scholarly journals The long-term actions of etonogestrel and levonorgestrel on decidualized and non-decidualized endometrium in a mouse model mimic some effects of progestogen-only contraceptives in women

Reproduction ◽  
2007 ◽  
Vol 133 (1) ◽  
pp. 309-321 ◽  
Author(s):  
Naomi B Morison ◽  
Jin Zhang ◽  
Tu’uhevaha J Kaitu’u-Lino ◽  
Ian S Fraser ◽  
Lois A Salamonsen
Keyword(s):  
Mouse Model ◽  
Morphological Changes ◽  
Luminal Epithelium ◽  
Tissue Remodelling ◽  
Breakthrough Bleeding ◽  
Functional Studies ◽  
Tissue Integrity ◽  
Uterine Natural Killer Cells ◽  
Long Acting

Breakthrough bleeding (BTB), a major side effect of long-acting progestogen (p)-only contraceptives in women, is the main reason for discontinuation of their use. To understand the mechanisms of BTB, a mouse model of endometrial breakdown and repair was adapted to evaluate the effects of long-term progestogens on the endometrium. Appropriately prepared mice received either an etonogestrel (ENG)- or levonorgestrel (LNG)-releasing subdermal implant. Forty eight hours after decidualization was induced in one uterine horn the majority of tissues were highly decidualized, designated 0 day (0d). Uteri were collected subsequently at 5-day intervals (to 45d) and both decidualized and non-decidualized horns were analysed for morphological changes, leukocyte infiltration and matrix metalloproteinase expression (MMP). In decidualized horns, large blood vessels (BV) developed and disturbance of tissue integrity was observed at 5d with substantial stromal breakdown by 10d, progressing until 25d when re-epithelialization was initiated. By 45d, the tissue was restored to its pre-decidualized state but with considerable tortuosity of the luminal epithelium. Tissue remodelling was not apparent in the non-decidualized horns before 35d, when hyperproliferation of the luminal epithelium resulted in tortuosity. Changes in morphology were similar with the two progestogens, but occurred more rapidly with LNG. Apart from macrophages, few leukocytes were present in non-decidualized horns but large infiltrates of neutrophils and uterine natural killer cells (uNK) were associated with tissue breakdown in decidualized tissue, many of these cells were MMP9-positive. MMP7 was primarily associated with tissue repair. Therefore, this model mimics some of the changes observed in endometria of women using p-only contraceptives and provides an opportunity for functional studies.

245. Endometrial changes in a mouse model for long-term progestin exposure: implications for break-through bleeding

2005 ◽  
Vol 17 (9) ◽  
pp. 97
Author(s):  
N. B. Morison ◽  
J. Shen ◽  
J. Zhang ◽  
T. J. Kaitu'u ◽  
L. A. Salamonsen
Keyword(s):  
Mouse Model ◽  
Morphological Changes ◽  
Steroid Hormone ◽  
Tissue Destruction ◽  
Tissue Integrity ◽  
Uterine Natural Killer Cells ◽  
Positive Immunostaining ◽  
Long Acting ◽  
Leukocyte Populations

A mouse model of menstruation1 was modified to evaluate the effects of long-term progestagens on the endometrium. Many women using long-acting progestin (P)-only contraceptives experience break-through bleeding (BTB) and this is the main reason for discontinuation of their use by 30% of users. To understand the mechanisms involved in BTB, ovariectomised mice treated with a strict steroid hormone regime, had etonogestrel- or levonorgestrel-releasing implants inserted subcutaneously. A decidualizing stimulus (oil) was administered into one uterine horn; decidualisation was maximal 48 h later, designated day 0 (d0). The implant was left in place for a further 45 days. Uteri were collected at 5-day intervals and analysed for morphological changes, leukocyte infiltration, and matrix metalloproteinase (MMP) expression. In uteri from mice treated with etonogestrel and examined at d0, decidualisation was maximal and very few leukocytes were present (neutrophils, NEU; Macrophages, Mac; uterine natural killer cells, uNK). Some loss of tissue integrity was seen at 5d, associated with some MMP-9 positive leukocytes. However, substantial stromal breakdown was observed at 10d and this progressed until 25d. A large infiltrate of NEU and uNKs, as well as increased MMP-9 expression, was observed at these times. At 25d there was evidence of re-epithelialisation and by 45d the tissue had fully repaired back to its pre-decidualised state. Re-epithelialisation was associated with a decline in NEU and uNKs, as well as MMP-9 positive immunostaining. The morphology of uteri from mice treated with levonorgestrel implants was compared to mice treated with etonogestrel. The changes observed were very similar with a loss of tissue integrity at 5d and tissue destruction at 10d. This mouse model mimics the changes in leukocyte populations and MMP expression observed in endometria of some women using P-only contraceptives. (1)Brasted M, White CA, Kennedy TG, Salamonsen LA. (2003) Biololgy of Reproduction 69(4), 1273–1280.

scholarly journals Long-lasting rescue of schizophrenia-relevant cognitive impairments via risperidone-loaded microPlates

2022 ◽  
Author(s):  
Elena Bellotti ◽  
Gabriella Contarini ◽  
Federica Geraci ◽  
Sebastiano Alfio Torrisi ◽  
Cateno Piazza ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mouse Model ◽  
Sustained Release ◽  
Temporal Order ◽  
Single Injection ◽  
Chronic Administration ◽  
Psychotic Symptoms ◽  
Residual Rate ◽  
Long Acting

AbstractSchizophrenia is a disorder characterized by cognitive impairment and psychotic symptoms that fluctuate over time and can only be mitigated with the chronic administration of antipsychotics. Here, we propose biodegradable microPlates made of PLGA for the sustained release of risperidone over several weeks. Two microPlate configurations – short: 20 × 20 × 10 μm; tall: 20 × 20 × 20 μm – are engineered and compared to conventional ~ 10 μm PLGA microspheres in terms of risperidone loading and release. Tall microPlates realize the slowest release documenting a 35% risperidone delivery at 100 days with a residual rate of 30 ng/ml. Short microPlates and microspheres present similar release profiles with over 50% of the loaded risperidone delivered within the first 40 days. Then, the therapeutic efficacy of one single intraperitoneal injection of risperidone microPlates is compared to the daily administration of free risperidone in heterozygous knockout mice for dysbindin-1, a clinically relevant mouse model of cognitive and psychiatric liability. In temporal order object recognition tasks, mice treated with risperidone microPlates outperform those receiving free risperidone up to 2, 4, 8, and 12 weeks of observation. This suggests that the sustained release of antipsychotics from one-time microPlate deposition can rescue cognitive impairment in dysbindin mice for up to several weeks. Overall, these results demonstrate that risperidone-loaded microPlates are a promising platform for improving cognitive symptoms associated to schizophrenia. Moreover, the long-term efficacy with one single administration could be of clinical relevance in terms of patient’s compliance and adherence to the treatment regimen. Graphical abstract Single injection of long-acting risperidone-loaded µPL ameliorates the dysbindin-induced deficit in a clinically relevant mouse model of cognitive and psychiatric liability for up to 12 weeks

Comparative assessment of morphological mechanisms of maintaining structural liver homeostasis in the dynamics of exposure to coal-rock dust and sodium fluoride on the body

2020 ◽  
pp. 189-194
Author(s):  
M. S. Bugaeva ◽  
O. I. Bondarev ◽  
N. N. Mikhailova ◽  
L. G. Gorokhova
Keyword(s):  
Sodium Fluoride ◽  
Morphological Changes ◽  
The Body ◽  
System Level ◽  
Production Factor ◽  
Coal Rock ◽  
The Impact ◽  
Structural Homeostasis ◽  
Rock Dust

Introduction. The impact on the body of such factors of the production environment as coal-rock dust and fluorine compounds leads to certain shift s in strict indicators of homeostasis at the system level. Maintaining the relative constancy of the internal environment of the body is provided by the functional consistency of all organs and systems, the leading of which is the liver. Organ repair plays a crucial role in restoring the structure of genetic material and maintaining normal cell viability. When this mechanism is damaged, the compensatory capabilities of the organ are disrupted, homeostasis is disrupted at the cellular and organizational levels, and the development of the main pathological processes is noted.The aim of the study is to compare the morphological mechanisms of maintaining structural homeostasis of the liver in the dynamics of the impact on the body of coal-rock dust and sodium fluoride.Materials and methods. Experimental studies were conducted on adult white male laboratory rats. Features of morphological mechanisms for maintaining structural homeostasis of the liver in the dynamics of exposure to coal-rock dust and sodium fluoride were studied on experimental models of pneumoconiosis and fluoride intoxication. For histological examination in experimental animals, liver sampling was performed after 1, 3, 6, 9, 12 weeks of the experiment.Results. The specificity of morphological changes in the liver depending on the harmful production factor was revealed. It is shown that chronic exposure to coal-rock dust and sodium fluoride is characterized by the development of similar morphological changes in the liver and its vessels from the predominance of the initial compensatory-adaptive to pronounced violations of the stromal and parenchymal components. Long-term inhalation of coal-rock dust at 1–3 weeks of seeding triggers adaptive mechanisms in the liver in the form of increased functional activity of cells, formation of double-core hepatocytes, activation of immunocompetent cells and endotheliocytes, ensuring the preservation of the parenchyma and the general morphostructure of the organ until the 12th week of the experiment. Exposure to sodium fluoride leads to early disruption of liver compensatory mechanisms and the development of dystrophic changes in the parenchyma with the formation of necrosis foci as early as the 6th week of the experiment.Conclusions. The study of mechanisms for compensating the liver structure in conditions of long-term exposure to coal-rock dust and sodium fluoride, as well as processes that indicate their failure, and the timing of their occurrence, is of theoretical and practical importance for developing recommendations for the timely prevention and correction of pathological conditions developing in employees of the aluminum and coal industry.The authors declare no conflict of interests.

scholarly journals Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

2020 ◽  
Vol 8 (2) ◽  
pp. e001513
Author(s):  
Nahee Park ◽  
Kamal Pandey ◽  
Sei Kyung Chang ◽  
Ah-Young Kwon ◽  
Young Bin Cho ◽  
...  
Keyword(s):  
Mouse Model ◽  
Humanized Mice ◽  
Preclinical Models ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Durable Response ◽  
Term Efficacy ◽  
Nsg Mice ◽  
Oncology Research

BackgroundWell-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.MethodsHumanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.ResultsBusulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.ConclusionsOur CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.

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