The novel antiviral agent cyclotriazadisulfonamide (CADA) inhibited human immunodeficiency virus (HIV) (IC50, 0.3-3.2 microM) and human herpesvirus 7 (HHV-7) infection (IC50, 0.3-1.5 microM) in T-cell lines and PBMCs. When T-cells were pretreated with CADA for 24 h, they became markedly protected from viral infection. Flow cytometric analysis revealed a significant decrease in the expression of the CD4 glycoprotein, the primary receptor needed for entry of both viruses. Moreover, the antiviral activity of CADA correlated with its ability to down-modulate the CD4 receptor. CADA did not alter the expression of any other cellular receptor (or HIV coreceptor) examined. Time course experiments showed that CD4 down-modulation by CADA differs in mechanism from the effects of aurintricarboxylic acid, which binds directly to CD4, and phorbol myristate acetate, which activates protein kinase C. Further analysis of CD4 mRNA levels suggested that CADA was not involved in the regulation of CD4 expression at a transcriptional level, but very likely at (post) translational levels. This unique mechanism of action makes CADA an important lead in developing new drugs for treatment of AIDS, autoimmune diseases, and inflammatory disorders.

Intravesical therapeutic delivery has been extensively investigated for various bladder diseases such as bladder cancer, overactive bladder, urinary incontinence, and interstitial cystitis. However, conventional drug carriers have a low therapeutic delivery efficiency because of the passive diffusion of drug molecules in a bladder and the rapid clearance by periodic urination. Here, we report biocompatible and bioavailable enzyme-powered polymer nanomotors which can deeply penetrate into a mucosa layer of the bladder wall and remain for a long-term period in the bladder. The successful fabrication of nanomotors was confirmed by high-resolution transmission electron microscopy, energy-dispersive X-ray mapping, zeta-potential analysis, Fourier transform infrared spectroscopy, and urease activity and nanomotor trajectory analyses. After injection into the bladder, urease-immobilized nanomotors became active, moving around in the bladder by converting urea into carbon dioxide and ammonia. The nanomotors resulted in the facilitated penetration to the mucosa layer of the bladder wall and the prolonged retention in the bladder even after repeated urination. The enhanced penetration and retention of the nanomotors as a drug delivery carrier in the bladder would be successfully harnessed for treating a variety of bladder diseases.

Machines have greatly contributed to the human civilization, enabling tasks beyond our capacities for improved quality of life. Recently, the progress in nanotechnology has triggered to build a miniaturized machine of nanoscale. In this context, synthetic nanomotors have gained considerable interest because of their great promise for diverse applications. Currently, the movement control of these nanomotors has been widely investigated using various stimuli. Here, we demonstrate near-infrared (NIR) light controlled on/off motion of stomatocyte nanomotors powered by the conversion of hydrogen peroxide. The nanomotors encapsulating naphthalocyanine (NC) are aggregated or separated (collective motion) with or without near-IR light illumination, resulting in the well-controlled movement. Remarkably, the nanomotors can move directionally toward hydrogen peroxide released from cancer cells and photothermally ablate the cancer cells. Taken together, our stomatocyte nanomotor systems can be effectively harnessed for autonomous photothermal cancer therapy.

9-Benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododecane (CADA) has been identified as a novel antiviral lead compound with significant anti-human immunodeficiency virus and anti-human herpesvirus 7 activity. Surprisingly, this compound selectively decreased the expression of the CD4 glycoprotein, the primary receptor needed for the entry of both viruses. Herein, we describe the CD4 down-modulating and antiviral potencies of more than 25 CADA derivatives. Flow cytometric evaluation of cellular CD4 receptor expression in T cells demonstrated the specific CD4 down-modulating capacity of the CADA derivatives, with IC 50 values similar to those obtained in the antiviral assays. The close correlation observed between the CD4 down-regulating and anti-HIV potencies of the CADA derivatives further points to CD4 receptor downmodulation as the primary mode of antiviral action for this group of compounds.It is well known that infection of target cells by human immunodeficiency virus (HIV) is dependent on the presence of the CD4 surface molecule, which serves as the main virus receptor (Dalgleish et al., 1984;Klatzmann et al., 1984). Also, human herpesvirus 7 (HHV-7) uses the CD4 receptor for viral entry (Furukawa et al., 1994;Lusso et al., 1994). Although CD4 is the primary receptor for HIV entry, several CD4-independent HIV-1 strains have been reported (Dumonceaux et al., 1998;Hoffman et al., 1999;Kolchinsky et al., 1999;LaBranche et al., 1999). These viruses, derived by passage on CD4-negative, CCR5-positive, or CXCR4-positive cells, can infect their target cells in the absence of the CD4 receptor by using a chemokine receptor. Interestingly, CD4-independent HIV isolates can be obtained from HIV-infected persons but these viruses show an enhanced sensitivity to antibody mediated neutralization Edwards et al., 2001;Kolchinsky et al., 2001).CD4 is a type I integral membrane glycoprotein that is expressed mainly on the surface of thymocytes, T helper lymphocytes, and cells of the macrophage/monocyte lineage (Maddon et al., 1986). It participates in the maturation of T lymphocytes and, as an intercellular adhesion molecule, plays an important role in the stabilization of the interaction between T cell receptors on T cells and MHC II complexes on antigen-presenting cells. After the antigenic stimulation of T lymphocytes, CD4 also provides a physical noncovalent link to p56 lck protein tyrosine kinase, resulting in cell proliferation and interleukin-2 production (reviewed by Weiss and Littman, 1994).The expression of the CD4 receptor is tightly regulated in various physiological processes. During the development of T cells in the thymus, the CD4 Ϫ CD8 Ϫ double-negative cells become CD4 ϩ CD8 ϩ double-positive before they differentiate into single positive T cells (Zuniga-Pflucker et al., 1989). Also, after antigen-induced T cell activation, CD4 is quickly internalized via clathrin-coated pits, leading to a temporary desensitization of the cell (Pelchen-Matthews et al., 1992). In nonlymphoid cells, CD4 i...

Fructose consumption has increased dramatically but little is known about mechanisms regulating the intestinal fructose transporter GLUT5 in vivo. In neonatal rats, GLUT5 can be induced only by luminal fructose and only after 14 days of age, unless the gut is primed with dexamethasone prior to fructose perfusion. To elucidate the mechanisms underlying dexamethasone modulation of GLUT5 development, we first identified the receptor mediating its effects then determined whether those effects were genomic. The glucocorticoid receptor (GR) antagonist RU486 dose-dependently prevented the dexamethasone-mediated effects on body weight, intestinal arginase2 (a known GR-regulated gene) and GLUT5. In contrast, an antagonist of the mineralocorticoid receptor as well as agonists of progesterone (PR) and pregnane-X (PXR) receptors did not block the effects of dexamethasone. These receptor antagonists and agonists had no effect on the intestinal glucose transporter SGLT1. Translocation of the GR into the enterocyte nucleus occurred only in dexamethasone-injected pups perfused with fructose, was accompanied by marked increases in brush border GLUT5 abundance, and was blocked by RU486. A priming duration of ∼24 h is optimal for induction but actinomycin D injection before dexamethasone priming prevented dexamethasone from allowing luminal fructose to induce GLUT5. Actinomycin D had no effect on dexamethasone-independent fructose-induced increases in glucose-6-phosphatase mRNA abundance, suggesting that it did not prevent fructose-induction of GLUT5, but instead prevented dexamethasone-induced synthesis of an intermediate required by fructose for GLUT5 regulation. In suckling rats < 14 days old, developmental regulation of transporters may involve cross-talk between hormonal signals modulating intestinal maturation and nutrient signals regulating specific transporters.

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The multistep syntheses of several bicyclic triamines are described, all of which have an imbedded 1,5,9-triazacyclododecane ring. In 1,5,9-triazabicyclo[7.3.3]pentadecanes 12, 13, 15, and 16, two nitrogens are bridged by three carbons. The monoprotonated forms of these triamines are highly stabilized by a hydrogen-bonded network involving the bridge and both bridgehead nitrogens, producing a difference of more than 8 pK(a) units in acidities of their monoprotonated and diprotonated forms. The one- and zero-carbon bridges in 1,5,9-triazabicyclo[9.1.1]tridecane (23) and 7-methyl-1,5,9-triazabicyclo[5.5.0]dodecane (39) do not enhance the stabilities of their monoprotonated forms. X-ray crystal structures and computational studies of 12.HI and 16.HI reveal similar, but somewhat weaker, hydrogen-bonded networks, relative to 15.HI. The activation free energies for conformational inversion of 13.HI (14.4 +/- 0.2 kcal/mol), 16.HI (15.0 +/- 0.1 kcal/mol) and 16 (8.8 +/- 0.3 kcal/mol) were measured by variable-temperature (1)H and (13)C NMR spectroscopy. These experimental barriers give an estimate of 6.2 kcal/mol for the strength of the bifurcated hydrogen bond between the bridge nitrogen and cavity proton in 16.HI. Computational studies support the hypothesis that N-inversion occurs in an open conformation, leading to an estimate of 10.32 kcal/mol for the enthalpy of the bifurcated hydrogen bond in 16.HI in the gas phase.

Continuous intraocular pressure (IOP) monitoring can provide a paradigm shift in the management of patients with glaucoma as a facile alternative to conventional diagnostic methods. However, the low sensitivity and functional instability of current IOP sensors have limited their clinical utility in the management of glaucoma. Here, we have developed a smart contact lens integrated with a transparent silver nanowire IOP strain sensor and wireless circuits for noninvasive, continuous IOP monitoring. After confirming the robust stability of the IOP sensor within the smart contact lens in the presence of tears and repeated eyelid blink model cycles, we were able to monitor IOP changes on polydimethylsiloxane model eyes in vitro. In vivo tests demonstrated that our fully integrated wireless smart contact lens could successfully monitor the change in IOP in living rabbit eyes, which was clearly validated by the conventional invasive tonometer IOP test. Taken together, we could confirm the feasibility of our smart contact lens as a noninvasive platform for continuous IOP monitoring of glaucoma patients.