Adaptive Changes in single-nephron GFR, Tubular Morphology, and Transport in a Pregnant Rat Nephron: Modeling and Analysis

Normal pregnancy is characterized by massive increases in plasma volume and electrolyte retention. Given that the kidneys regulate homeostasis of electrolytes and volume, the organ undergoes major adaptations in morphology, hemodynamics, and transport to achieve the volume and electrolyte retention required in pregnancy. These adaptations are complex, sometimes counterintuitive, and not fully understood. In addition, the demands of the developing fetus and placenta change throughout the pregnancy. For example, during late pregnancy, K+ retention and thus enhanced renal K+ reabsorption is required despite many kaliuretic factors. The goal of this study is to unravel how known adaptive changes along the nephrons contribute to the ability of the kidney to meet volume and electrolyte requirements in mid- and late pregnancy. We developed computational models of solute and water transport in the superficial nephron of the kidney of a rat in mid- and late pregnancy. The mid-pregnant and late-pregnant rat superficial nephron models predict that morphological adaptations and increased activity of the sodium hydrogen exchanger 3 (NHE3) and epithelial sodium channel (ENaC) are essential for enhanced Na+ reabsorption observed during pregnancy. Model simulations showed that for sufficient K+ reabsorption, increased H +-K +-ATPase activity and decreased K+ secretion along the distal segments is required in both mid- and late-pregnancy. Furthermore, certain known sex differences in renal transporter pattern (e.g., the higher NHE3 protein abundance but lower activity in the proximal tubules of virgin female rats compared to male) may serve to better prepare the female for the increased transport demand in pregnancy.

CRISPR/Cas9 mutagenesis against sex pheromone biosynthesis leads to loss of female attractiveness in Spodoptera exigua, an insect pestt

Virgin female moths are known to release sex pheromones to attract conspecific males. Accurate sex pheromones are required for their chemical communication. Sex pheromones of Spodoptera exigua, a lepidopteran insect, contain unsaturated fatty acid derivatives having a double bond at the 12th carbon position. A desaturase of S. exigua (SexiDES5) was proposed to have dual functions by forming double bonds at the 11th and 12th carbons to synthesize Z9,E12-tetradecedienoic acid, which could be acetylated to be a main sex pheromone component Z9,E12-tetradecenoic acetate (Z9E12-14:Ac). A deletion of SexiDES5 using CRISPR/Cas9 was generated and inbred to obtain homozygotes. Mutant females could not produce Z9E12-14:Ac along with Z9-14:Ac and Z11-14:Ac. Subsequently, pheromone extract of mutant females did not induce a sensory signal in male antennae. They failed to induce male mating behavior including hair pencil erection and orientation. In the field, these mutant females did not attract any males while control females attracted males. These results indicate that SexiDES5 can catalyze the desaturation at the 11th and 12th positions to produce sex pheromone components in S. exigua. This study also suggests an application of the genome editing technology to insect pest control by generating non-attractive female moths.

Detection of Active Compounds in the Water Extract of Foeniculum Vulgare L. and Its Effects on Serum Estrogen and Prolactin Levels in Female Albino Rats

The present study was designed to estimate the active ingredients in the aqueous extract of fennel Foeniculum vulgare L. fruits and test the effects of different concentrations of the extract on serum estrogen and prolactin levels in female rats. The work was conducted to prepare the aqueous extract in the laboratory, while the secondary active substances in the extract were estimated using High-Performance Liquid Chromatography (HPLC) technology. The experiments were conducted in the animal house of the College of Science, Tikrit university,on a total of 12 adult albino virgin female rats divided into four groups, each having three rats.The aqueous extract of the fruit plant was administrated orally to animals at three concentrations (50%, 75%, and 100%) per day for 45 days. The fourth group was the control group that was left without treatment. Blood samples were obtained from the corner of the eye with a capillary tube and the serum was extracted to determine the hormone levels. The results showed that the aqueous extract of fennel fruits contains eleven active secondary metabolites, namely Eucalyptol, Terpinene, Anisole, Camphor, Anethole, Anisaldehyde, Apiole, a-pinene, Estragole, Fenchone, and Limonene, which seemed to played a role in regulating the levels of prolactin and estrogen hormones in rats treated with the extract. The results showed a direct relationship between the concentration of the fruit extract given to the animals and their serum levels of estrogen and prolactin. Increases in the levels of estrogen (44.56 ± 0.90 ng/ml) and prolactin (134.66 ± 0.80 ng/ml) were recorded using the concentration of 100% of the watery extract of Foeniculum vulgare L., as compared to the control group (126.33 ± 1.18; 6.37 ± 0.45 ng / ml, respectively). The results demonstrated the effective role of the aqueous extract of fennel fruits in stimulating estrogen and prolactin in female rats through their content of active compounds, which can be of great importance in stimulating the process of milk secretion in animals.

Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

Background: The synthetic steroid mifepristone is reported to have anti-obesity and anti-diabetic effects in mammals on normal and high-fat diets (HFD). We previously reported that mifepristone blocks the negative effect on life span caused by mating in female Drosophila melanogaster.Methods: Here we asked if mifepristone could protect virgin females from the life span-shortening effect of HFD. Mifepristone was assayed for effects on life span in virgin females, in repeated assays, on regular media and on media supplemented with coconut oil (HFD). The excrement quantification (EX-Q) assay was used to measure food intake of the flies after 12 days mifepristone treatment. In addition, experiments were conducted to compare the effects of mifepristone in virgin and mated females, and to identify candidate mifepristone targets and mechanisms.Results: Mifepristone increased life span of virgin females on regular media, as well as on media supplemented with either 2.5 or 5% coconut oil. Food intake was not reduced in any assay, and was significantly increased by mifepristone in half of the assays. To ask if mifepristone might rescue virgin females from all life span-shortening stresses, the oxidative stressor paraquat was tested, and mifepristone produced little to no rescue. Analysis of extant metabolomics and transcriptomics data suggested similarities between effects of mifepristone in virgin and mated females, including reduced tryptophan breakdown and similarities to dietary restriction. Bioinformatics analysis identified candidate mifepristone targets, including transcription factors Paired and Extra-extra. In addition to shortening life span, mating also causes midgut hypertrophy and activation of the lipid metabolism regulatory factor SREBP. Mifepristone blocked the increase in midgut size caused by mating, but did not detectably affect midgut size in virgins. Finally, mating increased activity of a SREBP reporter in abdominal tissues, as expected, but reporter activity was not detectably reduced by mifepristone in either mated or virgin females.Conclusion: Mifepristone increases life span of virgin females on regular and HFD without reducing food intake. Metabolomics and transcriptomics analyses suggest some similar effects of mifepristone between virgin and mated females, however reduced midgut size was observed only in mated females. The results are discussed regarding possible mifepristone mechanisms and targets.

COX2: A Prognostic Inflammogenic Marker Drives Cervical Carcinogenesis in Vivo through the NFκB/IAP/p53Axis

Cycloxygenase 2, a prostaglandin synthesizing enzyme, is a key player in inflammation-induced vasculogenesis that enables tumor growth. This study explores the central role of COX2 and its relative prosurvival proteins in evoking inflammatory events during the development of an in vivo cervical cancer model upon chronic treatment with 3-methylcholanthrene (3MC; a chemical carcinogen) in virgin-female Swiss albino mice. Chronic painting of the mouse cervix with 3MC solution triggered the persistent expression and activity of COX2, eventuating the overexpression of major prosurvival molecules (NFκB, XIAP, survivin, GM-CSF1) and proliferative antigens (Ki67, PCNA). COX2-arbitrated prosurvival signaling subsequently deranged the expression profiles of tumor suppressor proteins (p53/acetyl-p53, p21, Rb) within the cervix. COX2 mediated molecular alterations successively surged leukocyte influx within the cervix, catering to localized inflammation that gradually distorted its tissue architecture. Cervical carcinogenesis was further braced by higher levels of systemic ROS and RNS, escalated iNOS activity and compromised antioxidant enzyme capacities, which were accompanied by splenomegaly. Additionally, circulation of blood leucocytes with damaged DNA throughout the mouse body envisaged the impact of cervix-limited inflammation on mouse physiology. Conclusively, the present study deciphered the role of COX2 in affecting NFκB/IAP/p53 functions in sequestering the contributors of localized and systemic inflammogenesis to propel 3MC-mediated cervical carcinogenesis in vivo.

COX2: A Prognostic Inflammogenic Marker Drives Cervical Carcinogenesis In Vivo Through NFκB/IAP/p53Axis

Cycloxygenase2, a prostaglandin synthesizing enzyme is a key player in inflammation-induced vasculogenesis that enables tumor growth. This study explores the central role of COX2 and its relative prosurvival proteins in evoking inflammatory events during development of an in vivo cervical cancer model upon chronic treatment with 3-methylcholanthrene (3MC; a chemical carcinogen) in virgin-female Swiss Albino mice. Chronic painting of mice cervix with 3MC solution triggered the persistent expression and activity of COX2; eventuating in overexpression of major prosurvival molecules (NFκB, XIAP, survivin, GM-CSF1) and proliferative antigens (Ki67, PCNA). COX2-arbitrated prosurvival signaling subsequently deranged the expression profiles of tumor supressor proteins (p53/Acetyl-p53, p21, Rb) within the cervix. COX2 helmed molecular alterations successively surged leukocyte influx within cervix; catering in localized inflammation which gradually distorted its tissue architecture. Cervical carcinogenesis was further braced by higher levels of systemic-ROS and RNS, escalated iNOS activity and compromised anti-oxidant enzyme capacities, which were accompanied by splenomegaly. Additionally, circulation of blood-leucocytes with damaged DNA throughout the mice body, envisaged the impact of cervix-limited inflammation upon the mice physiology. Conclusively, the present study deciphered the role of COX2 effectuated NFκB/IAP/p53 functions in sequestering the contributors of localized and systemic inflammogenesis for propelling 3MC-mediated cervical carcinogenesis in vivo.

Oxytocin and vasopressin within the ventral and dorsal lateral septum modulate aggression in female rats

In contrast to male rats, aggression in virgin female rats has been rarely studied. Here, we established a rat model of enhanced aggression in females using a combination of social isolation and aggression-training to specifically investigate the involvement of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the lateral septum (LS). Using neuropharmacological, optogenetic, chemogenetic as well as microdialysis approaches, we revealed that enhanced OXT release within the ventral LS (vLS), combined with reduced AVP release within the dorsal LS (dLS), is required for aggression in female rats. Accordingly, increased activity of putative OXT receptor-positive neurons in the vLS, and decreased activity of putative AVP receptor-positive neurons in the dLS, are likely to underly aggression in female rats. Finally, in vitro activation of OXT receptors in the vLS increased tonic GABAergic inhibition of dLS neurons. Overall, our data suggest a model showing that septal release of OXT and AVP differentially affects aggression in females by modulating the inhibitory tone within LS sub-networks.

An epigenomic shift in amygdala marks the transition from pup-aversive to maternal-like behaviors in alloparenting virgin female mice

In many species, adults will care for young offspring that are not their own, a phenomenon called alloparenting. However, most nonparental adults experience an initial aversion to newborns, which must be overcome before a robust display of parental-like behaviors can begin. To capture neurogenomic events underlying this dramatic behavioral transition, we analyzed brain gene expression and chromatin profiles of virgin female mice co-housed with mothers during pregnancy and after birth. After an initial display of agonistic behaviors and a surge of defense-related gene expression, we observed a dramatic shift in the chromatin landscape specifically in amygdala, accompanied by a dampening of the defense-related genes. This shift coincided with the emergence of behaviors and gene expression classically associated with maternal care. The results reveal the outlines of a neurogenomic program associated with this dramatic aversive-to-affiliative behavioral switch, and suggest molecular networks that may be relevant to human postpartum mental health.

Involvement of JAK-STAT-SOCS3 Pathway in the Regression of Mice X-Zone of Adrenal Cortex

Previously, we showed that the histological markers of the mice X-zone of adrenal cortex were still present in adult male and female postpartum SF1/SOCS3KO mice. Abnormal distribution of lipid droplets along the adrenal cortex and reduced ACTH-induced corticosterone secretion were observed in SF1/SOCS3KO mice (1). Here we have examined the adrenals of the SF1/SOCS3KO male and virgin female at 3, 8, 15 and 30 weeks through morphological and molecular analysis. Hematoxylin-eosin stains showed X-zone retention in the SF1/SOCS3KO mice adrenals regardless of the postnatal age analyzed. CYP17A1-positive cells were immunolocalized in the X-zone of SF1/SOCS3KO mice that were confirmed by immunoblotting. A fetal adrenal enhancer (FAdE) and Pik3c2g and 20αHSD genes expression were analyzed by RT-PCR, and these genes were present in the male SF1/SOCS3KO mice up to the age of 8 and 15 weeks, but not in the control mice. Therefore, we showed retention of X-zone in the adrenal cortex of SOCS3KO mice up to the age of 30 week, which suggest the involvement of JAK/STAT/SOCS3 signaling pathway in the differentiation process of adrenal cortex. Reference: (1) Pedroso et al., J Endocrinol.2017 Dec;235(3):207–222.