scholarly journals Phospholipogenic Pharmaceuticals Are Associated with a Higher Incidence of Histological Findings than Nonphospholipogenic Pharmaceuticals in Preclinical Toxicology Studies

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Linda R. Barone ◽  
Scott Boyer ◽  
James R. Damewood ◽  
James Fikes ◽  
Paul J. Ciaccio
Keyword(s):  
Adaptive Response ◽  
Reproductive Organs ◽  
Liver Necrosis ◽  
Neutral Compounds ◽  
Preclinical Species ◽  
Kidney Liver ◽  
Histologic Changes ◽  
Lung Lymph

While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZenecain vivotoxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validatedin silicoandin vitromodels. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics.

scholarly journals Overexpression of the Matrix Metalloproteinase Matrilysin Results in Premature Mammary Gland Differentiation and Male Infertility

1998 ◽  
Vol 9 (2) ◽  
pp. 421-435 ◽  
Author(s):  
Laura A. Rudolph-Owen ◽  
Paul Cannon ◽  
Lynn M. Matrisian
Keyword(s):  
Matrix Metalloproteinase ◽  
Transgenic Animals ◽  
Reproductive Organs ◽  
Mammary Development ◽  
Seminiferous Tubules ◽  
Interstitial Tissue ◽  
Wild Type ◽  
The Matrix

To examine the role of matrilysin (MAT), an epithelial cell-specific matrix metalloproteinase, in the normal development and function of reproductive tissues, we generated transgenic animals that overexpress MAT in several reproductive organs. Three distinct forms of human MAT (wild-type, active, and inactive) were placed under the control of the murine mammary tumor virus promoter/enhancer. Although wild-type, active, and inactive forms of the human MAT protein could be produced in an in vitro culture system, mutations of the MAT cDNA significantly decreased the efficiency with which the MAT protein was produced in vivo. Therefore, animals carrying the wild-type MAT transgene that expressed high levels of human MAT in vivo were further examined. Mammary glands from female transgenic animals were morphologically normal throughout mammary development, but displayed an increased ability to produce β-casein protein in virgin animals. In addition, beginning at approximately 8 mo of age, the testes of male transgenic animals became disorganized with apparent disintegration of interstitial tissue that normally surrounds the seminiferous tubules. The disruption of testis morphology was concurrent with the onset of infertility. These results suggest that overexpression of the matrix-degrading enzyme MAT alters the integrity of the extracellular matrix and thereby induces cellular differentiation and cellular destruction in a tissue-specific manner.

scholarly journals Studies on the pathogenesis of liver necrosis by α-amanitin. Effect of α-amanitin on ribonucleic acid synthesis and on ribonucleic acid polymerase in mouse liver nuclei

1967 ◽  
Vol 105 (2) ◽  
pp. 779-782 ◽  
Author(s):  
F. Stirpe ◽  
L. Fiume
Keyword(s):  
Rna Polymerase ◽  
Ammonium Sulphate ◽  
Ribonucleic Acid ◽  
Mouse Liver ◽  
Orotic Acid ◽  
Acid Synthesis ◽  
Liver Necrosis ◽  
Liver Nuclei

1. Injection of α-amanitin to mice causes a decreased incorporation of [6−14C]-orotic acid into liver RNA in vivo. 2. The activity of RNA polymerase activated by Mn2+ and ammonium sulphate is greatly impaired in liver nuclei isolated from mice poisoned with α-amanitin, and is inhibited by the addition of the same toxin in vitro. 3. The activity of the Mg2+-activated RNA polymerase is only slightly affected by α-amanitin either administered to mice or added in vitro.

scholarly journals The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-alpha and -beta

2004 ◽  
Vol 182 (2) ◽  
pp. 193-201 ◽  
Author(s):  
KC Lee ◽  
H Jessop ◽  
R Suswillo ◽  
G Zaman ◽  
LE Lanyon
Keyword(s):  
Mechanical Loading ◽  
Adaptive Response ◽  
Oestrogen Receptor ◽  
Cell Number ◽  
Wild Type ◽  
Oestrogen Receptor Alpha ◽  
Osteogenic Response ◽  
Related Increase

Postmenopausal osteoporosis represents a failure of the response by which bone cells adapt bone mass and architecture to be sufficiently strong to withstand loading without fracture. To address why this failure should be associated with oestrogen withdrawal, we investigated the ulna's adaptive response to mechanical loading in adult female mice lacking oestrogen receptor-alpha (ERalpha(-/-)), those lacking oestrogen receptor-beta (ERbeta(-/-)) and their wild-type littermates. In wild-type mice, short periods of physiologic cyclic compressive loading of the ulna in vivo over a 2-week period stimulates new bone formation. In ERalpha(-/-) and ERbeta(-/-) mice this osteogenic response was respectively threefold and twofold less (P<0.05). In vitro, primary cultures of osteoblast-like cells derived from these mice were subjected to a single short period of mechanical strain. Twenty-four hours after strain the number of wild-type cells was 61+/-25% higher than in unstrained controls (P<0.05), whereas in ERalpha(-/-) cells there was no strain-related increase in cell number. However, the strain-related response of ERalpha(-/-) cells could be partially rescued by transfection with functional human ERalpha (P<0.05). ERbeta(-/-) cells showed a 125+/-40% increase in cell number following strain. This was significantly greater than in wild types (P<0.05).These data support previous findings that functional ERalpha is required for the full osteogenic response to mechanical loading and particularly the stage of this response, which involves an increase in osteoblast number. ERbeta appears to depress the ERalpha-mediated strain-related increase in osteoblast number in vitro, but in female transgenic mice in vivo the constitutive absence of either ERalpha or ERbeta appears to diminish the osteogenic response to loading.

Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species

2016 ◽  
Vol 31 (1) ◽  
Author(s):  
Jouko Uusitalo ◽  
Miia Turpeinen ◽  
Ari Tolonen ◽  
Pasi Koskimies ◽  
Risto Lammintausta ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Animal Species ◽  
Active Metabolites ◽  
Receptor Modulator ◽  
Toxicological Studies ◽  
Metabolite Profiles ◽  
Preclinical Species ◽  
Pharmacologically Active

AbstractMetabolite profiles of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, were surveyed as part of its development.The pharmacokinetics of ospemifene and its two major, pharmacologically active metabolites 4-hydroxyospemifene and 4′-hydroxyospemifene, was elucidated in studies of volunteer humans given various doses of ospemifene and in experiments of several animal species (rat, mouse, dog, and cynomolgus monkey), which had been used either for pharmacological or toxicological studies of ospemifene. Metabolites produced inConsiderable interspecies differences were observed in the metabolite profiles and quantities. The major human metabolite, 4-hydroxyospemifene, was produced in substantial amounts bothOverall, there are quantitative and also some qualitative differences in the metabolism of ospemifene in different species. Generally,

scholarly journals THE ROLE OF PENICILLIN-INDUCED BACTERIAL VARIANTS IN EXPERIMENTAL PYELONEPHRITIS

1967 ◽  
Vol 125 (4) ◽  
pp. 607-618 ◽  
Author(s):  
Richard H. Winterbauer ◽  
Laura T. Gutman ◽  
Marvin Turck ◽  
Ralph J. Wedgwood ◽  
Robert G. Petersdorf
Keyword(s):  
Escherichia Coli ◽  
Renal Medulla ◽  
Round Cell ◽  
Histologic Response ◽  
E Coli ◽  
Round Cell Infiltration ◽  
Kidney Liver

1. After injection into the renal medulla of rats Escherichia coli 06 variants reverted rapidly in vivo in the absence of penicillin. These variants had previously been shown to be stable in vitro. 2. Variants failed to survive following intramedullary injection when animals were receiving penicillin. 3. Late reversion of variants also failed to occur in animals treated with penicillin for only 1 or 2 days. 4. Variants survived and reverted more readily when injected in the renal medulla, compared with liver and spleen. Classical bacteria injected into the kidney, liver, and spleen were recovered in approximately equal numbers. 5. The histologic response to nonreverting variants, medium not containing variants, and killed variants was similar and was characterized by a fibrotic reaction with moderate round cell infiltration. 6. In contrast, the histologic response to reverting variants and to classical E. coli was characterized by an intense, acute, polymorphonuclear leukocytosis typical of acute pyelonephritis.

scholarly journals Antioxidant and Inflammatory Effects of Nelumbo nucifera Gaertn. Leaves

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Chong Li ◽  
Yongpeng He ◽  
Yue Yang ◽  
Yuting Gou ◽  
Shuting Li ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Animal Studies ◽  
Organ Index ◽  
Tnf Α ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Kidney Liver ◽  
Lung And Kidney

This study is aimed at identifying the bioactive components in lotus leaf flavonoid extract (LLFE) and analyzing the antioxidant and anti-inflammatory activities of LLFE in vitro and in vivo. The flavonoids in LLFE were determined by UHPLC-MS/MS. The effect of LLFE on damaged 293T cells (H2O2, 0.3 mmol/L) was determined by MTT assay, and the activity of antioxidant enzymes was measured by kits. We studied the antioxidant and anti-inflammatory effects of LLFE on D-Gal/LPS (30 mg/kg·bw and 3 μg/kg·bw)-induced aging mice. We also evaluated the main organ index, pathological changes in the liver, lung, and kidney, liver function index, biochemical index, cytokine level, and mRNA expression level in serum and liver. The results showed that LLFE contains baicalein, kaempferol, kaempferid, quercetin, isorhamnetin, hyperoside, lespenephryl, and rutin. LLFE reduced the oxidative damage sustained by 293T cells, increased the levels of SOD, CAT, GSH, and GSH-Px, and decreased the level of MDA. The animal studies revealed that LLFE reduced oxidative damage and inflammation in injured mice, inhibited increases in AST, ALT, MDA, and NO, increased SOD, CAT, GSH, and GSH-Px levels, upregulated anti-inflammatory cytokines IL-10 and IL-12, and downregulated proinflammatory cytokines IL-6, IL-1β, TNF-α, and IFN-γ. Furthermore, the expression of antioxidant- and anti-inflammatory-related mRNA was consistent with the above results.

scholarly journals Tissue distribution of a menthyl-conjugated oligodeoxyribonucleotide antisense to PAI-1 mRNA.

2005 ◽  
Vol 52 (4) ◽  
pp. 849-856
Author(s):  
Janusz Szemraj ◽  
Khalid N I Al-Nedawi ◽  
Ewa Chabielska ◽  
Wlodzimierz Buczko ◽  
Zofia Pawlowska
Keyword(s):  
Rat Kidney ◽  
Inhibitory Effect ◽  
Organ Distribution ◽  
Ribonuclease Protection Assay ◽  
Ribonuclease Protection ◽  
And Control ◽  
Kidney Liver ◽  
Pai 1

The inhibitory effect of numerous analogues of PO-16, an hexadecadeoxyribonucleotide antisense to sequences -22 to -17 of PAI-1 mRNA coding for a fragment of the signal peptide, on the expression of PAI-1 in endothelial cells, and physiological consequences of the subsequently reduced PAI-1 activity tested in vitro and in vivo, were described in our previous studies. Of particular interest was PO-16 5'-O-conjugated with menthyl phosphorothioate (MPO-16R). In this work, tissue localisation of MPO-16R labelled with [(35)S] phosphorothioate at the 3'-end, was determined. [(35)S]MPO-16R and control [(35)S]MPO-16R-SENSE oligonucleotides were administered intravenously into 22 rats and organ distribution of the labelled bioconjugates was assessed after 24 and 48 h. For this purpose, tissue sections were subjected to autoradiography, and quantitated by liquid scintillation after solubilisation. Overall clearance of radioactivity was already seen after 24 h, with the radioactivity recovered mainly in the kidney and liver. A smaller fraction of radioactivity was also retained in the spleen and heart. The kidney concentration of the labelled probe was higher than that of liver by 50%. The distribution of PAI-1 mRNA in untreated rat kidney, liver, spleen and heart established by two independent techniques: Ribonuclease Protection Assay and Real-Time PCR, shows the same pattern as that observed for [(35)S]MPO-16R antisense.

Aerosolization of recombinant SLPI to augment antineutrophil elastase protection of pulmonary epithelium

1990 ◽  
Vol 69 (5) ◽  
pp. 1843-1848 ◽  
Author(s):  
C. Vogelmeier ◽  
R. Buhl ◽  
R. F. Hoyt ◽  
E. Wilson ◽  
G. A. Fells ◽  
...  
Keyword(s):  
Molar Ratio ◽  
Pulmonary Epithelium ◽  
Epithelial Surface ◽  
Epithelial Lining Fluid ◽  
Fourfold Increase ◽  
Alpha 1 Antitrypsin ◽  
Respiratory Epithelial ◽  
Lung Lymph

In a variety of lung diseases the respiratory epithelial surface must contend with an increased burden of neutrophil elastase (NE). One candidate for augmenting epithelial anti-NE protection is the secretory leukoprotease inhibitor (SLPI). In vitro evaluation demonstrated that 96 +/- 1% of the recombinant SLPI (rSLPI) molecules were capable of inhibiting NE, with an association rate constant of 7.1 +/- 0.1 X 10(6) M-1.s-1. Evaluation of rSLPI after in vitro and in vivo aerosolization showed that aerosolization did not alter rSLPI. Aerosolization of a single dose of 50 mg rSLPI to sheep resulted in a fourfold increase of the anti-NE capacity in epithelial lining fluid (ELF) at 3 h, with a half-life in ELF of 12 h. After aerosolization some rSLPI appeared in lung lymph. Simultaneous aerosolization of rSLPI and recombinant alpha 1-antitrypsin (rAAT) demonstrated a molar ratio of the concentration in lymph to the concentration in ELF 3 h after the aerosol eightfold higher for rAAT than for rSLPI. Overall, these observations demonstrate that it is feasible to use aerosolized rSLPI to directly augment the anti-NE capacity of the lung, particularly on the pulmonary epithelial surface.

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