scholarly journals Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis

2021 ◽  
Vol 7 (4) ◽  
pp. 313
Author(s):  
Teclegiorgis Gebremariam ◽  
Sondus Alkhazraji ◽  
Abdullah Alqarihi ◽  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mucor Circinelloides ◽  
Male Mice ◽  
Rhizopus Delemar ◽  
Female Mice ◽  
Pulmonary Mucormycosis ◽  
Susceptibility To Infection ◽  
Cytokine Levels ◽  
Untreated Female ◽  
The Difference

There is increased concern that the quality, generalizability and reproducibility of biomedical research can be influenced by the sex of animals used. We studied the differences between male and female mice in response to invasive pulmonary mucormycosis including susceptibility to infection, host immune reaction and responses to antifungal therapy. We used diabetic ketoacidotic (DKA) or neutropenic mice infected with either Rhizopus delemar or Mucor circinelloides. The only difference detected was that when DKA mice were infected with M. circinelloides, female mice were more resistant to infection than male mice (median survival time of 5 vs. 2 days for female and male mice, respectively). However, a 100% lethality was detected among infected animals of both sexes. Treatment with either liposomal amphotericin B (L-AMB) or posaconazole (POSA) protected mice from infection and eliminated the difference seen between infected but untreated female and male mice. Treatment with L-AMB consistently outperformed POSA in prolonging survival and reducing tissue fungal burden of DKA and neutropenic mice infected with R. delemar or M. circinelloides, in both mouse sexes. While little difference was detected in cytokine levels among both sexes, mucormycosis infection in the DKA mouse model induced more inflammatory cytokines/chemokines involved in neutrophil (CXCL1) and macrophage (CXCL2) recruitment vs. uninfected mice. As expected, this inflammatory response was reduced in the neutropenic mouse model. Our studies show that there are few differences between female and male DKA or neutropenic mice infected with mucormycosis with no effect on the outcome of treatment or host immune response.

scholarly journals Evaluation of Sex Differences in Murine Diabetic Ketoacidosis and Neutropenic Models of Invasive Mucormycosis

2021 ◽  
Author(s):  
Teclegiorgis Gebremariam ◽  
Sondus Alkhazraji ◽  
Abdullah Alqarihi ◽  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mucor Circinelloides ◽  
Male Mice ◽  
Rhizopus Delemar ◽  
Female Mice ◽  
Pulmonary Mucormycosis ◽  
Susceptibility To Infection ◽  
Cytokine Levels ◽  
Untreated Female ◽  
The Difference

There is increased concern that the quality, generalizability, and reproducibility of biomedical research can be influenced by the sex of animals used. We studied the differences between male and female mice in response to invasive pulmonary mucormycosis including susceptibility to infection, host immune reaction, and responses to antifungal therapy. We used diabetic ketoacidotic (DKA) or neutropenic mice infected with either Rhizopus delemar or Mucor circinelloides. The only difference detected was that when DKA mice were infected with M. circinelloides, female mice were more resistant to infection than male mice (median survival time of 5 vs. 2 days for female and male mice, respectively). However, a 100% lethality was detected among infected animals of both sexes. Treatment with either liposomal amphotericin B (L-AMB) or posaconazole (POSA) protected mice from infection and eliminated the difference seen between infected but untreated female and male mice. Treatment with L-AMB consistently outperformed POSA in prolonging survival and reducing tissue fungal burden of DKA and neutropenic mice infected with R. delemar or M. circinelloides, in both mouse sexes. Although little difference was detected in cytokine levels among both sexes, mucormycosis infection in the DKA mouse model induced more inflammatory cytokines/chemokines involved in neutrophil (CXCL1) and macrophage (CXCL2) recruitment vs. uninfected mice. As expected, this inflammatory response was reduced in the neutropenic mouse model. Our studies show that there are few differences between female and male DKA or neutropenic mice infected with mucormycosis with no effect on the outcome of treatment or host immune response.

scholarly journals Sex-Specific Difference in Adipose Tissue and Blood Pressure in a New Mouse Model Expressing Human Soluble Prorenin Receptor in Adipocytes

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 56-56
Author(s):  
Kellea Nichols ◽  
Audrey Poupeau ◽  
Eva Gatineau ◽  
Gertrude Arthur ◽  
Ming Gong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Mouse Model ◽  
Fat Mass ◽  
Lean Mass ◽  
Soluble Form ◽  
Male Mice ◽  
Female Mice ◽  
Prorenin Receptor ◽  
Body Weights

Abstract Objectives Sex differences exist in obesity associated with cardiovascular disease; however, underlying mechanisms are not completely understood. Previous studies from our laboratory demonstrated that the prorenin receptor (PRR) and its soluble form (sPRR) contribute to adipogenesis and blood pressure control. The present study aimed to determine whether adipose-sPRR stimulated obesity is associated with hypertension and whether it is sex-dependent. Methods Transgenic mice on the C57BL/6 J background were generated expressing the human form of the soluble prorenin receptor (HsPRR) in a Cre-inducible manner. Male mice expressing Cre recombinase under the control of the adiponectin promotor were bred to heterozygote HsPRR/+ female mice to generate mice over-secreting sPRR (adi-HsPRR) and control littermate mice (CTL). The secretion of sPRR in the media doubled in primary adipocytes of adi-HsPRR mice compared to control mice (sPRR. CTL: 3729 ± 805 pg/ml; adi-HsPRR: 6170 ± 1237 pg/ml, P < 0.05) validating the mouse model. Male (CTL = 4; adi-HsPRR = 8) and female mice (CTL = 10; adi-HsPRR = 10) were fed a low-fat (LF) diet or a high-fat diet (HF) for 20 weeks. Body weight was assessed weekly and EchoMRI was examined monthly. Results After 20 weeks on LF diet, adi-HsPRR male mice gained significantly more weight than CTL male mice (CTL: 25.1 ± 0.8 g; adi-HsPRR: 29.0 ± 0.8 g P < 0.05), whereas no significant differences in body weights were observed in female mice. The body composition revealed a significant increase of fat mass, specifically in the epidydimal fat (CTL: 0.35 ± 0.04 g; adi-HsPRR: 0.61 ± 0.07 g, P < 0.05), and lean mass of HsPRR male mice compared to CTL male mice. In contrast, female mice exhibited similar body weights (CTL: 20.6 ± 0.3 g; adi-HsPRR: 20.4 ± 0.4 g) and there was no differences of fat mass or lean mass between CTL and adi-HsPRR female mice. The sex-specific mechanism of sPRR on adipogenesis and blood pressure (by radiotelemetry) with LF and HF diet is currently under investigation. Conclusions Overall, sPRR stimulated body weight gain and fat mass expansion in male mice but not in female mice suggesting that female mice are protected from sPRR induced-hypertrophic effect. Funding Sources R01_HL142969–01 Yiannikouris, PI 07/15/2018–06/30/2022 NIH/NHLBI Title: The role of soluble prorenin receptor in hypertension associated with obesity Role: Ph.D Graduate Student.

scholarly journals Estrogen modulation of baroreflex function in conscious mice

2003 ◽  
Vol 284 (4) ◽  
pp. R983-R989 ◽  
Author(s):  
Jaya Pamidimukkala ◽  
Julia A. Taylor ◽  
Wade V. Welshons ◽  
Dennis B. Lubahn ◽  
Meredith Hay
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Mouse Model ◽  
Sodium Nitroprusside ◽  
Autonomic Function ◽  
Ang Ii ◽  
Male Mice ◽  
Female Mice ◽  
Reflex Bradycardia ◽  
Baroreflex Function

It has been suggested that estrogen modulates baroreflex regulation of autonomic function. The present study evaluated the effects of estrogen on baroreflex regulation of heart rate in response to changes in blood pressure with phenylephrine (PE), ANG II, and sodium nitroprusside (SNP) in a conscious mouse model. Males and ovariectomized females with (OvxE+) and without (OvxE−) estradiol replacement chronically implanted with arterial and venous catheters were used in these studies. The slope of the baroreflex bradycardic responses to PE was significantly facilitated in OvxE+ females (−7.65 ± 1.37) compared with OvxE− females (−4.5 ± 0.4). Likewise, the slope of the baroreflex bradycardic responses to ANG II was significantly facilitated in OvxE+ females (−7.97 ± 1.06) compared with OvxE− females (−4.8 ± 1.6). Reflex tachycardic responses to SNP were comparable in all the groups. Finally, in male mice, the slope of ANG II-induced baroreflex bradycardia (−5.17 ± 0.95) was significantly less than that induced by PE (−8.50 ± 0.92), but this ANG II-mediated attenuation of reflex bradycardia was not observed in the female mice. These data support the hypothesis that estrogen facilitates baroreflex function in female mice and suggest that ANG II-mediated acute blunting of baroreflex regulation of heart rate may be sex dependent.

scholarly journals Androgen aggravates liver fibrosis by activation of NLRP3 inflammasome in CCl4-induced liver injury mouse model

2020 ◽  
Vol 318 (5) ◽  
pp. E817-E829 ◽  
Author(s):  
Xingyu Ma ◽  
Yang Zhou ◽  
Bingke Qiao ◽  
Songhong Jiang ◽  
Qian Shen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Acute Injury ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Male Mice ◽  
Female Mice ◽  
Key Factor

Studies have shown that there are differences between the sexes regarding to the occurrence and development of liver diseases, which may be associated with sex hormones. However, the mechanisms behind it are largely unknown. In this study, we first investigated the differences of liver injury between male and female mice, using the CCl4-induced liver injury mouse model. It showed that the liver damage of male mice was much more severe than that of female mice. Both the acute injury and fibrosis of the liver were reduced when androgens were depleted by castration of male mice. The vulnerability of male liver was associated with testis endocrine and excessive activation of inflammatory response in the liver. Castrated male mice with testosterone supplementation showed aggravated liver inflammatory response and fibrosis. The activity of NOD-like receptor protein 3 (NLRP3) inflammasome was increased when testosterone supplementation was provided. However, the enhanced inflammatory response and fibrosis due to testosterone supplementation were negated by inhibiting the activation of NLRP3 using the specific small molecule inhibitor MCC950. It suggests that testosterone is a key factor that influences liver injury by regulating the NLRP3 inflammasome activation-mediated inflammatory response.

Gender-dependent physiological implications of combined PAI-1 and TIMP-1 gene deficiency characterized in a mouse model

2007 ◽  
Vol 293 (4) ◽  
pp. R1630-R1639 ◽  
Author(s):  
Jakob Harslund ◽  
Ole Lerberg Nielsen ◽  
Nils Brünner ◽  
Hanne Offenberg
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Mouse Model ◽  
Physiological Parameters ◽  
Male Mice ◽  
Female Mice ◽  
Leukocyte Counts ◽  
Blood Leukocyte ◽  
Pai 1

The endogenous proteinase inhibitors plasminogen activator inhibitor type 1 (PAI-1) and tissue inhibitor of metalloproteinase type 1 (TIMP-1) are two distinct proteins with separate molecular pathways. However, a close relationship between PAI-1 and TIMP-1 has been proposed indicating some degree of functional overlap due to their involvement in ECM turnover, tissue remodeling, and cellular migration and signaling. To study the housekeeping physiological implications of PAI-1 and TIMP-1, we generated a combined PAI-1 and TIMP-1 gene-deficient mouse model. We present the results on generating this specific mouse model with particular emphasis on phenotypical characteristics, blood leukocyte counts, histology, and gene expression studies of PAI-1 and TIMP-1 in various organs. We observed a significant deviation in segregation of offspring only in male mice ( P < 0.01) predominantly caused by PAI-1 deficiency. In addition, the body weight in 3- and 20-wk-old male and 20-wk-old female mice was significantly different between genotypes ( P ≤ 0.0008). Furthermore, blood leukocyte counts were significantly different between genotypes in 20-wk-old male mice ( P ≤ 0.0002), whereas no significant differences were observed between genotypes in 20-wk-old female mice ( P ≥ 0.13). Quantifying the relative expression of PAI-1 and TIMP-1 revealed upregulation of PAI-1 ( P < 0.001) in male mice only. Our data highlight the complex roles of PAI-1 and TIMP-1 on physiological parameters such as segregation of offspring (embryonic development and survival), body weight (metabolism), blood leukocyte counts (immunity), and gene expression (regulatory redundancy). We conclude that PAI-1 and TIMP-1 seem to possess gender-dependent regulatory properties on various housekeeping physiological parameters and stress the potential implications in pathological conditions.

scholarly journals Characterization of the Horizontal and Vertical Sexual Transmission ofChlamydiaGenital Infections in a New Mouse Model

2019 ◽  
Vol 87 (7) ◽  
Author(s):  
Sukumar Pal ◽  
Delia F. Tifrea ◽  
Luis M. de la Maza
Keyword(s):  
Mouse Model ◽  
Vertical Transmission ◽  
Sexual Transmission ◽  
Vaginal Swab ◽  
Male Mice ◽  
Infected Male ◽  
Newborn Mice ◽  
Content Type ◽  
Female Mice ◽  
Swab Specimen

ABSTRACTChlamydia trachomatisis the most common sexually transmitted bacterial pathogen worldwide, and there is a need to control this epidemic. So far there is no established animal model in which both the horizontal and the vertical transmission ofChlamydiacan be studied. To implement a horizontal sexual transmission model, male mice were inoculated in the meatus urethra withChlamydia muridarumand they were caged with naive female mice. Urine and vaginal swab specimens were collected for culture. To study vertical transmission, newborns were euthanized and specimens were cultured. As controls, females were mated with sham-infected male mice. AllC. muridarum-inoculated male mice had positive urine cultures. As determined by serology, all females caged withC. muridarum-inoculated males became infected, and 93% of them had positive vaginal swab specimen cultures. More females mated withC. muridarum-infected male mice (35%) than females mated with sham-infected male mice (0%) were infertile (P < 0.05). Also,C. muridarum-infected females delivered significantly fewer pups (3.8 ± 3.2/mouse) than control females (6.3 ± 1.6/mouse) (P < 0.05). Of the newborn mice, 32% wereC. muridarumpositive either in the lungs or in the intestines. Female mice housed with sham-infected males had no positive vaginal swab specimen cultures orC. muridarum-positive pups. This new mouse model of horizontal and vertical sexual transmission ofChlamydiaclosely parallelsC. trachomatissexual transmission in humans and may be a good model system to better understand the pathogenesis of these infections.

EFFECT OF SEX HORMONES ON EHRLICH MOUSE ASCITES CANCER

1960 ◽  
Vol XXXIV (III) ◽  
pp. 437-448
Author(s):  
C. G. Ahlström ◽  
N. Jonsson
Keyword(s):  
Cancer Cells ◽  
Sex Hormones ◽  
Previous Investigation ◽  
Early Growth ◽  
Male Mice ◽  
Female Mice ◽  
Small Doses ◽  
Mouse Ascites ◽  
Males And Females ◽  
The Difference

ABSTRACT Ehrlich mouse ascites cancer grew better during the first 3 days after inoculation in female than in male mice. The difference was only demonstrable on inoculation with small doses of cancer cells and could not be seen when large doses were used. On the 5th day after inoculation no difference could be observed in the growth of the cancer between males and females. Gonadectomy had no influence on the growth of the cancer. Testosterone inhibited the growth of the cancer in castrated male mice. It had no effect on the growth of the cancer in castrated female mice. Oestradiol did not influence the growth of the cancer in castrated male or female mice. It is noteworthy that the results obtained in a previous investigation on the growth of the Ehrlich mouse ascites cancer in hamsters revealed a hormonal influence which was only discernible in its natural host during the early growth of the cancer and then only after transplantation of a relatively small number of cancer cells.

scholarly journals Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington’s Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

2021 ◽  
Author(s):  
Danielle A. Simmons ◽  
Brian D. Mills ◽  
Robert R. Butler III ◽  
Jason Kuan ◽  
Tyne L. M. McHugh ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Treatment Response ◽  
Diffusion Tensor ◽  
Disease Onset ◽  
Therapeutic Effects ◽  
Plasma Cytokine ◽  
Cytokine Levels ◽  
Pharmacodynamic Biomarkers

AbstractHuntington’s disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

scholarly journals Differences in acidosis-stimulated renal ammonia metabolism in the male and female kidney

2019 ◽  
Vol 317 (4) ◽  
pp. F890-F905 ◽  
Author(s):  
Autumn N. Harris ◽  
Hyun-Wook Lee ◽  
Lijuan Fang ◽  
Jill W. Verlander ◽  
I. David Weiner
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Collecting Duct ◽  
Ammonia Excretion ◽  
Volume Density ◽  
Male Mice ◽  
Ammonia Metabolism ◽  
Female Mice ◽  
Predominant Component ◽  
Acid Load ◽  
Acid Loading

Renal ammonia excretion is a critical component of acid-base homeostasis, and changes in ammonia excretion are the predominant component of increased net acid excretion in response to metabolic acidosis. We recently reported substantial sex-dependent differences in basal ammonia metabolism that correlate with sex-dependent differences in renal structure and expression of key proteins involved in ammonia metabolism. The purpose of the present study was to investigate the effect of sex on the renal ammonia response to an exogenous acid load. We studied 4-mo-old C57BL/6 mice. Ammonia excretion, which was less in male mice under basal conditions, increased in response to acid loading to a greater extent in male mice, such that maximal ammonia excretion did not differ between the sexes. Fundamental structural sex differences in the nonacid-loaded kidney persisted after acid loading, with less cortical proximal tubule volume density in the female kidney than in the male kidney, whereas collecting duct volume density was greater in the female kidney. To further investigate sex-dependent differences in the response to acid loading, we examined the expression of proteins involved in ammonia metabolism. The change in expression of phosphoenolpyruvate carboxykinase and Rh family B glycoprotein with acid loading was greater in male mice than in female mice, whereas Na+-K+-2Cl– cotransporter and inner stripe of the outer medulla intercalated cell Rh family C glycoprotein expression were significantly greater in female mice than in male mice. There was no significant sex difference in glutamine synthetase, Na+/H+ exchanger isoform 3, or electrogenic Na+-bicarbonate cotransporter 1 variant A protein expression in response to acid loading. We conclude that substantial sex-dependent differences in the renal ammonia response to acid loading enable a similar maximum ammonia excretion response.

THE EFFECTS OF SPECIES, STRAIN AND SEX IN THYMOLYTIC TESTS OF BETAMETHASONE, DEXAMETHASONE AND OTHER STEROIDS

1962 ◽  
Vol 25 (1) ◽  
pp. 77-85 ◽  
Author(s):  
R. M. ATKINSON ◽  
M. A. PRATT ◽  
E. G. TOMICH
Keyword(s):  
Route Of Administration ◽  
Relative Potency ◽  
Male Mice ◽  
Female Mice ◽  
Betamethasone And Dexamethasone

SUMMARY Cortisol, prednisolone phosphate and the free alcohols and 21-phosphates of betamethasone and dexamethasone have been compared for thymolytic activity by the oral and subcutaneous routes in both sexes of two strains of rats and two strains of mice. The relative potency of betamethasone and dexamethasone differed with the route of administration and the sex, strain and species of animal employed. In female mice of the A2G strain, betamethasone was as potent as dexamethasone; in male mice of this strain, and in both sexes of GFF mice, WAG rats and PVG rats, betamethasone was much less potent than dexamethasone.

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