Inhibition of WNT/β-catenin signalling during sex-specific gonadal differentiation is essential for normal human fetal testis development.

Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail.

Identification of novel phenylalanine derivatives bearing a hydroxamic acid moiety as potent quorum sensing inhibitors.

Phenylalanine derivatives are a well-known small moiety responsible for controlling the virulence factors of several bacteria. Herein, for the first time, we report novel structures of phenylalanine derivatives bearing a hydroxamic acid moiety which were designed, synthesized, and evaluated for use as quorum sensing inhibitors. Biological results reveal that six compounds showed good quorum sensing inhibitors properties with an IC ranging from 7.

High incidence of imperforate vagina in ADGRA3-deficient mice.

Background: Ten percent of the female population suffers from congenital abnormalities of the vagina, uterus, or oviducts, with severe consequences for reproductive and psychological health. Yet, the underlying causes of most of these malformations remain largely unknown. ADGRA3 (GPR125) is involved in WNT signaling and planar cell polarity, mechanisms vital to female reproductive tract development.

The mechanism behind tenuazonic acid-mediated inhibition of plant plasma membrane H-ATPase and plant growth.

The increasing prevalence of herbicide-resistant weeds has led to a search for new herbicides that target plant growth processes differing from those targeted by current herbicides. In recent years, some studies have explored the use of natural compounds from microorganisms as potential new herbicides. We previously demonstrated that tenuazonic acid (TeA) from the phytopathogenic fungus Stemphylium loti inhibits the plant plasma membrane (PM) H-ATPase, representing a new target for herbicides.

Dexamethasone affects human fetal adrenal steroidogenesis and subsequent ACTH response in an culture model.

Introduction: Administration of dexamethasone (DEX) has been used experimentally to suppress androgenization of external genitalia in 46,XX fetuses with congenital adrenal hyperplasia. Despite this, the prenatal biological mechanism-of-action of DEX on fetal development is not known. This study aimed to examine direct effects of DEX on human fetal adrenal (HFA) steroidogenic activity including possible effects on the subsequent response to ACTH-stimulation.

Biogeographic-tectonic calibration of 14 nodes in a butterfly timetree.

The butterfly subtribe Coenonymphina (Nymphalidae: Satyrinae) comprises four main clades found, respectively, in (1) the Solomon Islands, (2) Australasia, (3) NW South America and (4) Laurasia, with a phylogeny: 1 (2 (3 + 4)). In assessing biogeographic evolution in the group we rejected the conversion of fossil-calibrated clade ages to likely maximum clade ages by the imposition of arbitrary priors. Instead, we used biogeographic-tectonic calibration, with fossil-calibrated ages accepted as minima.

Loss of Adgra3 causes obstructive azoospermia with high penetrance in male mice.

The adhesion receptor ADGRA3 (GPR125) is a known spermatogonial stem cell marker, but its impact on male reproduction and fertility has not been examined. Using a mouse model lacking Adgra3 (Adgra3 ), we show that 55% of the male mice are infertile from puberty despite having normal spermatogenesis and epididymal sperm count. Instead, male mice lacking Adgra3 exhibited decreased estrogen receptor alpha expression and transient dilation of the epididymis.

Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo.

Background: Reduced androgen action during early fetal development has been suggested as the origin of reproductive disorders comprised within the testicular dysgenesis syndrome (TDS). This hypothesis has been supported by studies in rats demonstrating that normal male development and adult reproductive function depend on sufficient androgen exposure during a sensitive fetal period, called the masculinization programming window (MPW). The main aim of this study was therefore to examine the effects of manipulating androgen production during different timepoints during early human fetal testis development to identify the existence and timing of a possible window of androgen sensitivity resembling the MPW in rats.

Drug Discovery and Development on Pma1, Where Are We Now? A Critical Review from 1995 to 2022.

Plasma membrane H -ATPase (Pma1) is an enzyme uniquely found in plants and fungi. The enzyme controls the nutrient uptake of plants and fungi via an electrochemical gradient processes, which is essential for their survival. Inhibiting Pma1, therefore, constitutes an alternative antifungal target void of toxicity to humans.

RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma.

Background: Testicular germ cell tumours (TGCTs) have a high sensitivity to chemotherapy and a high cure rate, although with serious adverse effects. In the search for tumour suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis, came up as a candidate since RANKL signalling was recently identified in the testis.

Methods: Expression of RANKL, RANK and OPG, and the effects of RANKL inhibition were investigated in human TGCTs, TGCT-derived cell-lines, and TGCT-xenograft models.

Prepubertal and pubertal gonadal morphology, expression of cell lineage markers and hormonal evaluation in two 46,XY siblings with 17β-hydroxysteroid dehydrogenase 3 deficiency.

Objectives: 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency results in insufficient biosynthesis of testosterone and consequently dihydrotestosterone. This is important for the fetal development of male genitalia. Thus, most 46,XY patients with 17β-HSD3 deficiency have a female appearance at birth and present with virilization at puberty.

Amide bond formation in aqueous solution: direct coupling of metal carboxylate salts with ammonium salts at room temperature.

Herein, we report a green, expeditious, and practically simple protocol for direct coupling of carboxylate salts and ammonium salts under ACN/HO conditions at room temperature without the addition of tertiary amine bases. The water-soluble coupling reagent EDC·HCl is a key component in the reaction. The reaction runs smoothly with unsubstituted/substituted ammonium salts and provides a clean product without column chromatography.

Calcium transport in male reproduction is possibly influenced by vitamin D and CaSR.

Vitamin D is important for gonadal function in rodents, and improvement of vitamin D status in men with low sperm counts increases live birth rate. Vitamin D is a regulator of transcellular calcium transport in the intestine and kidney and may influence the dramatic changes in the luminal calcium concentration in epididymis. Here, we show spatial expression in the male reproductive tract of vitamin D receptor (VDR)-regulated factors involved in calcium transport: transient receptor potential vanilloid 5/6 , sodium/calcium exchanger 1, plasma membrane calcium ATPase 1, calbindin D9k, calcium-sensing receptor (CaSR), and parathyroid hormone-related peptide (PTHrP) in mouse and human testis and epididymis.

Accelerated loss of oogonia and impaired folliculogenesis in females with Turner syndrome start during early fetal development.

Study Question: How are germ cell numbers and initiation of folliculogenesis affected in fetal Turner syndrome (TS) ovaries?

Summary Answer: Germ cell development was severely affected already in early second trimester pregnancies, including accelerated oogonia loss and impaired initiation of primordial follicle formation in TS ovaries, while the phenotype in TS mosaic ovaries was less severe.

What Is Known Already: Females with TS are characterized by premature ovarian insufficiency (POI). This phenotype is proposed to be a consequence of germ cell loss during development, but the timing and mechanisms behind this are not characterized in detail.

The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions.

Background: Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue.

Serum Concentrations and Gonadal Expression of INSL3 in Eighteen Males With 45,X/46,XY Mosaicism.

Objective: Insulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X/46,XY mosaicism.

Methods: Retrospectively collected data from medical records, gonadal tissue samples, and prospectively analyzed serum samples from eighteen male patients with 45,X/46,XY mosaicism (one prepubertal, four testosterone-treated, 13 untreated) were included.

RANKL regulates male reproductive function.

Infertile men have few treatment options. Here, we demonstrate that the transmembrane receptor activator of NF-kB ligand (RANKL) signaling system is active in mouse and human testis. RANKL is highly expressed in Sertoli cells and signals through RANK, expressed in most germ cells, whereas the RANKL-inhibitor osteoprotegerin (OPG) is expressed in germ and peritubular cells.

The Calcium-Sensing Receptor Is Essential for Calcium and Bicarbonate Sensitivity in Human Spermatozoa.

Context: The calcium-sensing receptor (CaSR) is essential to maintain a stable calcium concentration in serum. Spermatozoa are exposed to immense changes in concentrations of CaSR ligands such as calcium, magnesium, and spermine during epididymal maturation, in the ejaculate, and in the female reproductive environment. However, the role of CaSR in human spermatozoa is unknown.

Establishment of a Novel Human Fetal Adrenal Culture Model that Supports de Novo and Manipulated Steroidogenesis.

Context: Disorders affecting adrenal steroidogenesis promote an imbalance in the normally tightly controlled secretion of mineralocorticoids, glucocorticoids, and androgens. This may lead to differences/disorders of sex development in the fetus, as seen in virilized girls with congenital adrenal hyperplasia (CAH). Despite the important endocrine function of human fetal adrenals, neither normal nor dysregulated adrenal steroidogenesis is understood in detail.

A common deletion in the growth hormone receptor gene (d3-GHR) in the offspring is related to maternal placental GH levels during pregnancy.

Background: A common growth hormone receptor polymorphism with deletion of exon 3 (d3-GHR) has previously been linked to increased postnatal growth on the one hand and decreased fetal growth on the other. Regulation of fetal growth is positively dependent on secretion of placental GH (hGH-V).

Objective: We explored the effect of the fetal d3-GHR genotype on maternal serum levels of hGH-V and fetal growth.

Age-related changes in human Leydig cell status.

Study Question: What are the consequences of ageing on human Leydig cell number and hormonal function?

Summary Answer: Leydig cell number significantly decreases in parallel with INSL3 expression and Sertoli cell number in aged men, yet the in vitro Leydig cell androgenic potential does not appear to be compromised by advancing age.

What Is Known Already: There is extensive evidence that ageing is accompanied by decline in serum testosterone levels, a general involution of testis morphology and reduced spermatogenic function. A few studies have previously addressed single features of the human aged testis phenotype one at a time, but mostly in tissue from patients with prostate cancer.

Hypercalcemia After Cosmetic Oil Injections: Unraveling Etiology, Pathogenesis, and Severity.

Intramuscular injections of paraffin oil can cause foreign body granuloma formation and hypercalcemia. Macrophages with the ability to produce high levels of 1,25(OH) D may induce the mineral disturbance, but no major series of patients have been published to date. Here, medical history, physical evaluation, biochemical, and urinary analysis for calcium homeostasis were obtained from 88 males, who 6 years previously had injected paraffin or synthol oil into skeletal muscle.