Corona discharge amplification of acid group topochemistry

"May 2002."Submitted to Tappi Journal

Effects of chronic infusion of lipopolysaccharide on food intake and body temperature of the rat

Unrestrained male Sprague-Dawley rats were infused for seven days with a low (2.45 [mu]g/hr) or high (9.81 [mu]g/hr) concentration of E. coli lipopolysaccharide (LPS). Compared to control (saline-infused) rats, food intake in the LPS-infused rats remained depressed for the entire infusion period. Despite this long-term suppression of food intake, fever was observed only during the daytime hours for the first two days of infusion. No significant increase in nighttime body temperature was observed. These data indicate that although tolerance to LPS occurred in rats with regard to its fever-inducing effect, tolerance with respect to its anorexigenic action did not occur.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27525/1/0000569.pd

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

SummaryVascular endothelial growth factor C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here, we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C terminus in complex with the ligand binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition

Effect of centrally administered interleukin-1 and endotoxin on food intake of fasted rats

We have previously shown that interleukin-1 (IL-1), a polypeptide known to mediate many aspects of the acute phase response to infection, suppresses food intake when injected intraperitoneally into fasted rats. IL-1 acts at the level of the hypothalamus to induce fever. In view of the large number of peptides that have been shown to alter food intake as well as body temperature when injected intracerebroventricularly (ICV), we hypothesized that the receptor site for the anorexigenic activity of IL-1 would be located in a central nervous site bathed by the cerebrospinal fluid. In the present study, ICV injection of IL-1 or E. coli endotoxin (a stimulus for the synthesis of IL-1), significantly elevated body temperature, but did not affect food intake of fasted rats. We conclude that receptors mediating the anorexigenic actions of IL-1 or endotoxin are not located at a central nervous site bathed by the cerebrospinal fluid. Furthermore, fever per se is not reponsible for the reduction in food intake seen following peripheral injection of IL-1 or endotoxin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26437/1/0000525.pd

Stress-induced rise of body temperature in rats is the same in warm and cool environments

Several forms of psychological stress result in a rise in body temperature in rats. In this study, we report that rats housed at a low ambient temperature (11.1[deg]C) develop stress-induced rises in body temperature that do not differ from the responses seen when the animals are kept at a temperature within their thermoneutral zone (24.7[deg]C). These data support the hypothesis that stress-induced "hyperthermia" is a regulated rise in temperature (i.e., a rise in thermoregulatory "set-point," or fever), and is not simply the result of metabolic changes associated with the stress response itself.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28659/1/0000476.pd

The effects of pentoxifylline on lipopolysaccharide (LPS) fever, plasma interleukin 6 (IL 6), and tumor necrosis factor (TNF) in the rat

The purpose of these studies was to test whether pentoxifylline, a drug that can inhibit the production and action of cytokines hypothesized to be endogenous pyrogens (for example, interleukin 1 and tumor necrosis factor [TNF]), is antipyretic. We also tested the effects of pentoxifylline on plasma activities of interleukin 6 (IL 6) and TNF in response to an injection of a fever-inducing dose of lipopolysaccharide (LPS). Our results showed that a high dose of pentoxifylline (200 mg/kg) caused hypothermia in control rats and blocked LPS fever, while a low dose (50 mg/kg) did not have these effects. Injection of the high dose of pentoxifylline in control rats caused a rise in plasma IL 6 but not in plasma TNF. However, the peak levels of plasma IL 6 and TNF activities following an injection of LPS were significantly reduced by pretreatment with pentoxifylline. Overall, the data are consistent with the hypothesis that pentoxifylline is an antipyretic drug, which may act at least in part by inhibiting the secretion of pyrogenic cytokines.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28504/1/0000301.pd

The effects of psychological stress on plasma interleukin-6 activity in rats

The purpose of this study was to determine the effects of a particular psychological stress, exposure to an open-field, on plasma IL-6 activity in rats. Plasma IL-6 activity was 40.6+/-7.2 units/ml in control rats, 105+/-6.8 units/ml after 30 minutes exposure to an open-field, and 221+/-17 units/ml after 60 minutes of exposure (p=0.0003). There was a positive correlation (r=.71, p=0.043) between the change in plasma IL-6 activity and body temperature. However, we conclude, based on earlier data relating plasma IL-6 activity to body temperature changes following injection of lipopolysaccharide, that the plasma levels of IL-6 following exposure to an open-field are not high enough to account for the rise in body temperature observed in rats during this stress. In conclusion, these experiments indicate that exposure to psychological stress can elevate the plasma concentration of IL-6, a known mediator of the acute phase response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28610/1/0000422.pd

Clearance of renin in unanesthetized rats: Effects of chronic lead exposure

These experiments studied the influence of chronic lead exposure on the steady-state clearance of exogenous homologous renin in unanesthetized, unrestrained rats. Relative to time controls (TC), rats chronically exposed to 500 ppm lead in drinking water had significantly elevated basal plasma renin concentrations (PRC) (Pb = 12.0 +/- 1.6 ng/ml/hr, TC = 7.6 +/- 0.8). During the infusion of homologous renin sufficient to increase plasma renin approximately 10-fold, the clearance of renin was not different between the two groups (after 60-min infusion, Pb = 16.1 +/- 1.8 ml/kg/min, TC = 15.9 +/- 1.5). Rats exposed to 1000 ppm lead did not have higher PRCs than time controls (Pb = 10.9 +/- 2.2, TC = 9.2 +/- 1.8). The clearances of renin in these two groups were also not significantly different (Pb = 15.3 +/- 2.8, TC = 18.3 +/- 2.5). Renal renin concentrations were significantly elevated in the 500 ppm rats (Pb = 1426 +/- 110 ug/kidney, TC = 1065 +/- 118) consistent with an increased basal renin secretion, but were not elevated in the 1000-ppm rats. There were no significant differences in the clearances of sulfobromophthalein (BSP) between any of the groups. The renin infusion significantly reduced BSP clearance, but did so equally in all groups. It is concluded that in unanesthetized, unrestrained rats the clearance of renin is not altered by chronic lead exposure of either 500 or 1000 ppm and that increased secretion of renin accounts for the elevated basal PRC observed in rats exposed to the lower dose of lead.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25186/1/0000625.pd

A theoretical mode of action of aldosterone

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32373/1/0000448.pd

Acute effects of lead on the renal handling of zinc in dogs

Urinary zinc excretion was monitored in anesthetized dogs before and during 4 hr after acute exposure to lead (doses: 0.3 mg Pb (as acetate)/kg as iv prime, followed by infusion of 0.057 mg Pb/min; 3mg Pb/kg, followed by 0.57 mg Pb/min as infusion; or equimolar sodium acetate in the control group). Zinc excretion in time controls was relatively constant over the 4 hr, but it rose above baseline values an average of 140 ng/min in 0.3 mg Pb/kg injected animals, and an average of 300 ng/min in 3 mg Pb/kg injected animals. Other indices of renal function, including excretion of protein, Na, K, and Mg, were relatively constant. Plasma Zn concentration was stable in time control and low Pb-administered animals, but rose significantly after the higher Pb dose. Clearance experiments using 65Zn and in vitro ultrafiltration of plasma were performed in another series of dogs under antidiuretic conditions. Zn excretion (monitored by 65Zn) was sevenfold higher in Pb-treated dogs; plasma Zn concentration was slightly, but not significantly, elevated. Ultrafiltrable Zn concentration was 2.5-fold higher and fractional Zn excretion was three times higher in Pb-treated dogs. The stop-flow pattern for Zn after Pb treatment showed no change in the distal tubular handling of Zn, but revealed prominent net proximal tubular secretion of Zn in all animals, a frequency statistically different from that observed in control animals. Thus, acute Pb treatment in dogs produced an increase in urinary Zn excretion which was related both to an increase in ultrafilterable plasma Zn and a change in renal tubular Zn transport. The plasma concentrations of insulin and glucagon were not altered by lead.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24182/1/0000441.pd