No abstract

In uitro toxicological evaluation of Nerium oleander was carried out using different isolated preparations. The methanolic leaf extract potentiated both spontaneous and electrically evoked contractions of vas deferens of rats and guinea-pig ileum in a concentration dependent manner. The effect was not antagonized by the adrenergic blocker, tolazoliie. The extract inhibited electrically stimulated neurogenic twitch responses of rat phrenic nerve diaphragm preparation. The dose dependent inhibition of twitch response in this preparation could not be reversed by the anticholinesterase drug, neostigmine. The extract evoked a persistent depolarizing effect on the phrenic nerve diaphragm preparation. The extract exhibited its most potent action on the isolated right atrial preparation of rat. It inhibited the rate of spontaneously beating atria in a concentration dependent manner. The negative chronotropic effect was not antagonized either by antimuscarinic drug or adrenergic agonist.

I I Anatoxin-a, recognised as a potent toxin warfare agent, is considered as a weapon of mass desb"Uclidn due to its lethal anticholinesterase oclivity. The intravenous administration of cell-free extract of Anabenaflosaquae lJl"EX-2383 (anatoxin1a) pr

The exposure to chemical warfare agents is not restricted to the battlefield but as humans may be poisoned with nerve gases either from a chemical warfare stockpile or even in a public place. The recent use of nerve gas Sarin in a subway of Japan by a fanatic group has triggered global consternation about the extremists and homemade weapons of mass destruction. Nerve agents are organophosphorus (OP) compounds that exert acute toxic manifestations principally by inhibiting the enzyme acetylcholinesterase (AChE) resulting in a variety of physiological alterations and ultimately death from respiratory failure (Brimblecombe 1977). However, pharmacological studies indicate that nerve agents have plethora of actions other than inhibition of AChE (Worek and Szinicz 1995, Corbier and Robineau 1989, Robineau and Guittin 1987.Several studies have revealed that acute intravenous (i.v.) administration of an OP agent increased blood pressure in cat, dog and rat (Brezenoff and Giuliano 1982, Lang andRush 1973), while subcutaneous (s.c.) administration produced marked hypotension (Preston and Heath 1972). In a recent communication from this laboratory, it has been reported that i.v. administration of DFP/sarin produced a dose-dependent hypertension involving cholinergic-catecholaminergic interaction in rats. Subcutaneous administration of DFP/ sarin was found to produce a dose-responsive hypotension mediated through muscarinic receptors (Dube et al 1993). However, the mechanism of cardiovascular toxicity induced by nerve agents still remains obscure. Therefore, the effects on blood pressure, heart rate, tracheobronchial response, neuromuscular transmission, and modulatory role of various pharmacological agents were studied after systemic administration of VX (O-ethyl S-[2-(diisopropylamino) ethyl ] methyl phosphonothioate) to delineate the distinction in mechanism of action from other OP compounds.

Keratinocytes are key structural cells in cell migration during wound repair. Keratinocyte migration is dysfunctional in diabetes and results in non-healing, however, the reason for this is unclear. Using bulk and single cell sequencing, we identified that Th17 CD4+ T-cells predominate as does an IL-17A signature in human diabetic wound tissue compared to non-diabetic controls. The effects of increased IL-17A in diabetic skin on keratinocyte function is unknown. To examine this, we subjected isolated keratinocytes to scratch injury and a 24hr rIL-17A (20ng) stimulation. We observed a significant decrease in migration rate in IL-17A stimulated keratinocytes compared to their controls. Next, we examined migration related genes in keratinocytes from mice fed with a normal (ND) or a high fat (HFD) diet. Integrin alpha 3 subunit, Itga3, (a protein known to delay keratinocyte migration during wound re-epithelialization) was higher in diabetic (HFD) keratinocytes compared to ND controls at baseline and with rIL-17A. We analyzed epigenetic enzymes known to increase gene expression and identified that JMJD3, a histone demethylase that relaxes chromatin, was increased both in diabetic keratinocytes from our human scRNA-seq and in murine diabetic keratinocytes with rIL17A. Further, treatment with a JMJD3-specific inhibitor (GSK-J4) decreased Itga3 in diabetic keratinocytes, suggesting that JMJD3 may be relevant to IL-17A-mediated regulation of integrin alpha 3 and other keratinocyte migration genes. Continued investigation into upstream IL-17A signaling in normal and diabetic keratinocytes that alters downstream migration is crucial for our understanding of impaired keratinocyte functions associated with diabetic wound repair. NIH T32 AI 007413, Research Training in Experimental Immunology Rackham Pre-Candidate Graduate Student Research Grant, University of Michigan