin. Moreover, the Panx1 silencing significantly modulated ferroptosis-related protein expression. Furthermore, Panx1 deletion induced the expression of a cytoprotective chaperone, heme oxygenase-1 (HO-1), and inhibited ferroptinophagy via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. In summary, Panx1 deletion protects against renal IRI by attenuating MAPK/ERK activation in a ferroptotic pathway. Our findings provide critical insights into the role of PANX1 in ferroptotic cell death and highlight a potential therapeutic target for the management of acute kidney injury (AKI) during the perioperative period.Acute kidney injury (AKI) 2 is a frequent complication after cardiac surgery, which contributes to increased mortality, and

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The uptake mechanism, translocation, and subcellular distribution of azoxystrobin (5 mg kg–1) in wheat plants was investigated under laboratory conditions. The wheat–water system reached equilibrium after 96 h. Azoxystrobin concentrations in roots were much higher than those in stems and leaves under different exposure times. Azoxystrobin uptake by roots was highly linear at different exposure concentrations, while the bioconcentration factors and translocation factors were independent of the exposed concentration at the equilibrium state. Dead roots adsorbed a larger amount of azoxystrobin than fresh roots, which was measured at different concentrations. Azoxystrobin preferentially accumulated in organelles, and the highest distribution proportion was detected in the soluble cell fractions. This study elucidated that the passive transport and apoplastic pathway dominated the uptake of azoxystrobin by wheat roots. Azoxystrobin primarily accumulated in roots and could be acropetally translocated, but its translocation capacity from roots to stems was limited. Additionally, the uptake and distribution of azoxystrobin by wheat plants could be predicted well by a partition-limited model.