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Some imidazoline compounds have pleiotropic effects including cell death in vitro. We examined the antiproliferative action of a novel imidazoline compound S43126, and the role of the I1-imidazoline receptor, ROS, MAPKs and caspases in S43126-induced cell death.

Background: Some imidazoline compounds have pleiotropic effects including cell death in vitro. We examined the antiproliferative action of a novel imidazoline compound S43126, and the role of the I1-imidazoline receptor, ROS, MAPKs and caspases in S43126-induced cell death. Methods: PC 12 cells were treated with various concentrations of S43126 in the presence or absence of several ligands, and the effects on cell proliferation, ROS levels, and apoptosis were evaluated using Trypan Blue, Alamar Blue, Western blot and microscopy. Results: We showed that S43126 reduced PC12 cell proliferation by greater than 50%, increased cell death by greater than 40% and increased apoptotic body formation. These effects were reversed by I1R-antagonist, efaroxan. S43126 also increased intracellular ROS levels by greater than 2.5-fold relative to vehicle-treated control. These effects were significantly inhibited by N-acetyl-cysteine. In addition, pharmacologic inhibitors of ERK, JNK and p38 MAPK, significantly reduced S43126-induced antiproliferative activity. Caspases 3, 8 and 9 were all activated in a time-dependent manner by S43126. Pan caspase inhibitor z-VAD-fmk, ameliorated the effects of S43126 on cell death and cell proliferation. Conclusion: Our data showed that the effects of S43126 on PC12 cell death were partly mediated by ROS production, MAPK and caspase activation. These results further indicate an emerging role for I1R in apoptotic processes.

The I1-imidazoline receptor is a novel target for drug development for hypertension and insulin resistance, major disorders associated with type 2 diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126, on phosphorylation of protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK1/2) in PC12 cells. We further examined the effects of S43126 on insulin stimulated PKB and ERK phosphorylation. PC12 cells were treated with varying doses of S43126 (10-10to 10-6M) or insulin (10-10to 10-6M) or combination treatment with insulin (10-6M) and varying doses of S43126 (10-6- 10-11M) for 10 min. Western blot analysis of treated samples showed that S43126 increased both ERK1/2 and PKB phosphorylation by 5 fold. Combination treatment with insulin (10-6M) and varying doses of S43126 (10-6- 10-11M) enhanced phosphorylation of PKB and ERK1/2 above the level of insulin alone, in a dose and time dependent manner. Treatment with siRNA against Nischarin (mouse homologue of I1-imidazoline receptor) reduced the phosphorylation of both ERK and PKB following combination treatments. These results indicate that S43126 has the potential to augment insulin action and should be further studied as a possible candidate drug for the treatment of insulin resistance states.

: 1. Centrally acting imidazoline antihypertensive agents clonidine and moxonidine also act peripherally to contract blood vessels. While these agents act at both I1-imidazoline and alpha 2 adrenergic receptors centrally, the receptor types by which they mediate contraction require further definition. We therefore characterized the receptor subtype by which these agents mediate contraction of proximal rat-tail artery.2. Dose–response curves were determined for phenylephrine and for several imidazoline ligands, using endothelium denuded, isolated ring segments, of tail arteries from adult male Sprague-Dawley rats. Ring segments were mounted on a force transducer with platinum wires and immersed in a tissue bath containing Krebs solution, to which drugs could be added. Signals were digitized and recorded by a computer.3. Tail artery contractions expressed as a percent of contraction to 106 mM potassium were phenylephrine (96%), moxonidine (88%), clonidine (52%), and UK14304 (30%). Neither rilmenidine nor harmane caused contraction. Contraction of tail artery to moxonidine or clonidine could be blocked by alpha 1 antagonist urapidil or prazosin, and also by alpha 1A subtype selective antagonist WB4101. Schild plots were generated and a calculated pA2 value of 9.2 for prazosin in the presence of clonidine confirms clonidine as an agonist at alpha 1A receptors in proximal segments of rat-tail artery.4. Our work suggests that clonidine and moxonidine are promiscuous compounds at micromolar concentrations and that harmane and rilmenidine are more selective compounds for in vivo imidazoline research.

Abstract: Using the theory of measurable categories developed in [10], we provide a notion of representations of 2-groups better suited to physically and geometrically interesting examples than that using 2-VECT (cf. [8]). Using this theory we sketch a 2-categorical approach to the state-sum model for Lorentzian quantum gravity proposed in [6], and suggest state-integral constructions for 4-manifold invariants.

Teichmüller theory for super Riemann surfaces is rigorously developed using the supermanifold theory of Rogers. In the case of trivial topology in the soul directions, relevant for superstring applications, the following results are proven. The super Teichmüller space is a complex super-orbifold whose body is the ordinary Teichmüller space of the associated Riemann surfaces with spin structure. For genusg>1 it has 3g-3 complex even and 2g-2 complex odd dimensions. The super modular group which reduces super Teichmüller space to super moduli space is the ordinary modular group; there are no new discrete modular transformations in the odd directions. The boundary of super Teichmüller space contains not only super Riemann surfaces with pinched bodies, but Rogers supermanifolds having nontrivial topology in the odd dimensions as well. We also prove the uniformization theorem for super Riemann surfaces and discuss their representation by discrete supergroups of Fuchsian and Schottky type and by Beltrami differentials. Finally we present partial results for the more difficult problem of classifying super Riemann surfaces of arbitrary topology.

A DeWitt supermanifold always has the structure of a vector bundle over an ordinary spacetime manifold, whereas a Rogers supermanifold is not so restricted. Corresponding to the vector space fibers of the DeWitt supermanifold, a Rogers supermanifold has a foliation by submanifolds, or leaves, parametrized by soul coordinates only. We show that the universal covering space of any leaf always admits a flat metric. If the covering space is complete in this metric, it must in fact be a vector space. We combine this result with known theorems about foliations to give conditions under which a compact Rogers supermanifold with a single even dimension is necessarily a quotient space of flat superspace. We also show that a supermanifold defined by a polynomial equation in flat superspace is always of the DeWitt type. Finally, we exhibit new supermanifold structures forR2 and the 2-torus which show that the foliation of a Rogers supermanifold can be quite exotic.

We construct new examples of supermanifolds, and determine the vector bundle structure of the supermanifolds commonly used in physics. We show that any supermanifold admits a foliation whose leaves are locally tangent to the soul directions in the coordinate charts, and which is one of a nested sequence of foliations. We point out that the existence of these foliations implies restrictions on the possible topologies of supermanifolds. For example, a compact supermanifold with a single even dimension must have vanishing Euler characteristic. We also show that a globally defined superfield on a “nice” compact supermanifold must be constant along the leaves of the foliations. By this mechanism, the global topology of a supermanifold can be used to impose physically interesting constraints on superfields. As an example, we exhibit a supermanifold which has the local geometry of flat superspace but is such that all globally defined superfields are chiral.

Recently Kac-Moody symmetry has played an important role in mathematical physics. Dolan and Chau, Ge and Wu discovered an infinitesimal action of the Kac-Moody Lie algebra on the space of solutions of SDYM. We have discovered an action of the loop group on the space of generalized solutions of SDYM, which exponentiates the Kac-Moody action. The group acts by adding a special type of source onto the solution. The action is a geometric construction using the twistor picture.

A distribution of virtual black holes in the vacuum will induce modifications in the density of states for small perturbations of gravitational and matter fields. If the virtual black holes fill the volume of a typical spacelike surface then perturbation theory becomes more convergent and may even be finite, depending on how fast the number of virtual black holes increases as their size decreases. For distributions of virtual black holes which are scale invariant the effective dimension of space-time is lowered to a noninteger value less than 4, leading to an interpretation in terms of fractal geometry. In this case general relativity is renormalizable in the 1/N expansion without higher derivative terms. As the Hamiltonian is not modified the theory is stable.

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