In vivo regulation of macrophages in cynomolgus monkey endometrium: during menstrual cycle and after treatment with antiprogestin or GNRH-A

Abstract Background: Endometria undergo repeated repair and regeneration during the menstrual cycle. Using gene expression to define the menstrual cycle has been seen in a couple of researches, which shares little consistency. The possible reason lies in the fact that the composition of each specimen is different. The objective of this study was to reconstruct an integrated cell atlas of mouse uterus from the regenerative to maturational endometrium at the single-cell level.Methods: We used published single-cell RNA sequencing data of mice uteri to build an integrated cell atlas, including epithelial cells, stromal cells, and immune cells. Principal components analysis, hierarchical clustering, and other data mining procedures were performed with R software. Functional enrichment analyses were performed to identify the potential biological roles of molecular changes in different mice estrus states.Results: Based on the expression level of proliferating cell nuclear antigen and gene ontology terms, we reconstructed the cell atlas and delineated in detail the transitions that happened during the estrus cycle. We also depicted the transition and transcription factors that shaped the differentiation of ESCs and the mononuclear phagocyte system. Besides, the amounts and functions of immune cells varied sharply in two periods. We also found clues about uterus tissue-resident macrophages and Pdgfrb+ Aldh1a2+ Cd34+ endometrial mesenchymal stem cells in vivo.Conclusions: The cell atlas of mouse uterus presented here would improve our understanding of the functional changes that occurred in the endometrium and helped us identify abnormalities that have not been apparent histologically.

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Utilization of the chronic atrioventricular block cynomolgus monkey as an in vivo model to evaluate drug interaction-associated torsade de pointes

Journal of Pharmacological Sciences ◽

10.1016/j.jphs.2019.12.007 ◽

2020 ◽

Vol 142 (4) ◽

pp. 172-175 ◽

Cited By ~ 1

Author(s):

Ai Goto ◽

Kengo Sakamoto ◽

Mihoko Hagiwara-Nagasawa ◽

Ryuichi Kambayashi ◽

Koki Chiba ◽

...

Keyword(s):

Drug Interaction ◽

Atrioventricular Block ◽

Cynomolgus Monkey ◽

Torsade De Pointes ◽

In Vivo Model

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In vitro culture of cynomolgus monkey embryos beyond early gastrulation

Science ◽

10.1126/science.aax7890 ◽

2019 ◽

Vol 366 (6467) ◽

pp. eaax7890 ◽

Cited By ~ 28

Author(s):

Huaixiao Ma ◽

Jinglei Zhai ◽

Haifeng Wan ◽

Xiangxiang Jiang ◽

Xiaoxiao Wang ◽

...

Keyword(s):

In Vitro Culture ◽

Cynomolgus Monkey ◽

Primordial Germ Cells ◽

Lineage Specification ◽

Single Cell Rna Sequencing ◽

Human Embryogenesis ◽

Key Events ◽

Anterior Posterior

Gastrulation is a key event in embryonic development when the germ layers are specified and the basic animal body plan is established. The complexities of primate gastrulation remain a mystery because of the difficulties in accessing primate embryos at this stage. Here, we report the establishment of an in vitro culture (IVC) system that supports the continuous development of cynomolgus monkey blastocysts beyond early gastrulation up to 20 days after fertilization. The IVC embryos highly recapitulated the key events of in vivo early postimplantation development, including segregation of the epiblast and hypoblast, formation of the amniotic and yolk sac cavities, appearance of the primordial germ cells, and establishment of the anterior-posterior axis. Single-cell RNA-sequencing analyses of the IVC embryos provide information about lineage specification during primate early postimplantation development. This system provides a platform with which to explore the characteristics and mechanisms of early postimplantation embryogenesis in primates with possible conservation of cell movements and lineages in human embryogenesis.

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Interspecies Variation in NCMN-O-Demethylation in Liver Microsomes from Various Species

Molecules ◽

10.3390/molecules24152765 ◽

2019 ◽

Vol 24 (15) ◽

pp. 2765

Author(s):

Ziru Dai ◽

Guibo Sun ◽

Jiada Yang ◽

Jie Hou ◽

Ping Zhou ◽

...

Keyword(s):

Cynomolgus Monkey ◽

Liver Microsomes ◽

Specific Inhibitor ◽

Intrinsic Clearance ◽

Beagle Dog ◽

Interspecies Variation ◽

Human Cytochrome ◽

Practical Tool ◽

Cytochrome P450 1A

NCMN (N-(3-carboxy propyl)-4-methoxy-1,8-naphthalimide), a newly developed ratiometric two-photon fluorescent probe for human Cytochrome P450 1A (CYP1A), shows the best combination of specificity and reactivity for real-time detection of the enzymatic activities of CYP1A in complex biological systems. This study aimed to investigate the interspecies variation in NCMN-O-demethylation in commercially available liver microsomes from human, mouse, rat, beagle dog, minipig and cynomolgus monkey. Metabolite profiling demonstrated that NCMN could be O-demethylated in liver microsomes from all species but the reaction rate varied considerably. CYP1A was the major isoform involved in NCMN-O-demethylation in all examined liver microsomes based on the chemical inhibition assays. Furafylline, a specific inhibitor of mammalian CYP1A, displayed differential inhibitory effects on NCMN-O-demethylation in all tested species. Kinetic analyses demonstrated that NCMN-O-demethylation in liver microsomes form rat, minipig and cynomolgus monkey followed biphasic kinetics, while in liver microsomes form human, mouse and beagle dog obeyed Michaelis-Menten kinetics, the kinetic parameters from various species are much varied, while NCMN-O-demethylation in MLM exhibited the highest similarity of specificity, kinetic behavior and intrinsic clearance as that in HLM. These findings will be very helpful for the rational use of NCMN as a practical tool to decipher the functions of mammalian CYP1A or to study CYP1A associated drug-drug interactions in vivo.

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Preexisting Antibodies to an F(ab′)2Antibody Therapeutic and Novel Method for Immunogenicity Assessment

Journal of Immunology Research ◽

10.1155/2016/2921758 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Jane Ruppel ◽

Ann Brady ◽

Rebecca Elliott ◽

Cecilia Leddy ◽

Marco Palencia ◽

...

Keyword(s):

Cynomolgus Monkey ◽

Drug Exposure ◽

Therapeutic Antibodies ◽

Competition Assay ◽

Safety And Efficacy ◽

Immunogenicity Assessment ◽

Novel Method ◽

Assay Methods ◽

Potential Antitumor

Anti-therapeutic antibodies (ATAs) may impact drug exposure and activity and induce immune complex mediated toxicity; therefore the accurate measurement of ATA is important for the analysis of drug safety and efficacy. Preexisting ATAs to the hinge region of anti-Delta like ligand 4 (anti-DLL4) F(ab′)2, a potential antitumor therapeutic, were detected in cynomolgus monkey serum, which presented a challenge in developing assays for detecting treatment induced ATA. A total ATA assay was developed using a bridging ELISA that detected both anti-CDR and anti-framework ATA including anti-hinge reactivity. A competition assay that could detect 500 ng/mL of anti-CDR ATA in the presence of preexisting ATA was also developed to determine ATA specific to the anti-DLL4 F(ab′)2CDR using anti-DLL4 F(ab′)2and a control F(ab′)2. We used these assay methods in a cynomolgus monkey in vivo study to successfully evaluate total and anti-CDR ATA. The preexisting anti-hinge reactivity was also observed to a lesser extent in human serum, and a similar approach could be applied for specific immunogenicity assessment in clinical trials.

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Detection of drug specific circulating immune complexes from in vivo cynomolgus monkey serum samples

Journal of Immunological Methods ◽

10.1016/j.jim.2014.11.007 ◽

2015 ◽

Vol 416 ◽

pp. 124-136 ◽

Cited By ~ 14

Author(s):

Piotr Pierog ◽

Murli Krishna ◽

Aaron Yamniuk ◽

Anil Chauhan ◽

Binodh DeSilva

Keyword(s):

Immune Complexes ◽

Cynomolgus Monkey ◽

Circulating Immune Complexes ◽

Serum Samples

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Neither gender nor menstrual cycle phase influences exercise-induced lymphocyte apoptosis in untrained subjects

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-022 ◽

2007 ◽

Vol 32 (3) ◽

pp. 481-486 ◽

Cited By ~ 14

Author(s):

James W. Navalta ◽

Darlene A. Sedlock ◽

Kyung-Shin Park ◽

Brian K. McFarlin

Keyword(s):

Menstrual Cycle ◽

Maximal Exercise ◽

Hormonal Contraceptives ◽

Cycle Phase ◽

Lymphocyte Apoptosis ◽

Menstrual Cycle Phase ◽

Apoptotic Response ◽

Exercise Induced

Lymphocyte apoptosis increases following maximal exercise. Estrogen hormones (E2) have been shown to protect lymphocytes from apoptosis in vitro, but it is unknown whether they can attenuate the apoptotic response to maximal exercise. The purpose of this study was to examine the effect of menstrual cycle variation on exercise-induced lymphocyte apoptosis in humans following exercise. Untrained healthy young men and regularly menstruating women not using hormonal contraceptives volunteered for the study. Women performed a maximal effort treadmill test for VO2 max once in the follicular phase (FOL) and once in the mid-luteal phase (ML) of their cycles. Men completed two VO2 max tests with periods of time between tests matched to those of the female subjects. Blood was collected before (PRE) and immediately after exercise (POST), and analyzed for apoptotic lymphocytes and estradiol. E2 concentrations in women were significantly greater during ML versus during FOL, both PRE and POST (p < 0.0001). The percent of exercise-induced lymphocyte apoptosis was similar between women (23.2% ± 1.0%) and men (21.5% ± 0.4%). In women, the apoptotic response to maximal exercise was similar regardless of menstrual cycle phase (FOL = 23.7% ± 0.9%, ML = 22.7% ± 1.1%). Although elevated female sex hormones in vitro may exert anti-apoptotic effects, these data suggest that in vivo concentrations confer no protection to lymphocytes during exhaustive exercise.

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