Trichinella spiralis: acceleration and inhibition of cyst calcification in rats.

Daily administration of vitamin D3 (75,000 IU/kg b. wt) for 7 days accelerated Trichinella spiralis cyst calcification in rats with a 14-week-old infection. When disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP) was administered (50 mg/kg b. wt) from 2 days before until 2 days after vitamin D3 treatment, cyst calcification was inhibited. Thus, the ability to inhibit E. spiralis calcification has demonstrated for the first time.     

Trichinella spiralis: Acceleration and inhibition of cyst calcification in rats

Summary Daily administration of vitamin D₃ (75,000 IU/kg b.wt) for 7 days acceleratedTrichinella spiralis cyst calcification in rats with a 14-week-old infection. When disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) was administered (50 mg/kg b.wt) from 2 days before until 2 days after vitamin D₃ treatment, cyst calcification was inhibited. Thus, the ability to inhibitT. spiralis calcification has been demonstrated for the first time.Supported in part by EKU faculty research grant No. 03-05.Much appreciation goes to Dr Gordon S. Hassings and the Proctor and Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio USA for providing the EHDP used in this study.     

In vivo effect of sodium valproate on mouse liver

The in vivo effect of sodium valproate (SV) on the activity of uridine diphosphate glucuronosyltransferase (UDP-GT) and hepatotoxicity in the mouse liver was studied. Mice were injected intraperitoneally (IP) with SV at doses varying from 50 to 800 mg/kg per day, for six consecutive days (dose-response group) or at a standard dose of 300 mg/g per day for 2-10 days (time-response group), whereas the controls were injected with normal saline. Valproic acid levels had a positive correlation to the dose (P < 0.001) and duration of drug administration (P = 0.006). A gradual increase in UDP-GT activity was observed in doses of up to approximately 400 mg/kg per day, whereas in higher doses the enzyme activity gradually decreased. The time course of UDP-GT activity at the standard dose of 300 mg/kg per day increased progressively, with a maximum up to the sixth day and then had a gradual reduction. Hepatic necrosis (which was unrelated to the dose or the duration of drug administration) was found in 13% of the SV-treated animals and in none of the controls. We conclude that at an optimal dose (300-400 mg/kg per day) and at a time course of 6 days, SV causes liver UDP-GT induction, whereas in higher doses and longer duration of administration, UDP-GT activity is gradually reduced. SV also causes hepatotoxicity unrelated to dose and time course.     

Leishmania donovani in hamsters: Stimulation of non-specific resistance by novel lipopeptides and their effect in antileishmanial therapy

Several novel type of lipopeptides were synthesized and evaluated for their ability to stimulate non-specific resistance againstLeishmania donovani infection. Peritoneal macrophages isolated from young male hamsters treated with muramyl dipeptide (MDP) and various synthetic lipopeptides (6 mg/kg i.p.) 7 days earlier, were cultured in vitro and challenged 24 h later withL. donovani promastigotes. One lipopeptide, Central Drug Research Institute (CDRI) compound 86/450, exhibited significantly higher immunostimulatory activity than MDP. Its prophylactic activity was further confirmed in hamsters by giving 2 split doses of 3 mg/kg of the compound spaced at 2 weeks, i.e. on day –7 and +7 of challenge withL. donovani amastigotes. The prophylactic effect lasted for 7 days following the last treatment with compound 86/450. The antileishmanial action of sodium stibogluconate (SAG) was also found to be enhanced by 16% in hamsters primed with compound 86/450.CDRI Communication No. 5034.     

The sedative effects of nicotinamide on gerbil wheel-running activity

Summary The activity of 5 groups of gerbils was monitored over 22 days. 3 of the groups received daily injections of nicotinamide (125, 250 or 500 mg/kg) and a 4th group received saline. The 5th group was untreated. The results indicated that both the 250 and 500 mg/kg nicotinamide administrations greatly reduced the activity levels of the gerbils.This work was supported in part by Faculty Research Grant No. 82-6209 from the University of Alabama in Birmingham to J.M.B.     

The sedative effects of nicotinamide on gerbil wheel-running activity.

The activity of 5 groups of gerbils was monitored over 22 days. 3 of the groups received daily injections of nicotinamide (125, 250 or 500 mg/kg) and a 4th group received saline. The 5th group was untreated. The results indicated that both the 250 and 500 mg/kg nicotinamide administrations greatly reduced the activity levels of the gerbils.     

Effect of borax on testis of Indian desert gerbil,Meriones hurriane Jerdon

Summary Borax was injected at a dose level of 250 mg/kg b. wt for 16 days (total dose 4 g/kg b.wt) s.c. to active adult male gerbils. Borax caused several degenerative changes in the testes of which giant cell formation, pyknosis and exfoliation are prominent. The increased activity of phosphatases was also noticed.The autors are grateful to University of Rajasthan for providing research scholarship to (M.P. Sharma) and (K. Mehta) and the necessary facilities.     

Duration of bone protection by a single osteoprotegerin injection in rats with adjuvant-induced arthritis

Daily osteoprotegerin (OPG) injection for 7 or more days prevents bone loss for 3 weeks in rats with adjuvant-induced arthritis (AdA). The present experiments defined the duration of bone protection in AdA provided by a single OPG bolus. Male Lewis rats received OPG at the onset or peak of clinical disease, after which bone mineral density (BMD), erosions, and osteoclasts were evaluated. An OPG bolus (4 mg/kg subcutaneously) at onset eliminated osteoclasts, preserved BMD for 7 days, and prevented bone erosions for 4 days. In contrast, an OPG bolus (1, 3, 10, or 30 mg/kg intravenously) given at the peak of disease eradicated osteoclasts in a dose-dependent manner but had no impact on bone integrity due to extensive pre-existing bone loss. These data indicate that one OPG injection will inhibit joint erosions for several days, and confirm that bone-sparing therapy must be initiated early in disease to protect joint integrity.     

The influence of lithium on serum ceruloplasmin.

Serum ceruloplasmin oxidase activity did not change in mice treated orally for 120 days with Li2CO3 (0.58 mEq/kg/day). After a single i.p. injection of LiCl (20 mEq/kg), a significant activation of ceruloplasmin was observed.     

Synergism between long-acting bromocryptine microcapsules and cyclosporine A in the prevention of various autoimmune diseases in rats

Pre-treatment of male Sprague-Dawley rats with long-acting bromocryptine microcapsules (CBLA) significantly inhibited the arthritic response to Freund's complete adjuvant and reduced weight loss, thymolysis, splenomegaly and leukocytosis. In the prevention of adjuvant arthritis (AA), the combination of CBLA plus sub-optimal doses of cyclosporine A (CsA) was more efficient than either of the drugs alone. Sub-optimal doses of CsA were 0.1 and 1.0 mg/kg/day s.c. for 5 days. Furthermore, CBLA alone did not decrease the incidence of experimental allergic uveitis (EAU) in the male Lewis rats. Low-dose CsA reduced the incidence of uveitis by 50%, and with the addition of CBLA, 100% of rats were protected. Low-dose CsA was 2 mg/kg/day i.m. for 14 days. Long-term treatment of male Sprague-Dawley rats with CBLA alone reduced the incidence and severity of spontaneous autoimmune periateritis nodosa (PN) in a dose-dependent manner; CsA was less potent than CBLA, and only additive effects were obtained. Finally, for the prevention of spontaneous autoimmune insulin-dependent diabetes (DM), the administration of CBLA did not improve the effect of a low-dose CsA in male BB rats. Nevertheless, a delay in onset of DM could be achieved. A sequential therapy using CsA plus CBLA clearly showed beneficial effects. The dose of CsA was 10 mg/kg p.o. 6 days/week for 21 weeks. Compared with Sprague-Dawley or Lewis male rats, BB male rats showed only weak prolactin suppression after the same doses of CBLA. It is suggested that the use of CBLA may be particularly beneficial in autoimmune disorders. The effectiveness of the combination therapy CBLA plus CsA, however, was dependent on the model considered. Various factors could play a role: (1) the different ways of administering CsA (s.c. in AA, i.m. in EAU and PN, oral in DM); (2) strain-dependency in the capacity of CBLA to suppress Prl secretion; and(3) at least in the BB rats, the transient increase of CsA bioavailibility which was possibly induced by CBLA.     

Protective effect of Shigyaku-to,a traditional Chinese herbal medicine,on the infection of herpes simplex virus type 1 (HSV-1) in mice

The antiviral activity of Shigyaku-to (TJS-109), a traditional Chinese herbal medicine, was investigated in mice infected with herpes simplex virus type 1 (HSV-1). TJS-109 is a combination of the medicinal plant extracts fromZingiberis siccatum rhizoma,Aconiti tuber andGlycyrrhizae radix in a specific proportion. Mice infected with a 10 LD₅₀ dose of HSV-1 were treated with TJS-109 orally at doses of 1.25 to 20 mg/kg 2 days before, and 1 and 4 days after the infection. The treated groups had 80% (1.25 mg/kg), 40% (5 mg/kg) and 23% (20 mg/kg) mortality rates 25 days after the infection as compared with a 100% mortality rate in control mice treated with saline. When HSV-1 infected mice (recipients) received CD8⁺T cell fractions derived from spleens of mice treated with TJS-109 (donors), 70% of recipients survived, as compared with 0% survivors in the groups of mice treated with saline, B cell fractions, CD4⁺ T cell fractions or macrophage-enriched fractions prepared from the same donors. TJS-109 did not show any virucidal activities against HSV-1 or any virostatic activities on the growth of HSV-1 in Vero cells. These results suggest that TJS-109 protected mice exposed to lethal amounts of HSV-1 through the activation of CD8⁺ T cells.     

Time and theophylline influence on the quantitative variations of the glomerular basement membrane ferritin pathway (author's transl)

A fine quantitative evaluation of ferritin aggregates in rat GBM permits to counts 5.08 +/- 1.51 and 18.30 +/- 3.21 g/cm2, respectively 30 and 60 min after ferritin injection; likewise, 30 min after ferritin administration, 5.08 +/- 1.51 and 17.11 +/- 3.9 g/cm2, respectively in normal and theophylline-treated animals.     

Cimetidine induces hepatic heme oxygenase activity without altering hepatic heme catabolism

Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a 14CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p less than 0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.     

Interaction of salicylate and noise results in mortality of rats

Summary Survival as a function of salicylate dose and the intensity of environmental noise was investigated in 150 adult female pigmented rats. Rats were assigned to groups (n=6/group) defined by combinations of salicylate levels from 0- (saline) to 300 mg/kg, injected subcutaneously, and noise levels from ambient noise to 98 dB SPL, presented daily for 10-h periods for up to 17 days. Mortality occurred in groups exposed to the higher combinations of salicylate and noise.     

Insensitivity of the ferritin iron core to heat treatment

Summary To test whether the reactivity of ferritin iron is affected by the heat treatment used in ferritin isolation, we prepared ferritin from the same horse spleen with or without heating. Both samples exhibited similar reactivity upon reduction or chelation of iron.Acknowledgments. We are indebted to George Rossman who brought this problem to our attention. Work was supported in part by NIH Grant HL20141 and by the Petroleum Research Fund.     

Cimetidine induces hepatic heme oxygenase activity without altering hepatic heme catabolism

Summary Cimetidine inhibits oxidative drug metabolism; it is not known whether this drug alters the catabolic fate of hepatic heme. We therefore investigated hepatic heme turnover both by a¹⁴CO breath test and directly by labeling the heme pool. Neither acute (150 mg/kg i.p.) nor chronic (150 mg/kg i.p. bid for 3 days) cimetidine administration significantly affected hepatic heme turnover. Chronic, but not acute, cimetidine significantly (p<0.025) increased heme oxygenase activity. Cimetidine inhibited heme oxygenase activity in vitro at concentrations achieved in vivo.     

Études des variations quantitatives du passage de la ferritine au niveau de la membrane basale glomérulaire en fonction du temps et sous l'influence de la théophylline

Summary A fine quantitative evaluation of ferritin aggregates in rat GBM permits to counts 5.08±1.51 and 18.30±3.21 g/cm², respectively 30 and 60 min after ferritin injection; likewise, 30 min after ferritin administration, 5.08±1.51 and 17.11±3.9 g/cm², respectively in normal and theophylline-treated animals.     

Cellular regulation and molecular interactions of the ferritins

Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA (mRNA) structures, signaling pathways and protein catalysts. Ferritin, a protein nanocage around an iron/oxy mineral, centralizes the control. Complementary DNA (antioxidant responsive element/Maf recognition element) and mRNA (iron responsive element) responses regulate ferritin synthesis rates. Multiple iron-protein interactions control iron and oxygen substrate movement through the protein cage, from dynamic gated pores to catalytic sites related to di-iron oxygenase cofactor sites. Maxi-ferritins concentrate iron for the bio-synthesis of iron/heme proteins, trapping oxygen; bacterial mini-ferritins, DNA protection during starvation proteins, reverse the substrate roles, destroying oxidants, trapping iron and protecting DNA. Ferritin is nature’s unique and conserved approach to controlled, safe use of iron and oxygen, with protein synthesis in animals adjusted by dual, genetic DNA and mRNA sequences that selectively respond to iron or oxidant signals and link ferritin to proteins of iron, oxygen and antioxidant metabolism. Received 25 June 2005; received after revision 17 October 2005; accepted 25 November 2005     

Ferritin synthesis by splenic tumor tissue of Hodgkin's disease.

Increased ferritin synthesis by Hodgkin's disease splenic tumor tissue was demonstrated by incorporation of 14C-leucine and radioautography. This suggests that elevated tumor and serum ferritin concentrations found in patients with Hodgkin's disease is derived from tumor tissue per se.     

Antifertility activity of trimethylphosphate in male rats

Summary The toxic effect of trimethylphosphate on rat testes was investigated after oral dosing with 250 mg/kg for either 5 days/week for 30 days or 6 days/week for 60 days. After these prolonged treatments azoospermia resulted.Acknowledgments. The authors wish to thank Ms M. Michelles, Ms A. Murray and Ms R. Peake for their technical support.