3D microscopic reconstruction of pearls using combined optical microscopy and photogrammetry.

In this study, we introduce an affordable and accessible method that combines optical microscopy and photogrammetry to reconstruct 3D models of Tahitian pearls. We present a novel device designed for acquiring microscopic images around a sphere using translational displacement stages and outline our method for reconstructing these images. We successfully created 3D models of two individual pearl rings, each representing 6.3% of the pearl's surface. Additionally, we generated a combined model representing 10.3% of the pearl's surface. This showcases the potential for reconstructing entire pearls with appropriate instrumentation. We emphasize that our approach extends beyond pearls and spherical objects and can be adapted for various object types using appropriate acquisition devices. We provide a proof of concept demonstrating the feasibility of 3D photogrammetry using optical microscopy. Consequently, our method offers a practical and cost-effective alternative for generating 3D models at a microscopic scale, particularly when detailed internal structure information is unnecessary.

Unraveling the Molecular Landscape of Uterine Fibroids, Insights into HMGA2 and Stem Cell Involvement.

Uterine fibroids are prevalent benign tumors in women that exhibit considerable heterogeneity in clinical presentation and molecular characteristics, necessitating a deeper understanding of their etiology and pathogenesis. HMGA2 overexpression has been associated with fibroid development, yet its precise role remains elusive. Mutations in fibroids are mutually exclusive and largely clonal, suggesting that tumors originate from a single mutant cell. We explored a possible role for HMGA2 overexpression in differentiated myometrial cells, hypothesizing its potential to induce a stem cell-like or dedifferentiating phenotype and drive fibroid development. Myometrial cells were immortalized and transduced with an HMGA2 lentivirus to produce HMGA2hi cells. In vitro stem cell assays were conducted and RNA from HMGA2hi and control cells and fibroid-free myometrial and HMGA2 fibroid (HMGA2F) tissues were submitted for RNA-sequencing. HMGA2hi cells have enhanced self-renewal capacity, decreased proliferation, and have a greater ability to differentiate into other mesenchymal cell types. HMGA2hi cells exhibit a stem cell-like signature and share transcriptomic similarities with HMGA2F. Moreover, dysregulated extracellular matrix pathways are observed in both HMGA2hi cells and HMGA2F. Our findings suggest that HMGA2 overexpression drives myometrial cells to dedifferentiate into a more plastic phenotype and underscore a pivotal role for HMGA2 in fibroid pathogenesis.

Advancing Molecular Sieving via Å-Scale Pore Tuning in Bottom-Up Graphene Synthesis.

Porous graphene films are attractive as a gas separation membrane given that the selective layer can be just one atom thick, allowing high-flux separation. A favorable aspect of porous graphene is that the pore size, essentially gaps created by lattice defects, can be tuned. While this has been demonstrated for postsynthetic, top-down pore etching in graphene, it does not exist in the more scalable, bottom-up synthesis of porous graphene. Inspired by the mechanism of precipitation-based synthesis of porous graphene over catalytic nickel foil, we herein conceive an extremely simple way to tune the pore size. This is implemented by increasing the cooling rate by over 100-fold from -1 °C min-1 to over -5 °C s-1. Rapid cooling restricts carbon diffusion, resulting in a higher availability of dissolved carbon for precipitation, as evidenced by quantitative carbon-diffusion simulation, measurement of carbon concentration as a function of nickel depth, and imaging of the graphene nanostructure. The resulting enhanced grain (inter)growth reduces the effective pore size which leads to an increase of the H2/CH4 separation factor from 6.2 up to 53.3.

Exogenous corticosterone administration during pregnancy in mice alters placental and fetal thyroid hormone availability in females.

INTRODUCTION: Maternal prenatal psychological stress is associated with adverse pregnancy outcomes and increased risk of adverse health outcomes in children. While the molecular mechanisms that govern these associations has not been fully teased apart, stress-induced changes in placental function can drive sex-specific phenotypes in offspring. We sought to identify and examine molecular pathways in the placenta that are altered in response to maternal prenatal stress. METHODS: We previously employed a mouse model of maternal prenatal stress where pregnant dams were treated with stress hormone (CORT) beginning in mid-gestation. Using this model, we conducted RNAseq analysis of whole placenta at E18.5. We used qRT-PCR to validate gene expression changes in the placenta and in a trophoblast cell line. ELISAs were used to measure the abundance of thyroid hormones in maternal and fetal serum and in the placenta. RESULTS: Dio2 was amongst the top differentially expressed genes in response to exogenous stress hormone. Dio2 expression was more downregulated in placenta of female fetuses from CORT-treated dams than both control placenta from females and placenta from male fetuses. Consistent with Dio2's role in production of bioactive thyroid hormone (T3), we found that there was a reduction of T3 in placenta and serum of female embryos from CORT-treated dams at E18.5. Both T3 and T4 were reduced in the fetal compartment of the placenta of female fetuses from CORT-treated dams at E16.5. Exogenous stress hormone induced reduction in thyroid hormone in females was independent of circulating levels of TH in the dams. DISCUSSION: The placental thyroid hormone synthesis pathway may be a target of elevated maternal stress hormone and modulate fetal programming of health and disease of offspring in a sex-specific fashion.

Amine Adsorbents Stability for Post-Combustion CO2 Capture: Determination and Validation of Laboratory Degradation Rates in a Multi-staged Fluidized Bed Pilot Plant.

Alternative to current liquid amine technologies for post-combustion CO2 capture, new technologies such as adsorbent-based processes are developed, wherein material lifetime and degradation is important. Herein a robust method to determine degradation rates in a laboratory setup is developed, which was validated with a continuous multi-staged fluidized bed pilot plant designed to capture 1 ton CO2 per day. An amine functionalized polystyrene adsorbent showed very good agreement between the experimental 1000-hour laboratory degradation rates and 2200 hours of degradation in a pilot plant. This validates how laboratory experiments can be extrapolated for sorbent screening and for scale-up. Resulting, the oxidative degradation in the desorber at high temperatures (120 °C) and low O2 concentrations (150 ppmv) is 3 times higher compared to the adsorber at low temperatures and high O2 (56 °C, 7 vol %). Laboratory degradation experiments can hence be used to further optimize process operations to limit degradation or screen for potential new adsorbents.

Pearl shape classification using deep convolutional neural networks from Tahitian pearl rotation in Pinctada margaritifera.

Tahitian pearls, artificially cultivated from the black-lipped pearl oyster Pinctada margaritifera, are renowned for their unique color and large size, making the pearl industry vital for the French Polynesian economy. Understanding the mechanisms of pearl formation is essential for enabling quality and sustainable production. In this paper, we explore the process of pearl formation by studying pearl rotation. Here we show, using a deep convolutional neural network, a direct link between the rotation of the pearl during its formation in the oyster and its final shape. We propose a new method for non-invasive pearl monitoring and a model for predicting the final shape of the pearl from rotation data with 81.9% accuracy. These novel resources provide a fresh perspective to study and enhance our comprehension of the overall mechanism of pearl formation, with potential long-term applications for improving pearl production and quality control in the industry.

Exogenous corticosterone administration during pregnancy alters placental and fetal thyroid hormone availability in females.

Introduction: Maternal prenatal stress is associated with adverse pregnancy outcomes and predisposition to long-term adverse health outcomes in children. While the molecular mechanisms that govern these associations has not been fully teased apart, stress-induced changes in placental function can drive sex-specific phenotypes in offspring. We sought to identify and examine molecular pathways in the placenta that are altered in response to maternal prenatal stress. Methods: Using a mouse model of maternal prenatal stress, we conducted RNA-seq analysis of whole placenta at E18.5. We used qRT-PCR to validate gene expression changes in the placenta and in a trophoblast cell line. ELISAs were used to measure the abundance of thyroid hormones in maternal and fetal serum and in the placenta. Results: Dio2 was amongst the top differentially expressed genes in response to elevated maternal stress hormone. Dio2 expression was more downregulated in female placenta from stressed dams than both female control and male placenta. Consistent with Dio2's role in production of bioactive thyroid hormone (T3), we found that there was a reduction of T3 in placenta and serum of female embryos from stressed dams at E18.5. Both T3 and T4 were reduced in the fetal compartment of the female placenta from stressed dams at E16.5. Stress hormone induced reduction in thyroid hormone in females was independent of circulating levels of TH in the dams. Discussion: The placental thyroid hormone synthesis pathway may be a target of maternal stress and modulate fetal programming of health and disease of offspring in a sex-specific fashion.

Cysteine-rich intestinal protein 1 is a novel surface marker for human myometrial stem/progenitor cells.

Myometrial stem/progenitor cells (MyoSPCs) have been proposed as the cells of origin for uterine fibroids, but the identity of the MyoSPC has not been well established. We previously identified SUSD2 as a possible MyoSPC marker, but the relatively poor enrichment in stem cell characteristics of SUSD2+ over SUSD2- cells compelled us to find better markers. We combined bulk RNA-seq of SUSD2+/- cells with single cell RNA-seq to identify markers for MyoSPCs. We observed seven distinct cell clusters within the myometrium, with the vascular myocyte cluster most highly enriched for MyoSPC characteristics and markers. CRIP1 expression was found highly upregulated by both techniques and was used as a marker to sort CRIP1+/PECAM1- cells that were both enriched for colony forming potential and able to differentiate into mesenchymal lineages, suggesting that CRIP1+/PECAM1- cells could be used to better study the etiology of uterine fibroids.

Cysteine-Rich Intestinal Protein 1 is a Novel Surface Marker for Myometrial Stem/Progenitor Cells.

Myometrial stem/progenitor cells (MyoSPCs) have been proposed as the cells of origin for uterine fibroids, which are benign tumors that develop in the myometrium of most reproductive age women, but the identity of the MyoSPC has not been well established. We previously identified SUSD2 as a possible MyoSPC marker, but the relatively poor enrichment in stem cell characteristics of SUSD2+ over SUSD2- cells compelled us to find better discerning markers for more rigorous downstream analyses. We combined bulk RNA-seq of SUSD2+/- cells with single cell RNA-seq to identify markers capable of further enriching for MyoSPCs. We observed seven distinct cell clusters within the myometrium, with the vascular myocyte cluster most highly enriched for MyoSPC characteristics and markers, including SUSD2. CRIP1 expression was found highly upregulated in both techniques and was used as a marker to sort CRIP1+/PECAM1- cells that were both enriched for colony forming potential and able to differentiate into mesenchymal lineages, suggesting that CRIP1+/PECAM1- cells could be used to better study the etiology of uterine fibroids.

A Polyaminobiaryl-Based ß-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APPSwe/PSEN1ΔE9 Mice Model of Amyloid Pathology.

The progress in Alzheimer's disease (AD) treatment suggests a combined therapeutic approach targeting the two lesional processes of AD, which include amyloid plaques made of toxic Aß species and neurofibrillary tangles formed of aggregates of abnormally modified Tau proteins. A pharmacophoric design, novel drug synthesis, and structure-activity relationship enabled the selection of a polyamino biaryl PEL24-199 compound. The pharmacologic activity consists of a non-competitive ß-secretase (BACE1) modulatory activity in cells. Curative treatment of the Thy-Tau22 model of Tau pathology restores short-term spatial memory, decreases neurofibrillary degeneration, and alleviates astrogliosis and neuroinflammatory reactions. Modulatory effects of PEL24-199 towards APP catalytic byproducts are described in vitro, but whether PEL24-199 can alleviate the Aß plaque load and associated inflammatory counterparts in vivo remains to be elucidated. We investigated short- and long-term spatial memory, Aß plaque load, and inflammatory processes in APPSwe/PSEN1ΔE9 PEL24-199 treated transgenic model of amyloid pathology to achieve this objective. PEL24-199 curative treatment induced the recovery of spatial memory and decreased the amyloid plaque load in association with decreased astrogliosis and neuroinflammation. The present results underline the synthesis and selection of a promising polyaminobiaryl-based drug that modulates both Tau and, in this case, APP pathology in vivo via a neuroinflammatory-dependent process.

The telomerase activator TA-65 protects from cigarette smoke-induced small airway remodeling in mice through extra-telomeric effects.

Small airway remodeling (SAR) is a key phenomenon of airflow obstruction in smokers, leading to chronic obstructive pulmonary disease (COPD). SAR results in an increased thickness of small airway walls, with a combination of peribronchiolar fibrosis with increased fibrous tissue and accumulation of mesenchymal and epithelial cells. SAR pathogenesis is still unclear but recent data suggest that alterations in telomerase activity could represent a possible underlying mechanism of SAR. Our study was dedicated to identify a potential protective role of TA-65, a pharmacological telomerase activator, in a cigarette smoke (CS) model of SAR in mice, and to further precise if extra-telomeric effects of telomerase, involving oxidative stress modulation, could explain it. C57BL/6J mice were daily exposed to air or CS during 4 weeks with or without a concomitant administration of TA-65 starting 7 days before CS exposure. Morphological analyses were performed, and mucus production, myofibroblast differentiation, collagen deposition, as well as transforming growth factor-ß1 (TGF-ß1) expression in the small airway walls were examined. In addition, the effects of TA-65 treatment on TGF-ß expression, fibroblast-to-myofibroblast differentiation, reactive oxygen species (ROS) production and catalase expression and activity were evaluated in primary cultures of pulmonary fibroblasts and/or mouse embryonic fibroblasts in vitro. Exposure to CS during 4 weeks induced SAR in mice, characterized by small airway walls thickening and peribronchiolar fibrosis (increased deposition of collagen, expression of α-SMA in small airway walls), without mucus overproduction. Treatment of mice with TA-65 protected them from CS-induced SAR. This effect was associated with the prevention of CS-induced TGF-ß expression in vivo, the blockade of TGF-ß-induced myofibroblast differentiation, and the reduction of TGF-ß-induced ROS production that correlates with an increase of catalase expression and activity. Our findings demonstrate that telomerase is a critical player of SAR, probably through extra-telomeric anti-oxidant effects, and therefore provide new insights in the understanding and treatment of COPD pathogenesis.

Discovery of Compounds That Selectively Repress the Amyloidogenic Processing of the Amyloid Precursor Protein: Design, Synthesis and Pharmacological Evaluation of Diphenylpyrazoles.

The rationale to define the biological and molecular parameters derived from structure-activity relationships (SAR) is mandatory for the lead selection of small drug compounds. Several series of small molecules have been synthesized based on a computer-assisted pharmacophore design derived from two series of compounds whose scaffold originates from chloroquine or amodiaquine. All compounds share similar biological activities. In vivo, Alzheimer's disease-related pathological lesions are reduced, consisting of amyloid deposition and neurofibrillary degeneration, which restore and reduce cognitive-associated impairments and neuroinflammation, respectively. Screening election was performed using a cell-based assay to measure the repression of Aß1-x peptide production, the increased stability of APP metabolites, and modulation of the ratio of autophagy markers. These screening parameters enabled us to select compounds as potent non-competitive ß-secretase modulators, associated with various levels of lysosomotropic or autophagy modulatory activities. Structure-activity relationship analyses enabled us to define that (1) selectively reducing the production of Aß1-x, and (2) little Aßx-40/42 modification together with (3) a decreased ratio of p62/(LC3-I/LC3-II) enabled the selection of non-competitive ß-secretase modulators. Increased stability of CTFα and AICD precluded the selection of compounds with lysosomotropic activity whereas cell toxicity was associated with the sole p62 enhanced expression shown to be driven by the loss of nitrogen moieties. These SAR parameters are herein proposed with thresholds that enable the selection of potent anti-Alzheimer drugs for which further investigation is necessary to determine the basic mechanism underlying their mode of action.

Transcriptome and DNA methylome analyses reveal underlying mechanisms for the racial disparity in uterine fibroids.

Uterine fibroids (leiomyomas) affect Black women disproportionately compared with women of other races and ethnicities in terms of prevalence, incidence, and severity of symptoms. The causes of this racial disparity are essentially unknown. We hypothesized that myometria of Black women are more susceptible to developing fibroids, and we examined the transcriptomic and DNA methylation profiles of myometria and fibroids from Black and White women for comparison. Myometrial samples cluster by race in both their transcriptome and DNA methylation profiles, whereas fibroid samples only cluster by race in the latter. More differentially expressed genes (DEGs) were detected in the Black and White myometrial sample comparison than in the fibroid comparison. Leiomyoma gene set expression analysis identified 4 clusters of DEGs, including a cluster of 24 genes with higher expression in myometrial samples from Black women. One of the DEGs in this group, von Willibrands factor (VWF), was significantly hypomethylated in both myometrial samples from Black women and in all fibroids at 2 CpG probes that are near a putative enhancer site and that are correlated with VWF expression levels. These results suggest that the molecular basis for the disparity in fibroid disease between Black and White women could be found in the myometria before fibroid development and not in the fibroids themselves.

Stress-Induced Premature Senescence Related to Oxidative Stress in the Developmental Programming of Nonalcoholic Fatty Liver Disease in a Rat Model of Intrauterine Growth Restriction.

Metabolic syndrome (MetS) refers to cardiometabolic risk factors, such as visceral obesity, dyslipidemia, hyperglycemia/insulin resistance, arterial hypertension and non-alcoholic fatty liver disease (NAFLD). Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing metabolic/hepatic disorders later in life. Oxidative stress and cellular senescence have been associated with MetS and are observed in infants born following IUGR. However, whether these mechanisms could be particularly associated with the development of NAFLD in these individuals is still unknown. IUGR was induced in rats by a maternal low-protein diet during gestation versus. a control (CTRL) diet. In six-month-old offspring, we observed an increased visceral fat mass, glucose intolerance, and hepatic alterations (increased transaminase levels, triglyceride and neutral lipid deposit) in male rats with induced IUGR compared with the CTRL males; no differences were found in females. In IUGR male livers, we identified some markers of stress-induced premature senescence (SIPS) (lipofuscin deposit, increased protein expression of p21WAF, p16INK4a and Acp53, but decreased pRb/Rb ratio, foxo-1 and sirtuin-1 protein and mRNA expression) associated with oxidative stress (higher superoxide anion levels, DNA damages, decreased Cu/Zn SOD, increased catalase protein expression, increased nfe2 and decreased keap1 mRNA expression). Impaired lipogenesis pathways (decreased pAMPK/AMPK ratio, increased pAKT/AKT ratio, SREBP1 and PPARγ protein expression) were also observed in IUGR male livers. At birth, no differences were observed in liver histology, markers of SIPS and oxidative stress between CTRL and IUGR males. These data demonstrate that the livers of IUGR males at adulthood display SIPS and impaired liver structure and function related to oxidative stress and allow the identification of specific therapeutic strategies to limit or prevent adverse consequences of IUGR, particularly metabolic and hepatic disorders.

Could Repeated Cardio-Renal Injury Trigger Late Cardiovascular Sequelae in Extreme Endurance Athletes?

Regular exercise confers multifaceted and well-established health benefits. Yet, transient and asymptomatic increases in markers of cardio-renal injury are commonly observed in ultra-endurance athletes during and after competition. This has raised concerns that chronic recurring insults could cause long-term cardiac and/or renal damage. Indeed, extreme endurance exercise (EEE) over decades has sometimes been linked with untoward cardiac effects, but a causal relation with acute injury markers has not yet been established. Here, we summarize the current knowledge on markers of cardiac and/or renal injury in EEE athletes, outline the possible interplay between cardiac and kidney damage, and explore the roles of various factors in the development of potential exercise-related cardiac damage, including underlying diseases, medication, sex, training, competition, regeneration, mitochondrial dysfunction, oxidative stress, and inflammation. In conclusion, despite the undisputed health benefits of regular exercise, we speculate, based on the intimate link between heart and kidney diseases, that in rare cases excessive endurance sport may induce adverse cardio-renal interactions that under specific, hitherto undefined conditions could result in persistent cardiac damage. We highlight future research priorities and provide decision support for athletes and clinical consultants who are seeking safe strategies for participation in EEE training and competition.

Role of glucocorticoid receptor mutations in hypertension and adrenal gland hyperplasia.

Hypertension is one of the leading causes of premature death in humans and exhibits a complex aetiology including environmental and genetic factors. Mutations within the glucocorticoid receptor (GR) can cause glucocorticoid resistance, which is characterized by several clinical features like hypercortisolism, hypokalaemia, adrenal hyperplasia and hypertension. Altered glucocorticoid receptor signalling further affects sodium and potassium homeostasis as well as blood pressure regulation and cell proliferation and differentiation that influence organ development and function. In salt-sensitive hypertension, excessive renal salt transport and sympathetic nervous system stimulation may occur simultaneously, and, thus, both the mineralocorticoid receptor (MR) and the GR-signalling may be implicated or even act interdependently. This review focuses on identified GR mutations in human primary generalized glucocorticoid resistance (PGGR) patients and their related clinical phenotype with specific emphasis on adrenal gland hyperplasia and hypertension. We compare these findings to mouse and rat mutants harbouring genetically engineered mutations to further dissect the cause and/or the consequence of clinical features which are common or different.

Maternal Herpesviridae infection during pregnancy alters midbrain dopaminergic signatures in adult offspring.

BACKGROUND: Motor symptoms of Parkinson's disease (PD) are apparent after a high proportion of dopamine neurons in the substantia nigra have degenerated. The vast majority of PD cases are sporadic, and the underlying pathobiological causes are poorly understood. Adults exhibit great variability in the numbers of nigral dopamine neurons, suggesting that factors during embryonic or early life regulate the development and physiology of dopaminergic neurons. Furthermore, exposure to infections and inflammation in utero has been shown to affect fetal brain development in models of schizophrenia and autism. Here, we utilize a mouse maternal infection model to examine how maternal herpesvirus infection impacts dopaminergic neuron-related gene and protein expression in the adult offspring. METHODS: Pregnant mice were injected with murine cytomegalovirus (MCMV), murine gamma herpes virus-68 (MHV68) or phosphate buffered saline (PBS) at embryonic day 8.5. Offspring were sacrificed at eight weeks of age and midbrains were processed for whole genome RNA sequencing, DNA methylation analysis, targeted protein expression and high-performance liquid chromatography for quantification of dopamine and its metabolites. RESULTS: The midbrain of adult offspring from MHV68 infected dams had significantly decreased expression of genes linked to dopamine neurons (Th, Lmx1b, and Foxa1) and increased Lrrk2, a gene involved in familial PD and PD risk that associates with neuroinflammation. Deconvolution analysis revealed that the proportion of dopamine neuron genes in the midbrain was reduced. There was an overall increase in DNA methylation in the midbrain of animals from MHV68-infected dams and pathway analyses indicated mitochondrial dysfunction, with reductions in genes associated with ATP synthesis, mitochondrial respiratory chain, and mitochondrial translation in the offspring of dams infected with MHV68. TIGAR (a negative regulator of mitophagy) and SDHA (mitochondrial complex II subunit) protein levels were increased, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum were increased in these offspring compared to offspring from uninfected control dams. No such changes were observed in the offspring of dams infected with MCMV. CONCLUSION: Our data suggest that maternal infection with Herpesviridae, specifically MHV68, can trigger changes in the development of the midbrain that impact dopamine neuron physiology in adulthood. Our work is of importance for the understanding of neuronal susceptibility underlying neurodegenerative disease, with particular relevance for PD.

Giant appendiceal mucocele as a first manifestation in a patient with silent ulcerative colitis: A case report.

Appendiceal mucocele (AM) is a rare lesion found in only 0.3% of all appendectomies and it is characterized by distention of the appendix by the accumulating intraluminal mucinous material. Four main histopathological subtypes of appendiceal mucocele has been described including: retention cyst, mucosal hyperplasia, mucinous cystadenoma, and cystadenocarcinoma. We report a case of 48-year-old middle eastern female, previously healthy, presented to the primary health center with right iliac fossa discomfort, and referred to our hospital for further evaluation. Contrast enhanced computed tomography of the abdomen and pelvis and focused ultrasonography over the right iliac fossa showed the characteristic CT and sonographic appearance of appendiceal mucocele. An additional incidental note of lack of colonic haustral pattern involving the rectum and descending colon was noted on abdominal CT raising the suspicion of Ulcerative Colitis which was then confirmed by colonoscopy and histopathology. Although no causal relationship between appendicular mucocele and inflammatory bowel disease has been established yet and few case reports had reported appendicular mucocele in patients with ulcerative colitis, close surveillance in these patients, and early recognition of the characteristic imaging features is crucial in preventing dreadful complications like pseudomyxoma peritonei.

Carbon Black Nanoparticles Selectively Alter Follicle-Stimulating Hormone Expression in vitro and in vivo in Female Mice.

Toxic effects of nanoparticles on female reproductive health have been documented but the underlying mechanisms still need to be clarified. Here, we investigated the effect of carbon black nanoparticles (CB NPs) on the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are key regulators of gonadal gametogenesis and steroidogenesis. To that purpose, we subjected adult female mice to a weekly non-surgical intratracheal administration of CB NPs at an occupationally relevant dose over 4 weeks. We also analyzed the effects of CB NPs in vitro, using both primary cultures of pituitary cells and the LßT2 gonadotrope cell line. We report here that exposure to CB NPs does not disrupt estrous cyclicity but increases both circulating FSH levels and pituitary FSH ß-subunit gene (Fshb) expression in female mice without altering circulating LH levels. Similarly, treatment of anterior pituitary or gonadotrope LßT2 cells with increasing concentrations of CB NPs dose-dependently up-regulates FSH but not LH gene expression or release. Moreover, CB NPs enhance the stimulatory effect of GnRH on Fshb expression in LßT2 cells without interfering with LH regulation. We provide evidence that CB NPs are internalized by LßT2 cells and rapidly activate the cAMP/PKA pathway. We further show that pharmacological inhibition of PKA significantly attenuates the stimulatory effect of CB NPs on Fshb expression. Altogether, our study demonstrates that exposure to CB NPs alters FSH but not LH expression and may thus lead to gonadotropin imbalance.

Salt-Sensitive Hypertension in GR+/- Rats Is Accompanied with Dysregulation in Adrenal Soluble Epoxide Hydrolase and Polyunsaturated Fatty Acid Pathways.

Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR+/-) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats. Furthermore, GR+/- rats showed dysregulation of the equilibrated linoleic and arachidonic acid pathways, with a significant increase of less active metabolites such as 8,9-DiHETrE. In Sprague Dawley rats, GR haploinsufficiency induced steroid disturbances, which provoked hypertension only in combination with high salt intake, which was accompanied by disturbances in sEH and fatty acid metabolism. Our results suggest that sEH inhibition could be a potential target to treat hypertension in patients with GR haploinsufficiency.