The role of iron in neurotoxicity: a study of novel antimalarial drugs

The antimalarial drug artemisinin and its derivatives display neurotoxicity in animal studies in vivo and in neuronal cells in vitro. Their toxicity may be due to an interaction of iron with the endoperoxide bridge of the derivative to produce toxic free radicals and/or other toxic metabolites. In this study, 0.3 microM artemether (AEM) in the presence of 2 microM haemin significantly inhibited the outgrowth of neurites from differentiating NB2a neuroblastoma cells by up to 76%. The antioxidants ascorbic acid and glutathione completely protected against this toxicity at a concentration of 100 microM. AEM was found to be partially converted to two isomeric products, which were identified as the tetrahydrofuran acetate isomer of AEM and 3alpha-hydroxydesoxyartemether.     

Atrial natriuretic factor and digoxin-like immunoreactive factor in diabetic patients: their interrelation and the influence of the autonomic nervous system

In diabetic patients, several factors contribute to volume expansion and have to be counteracted by humoral and neuronal feedback control systems. We investigated N-terminal proatrial natriuretic factor (ANF1-98) and digoxin-like immunoreactive factor (DLIF), which are two counteracting hormones, and their interrelationship, with additional consideration given to autonomic nervous function in diabetic patients. ANF1-98 and DLIF were measured in 64 diabetic patients. Autonomic nervous function was assessed using nine autonomic nervous function tests. The patients were subdivided into two groups, one with four or more (group 1) and one with less than four abnormal results in autonomic function tests (group 2). Compared with group 2, group 1 demonstrated detectable DLIF levels less often (17.2 vs. 45.7, P = 0.0195) and increased levels of ANF1-98 (mean +/- SEM: 850.0 +/- 108.8 vs. 554.8 +/- 45.9 pmol/L, P = 0.0099). However, the groups did not differ in blood pressure, daily sodium, and daily potassium excretion. The number of abnormal autonomic function tests correlated significantly with ANF1-98 (P = 0.0002). In patients with detectable DLIF, DLIF correlated with ANF1-98 (P = 0.0080). These results demonstrate close interactions between the autonomic nervous system and the two natriuretic hormones. In patients with autonomic nervous dysfunction, higher levels of ANF may possibly compensate for the lack of the natriuretic DLIF to counteract hypertension and chronic volume expansion.     

Construction of a form of the MoFe protein of nitrogenase that accepts electrons from the Fe protein but does not reduce substrate

The direction of electron flow through nitrogenase is generally believed to be from the Fe protein to the P-clusters to the FeMo cofactor and then to substrate. In order to examine oxidation states of the P-clusters that might be involved in this pathway, we have constructed a form of the MoFe protein that contains a species called the MoFe cluster (Gavini, N., Ma, L., Watt, G., and Burgess, B.K. (1995) Biochemistry 33, 11842-11849) in place of FeMo cofactor. This MoFe cluster-containing protein was purified, and the presence of the cluster was confirmed by reisolation of the MoFe cluster followed by EPR spectroscopy. The protein does not reduce protons or acetylene, however, upon the addition of the Fe protein and MgATP, MgATP hydrolysis occurs at a rate 28% of the wild-type protein. As isolated in the presence of excess dithionite the MoFe cluster-containing protein is EPR silent. Upon addition of the Fe protein and MgATP a g = 1.94 EPR signal develops that integrates to about 1 spin per P-cluster. This signal only develops when both the Fe protein and MgATP are added and it arises from the P-clusters.     

Immunohistological demonstration of transforming growth factor-beta isoforms in the skin of patients with systemic sclerosis

The objective of the present study was to investigate whether oxytocinergic mechanisms may contribute to the antinociceptive effect of non-noxious, sensory stimulation. To test this hypothesis, oxytocin levels in plasma and cerebrospinal fluid (CSF) were measured in control rats as well as in rats exposed for 30 min to electro-acupuncture (2 Hz), thermal stimulation (40 degrees C) or vibration (100 Hz). All modes of stimulation induced significant elevations of oxytocin levels in plasma and/or in CSF, 30 or 90 min after the end of stimulation. Secondly, the antinociceptive effects of these treatments were investigated in the tail-flick test with and without prior administration of the oxytocin antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin (1 mg kg-1 i.p.). All three modes of stimulation caused a significant delay of the tail-flick latency to the same degree as that caused by injection of oxytocin 1 mg kg-1 i.p. (electro-acupuncture P < 0.01, thermal stimulation and vibration P < 0.05). In all cases, the delay was reversed by administration of the oxytocin antagonist (1 mg kg-1 i.p.). These findings suggest that analgesic effects induced by non-noxious sensory stimulation may, in part, be mediated through activation of oxytocinergic mechanisms.