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Molecular Human Reproduction Apr 2024Paxillin is a ubiquitously expressed adaptor protein integral to focal adhesions, cell motility, and apoptosis. Paxillin has also recently been implicated as a mediator...
Paxillin is a ubiquitously expressed adaptor protein integral to focal adhesions, cell motility, and apoptosis. Paxillin has also recently been implicated as a mediator of nongenomic androgen receptor (AR) signaling in prostate cancer and other cells. We sought to investigate the relationship between paxillin and AR in granulosa cells (GCs), where androgen actions, apoptosis, and focal adhesions are of known importance, but where the role of paxillin is understudied. We recently showed that paxillin knockout in mouse GCs increases fertility in older mice. Here, we demonstrate that paxillin knockdown in human granulosa-derived KGN cells, as well as knockout in mouse primary GCs, results in reduced AR protein but not reduced mRNA expression. Further, we find that both AR protein and mRNA half-lives are reduced by approximately one-third in the absence of paxillin, but that cells adapt to chronic loss of paxillin by upregulating AR gene expression. Using co-immunofluorescence and proximity ligation assays, we show that paxillin and AR co-localize at the plasma membrane in GCs in a focal adhesion kinase-dependent way, and that disruption of focal adhesions leads to reduced AR protein level. Our findings suggest that paxillin recruits AR to the GC membrane, where it may be sequestered from proteasomal degradation and poised for nongenomic signaling, as reported in other tissues. To investigate the physiological significance of this in disorders of androgen excess, we tested the effect of GC-specific paxillin knockout in a mouse model of polycystic ovary syndrome (PCOS) induced by chronic postnatal dihydrotestosterone (DHT) exposure. While none of the control mice had estrous cycles, 33% of paxillin knockout mice were cycling, indicating that paxillin deletion may offer partial protection from the negative effects of androgen excess by reducing AR expression. Paxillin-knockout GCs from mice with DHT-induced PCOS also produced more estradiol than GCs from littermate controls. Thus, paxillin may be a novel target in the management of androgen-related disorders in women, such as PCOS.
Topics: Animals; Female; Humans; Mice; Focal Adhesions; Gene Expression Regulation; Granulosa Cells; Mice, Knockout; Paxillin; Receptors, Androgen; Signal Transduction
PubMed: 38718206
DOI: 10.1093/molehr/gaae018 -
Journal of Ethnopharmacology Aug 2024Androgenic alopecia (AGA) is the most prevalent form of hair loss in clinical practice and affects the physical and psychological well-being of adolescents. Paeonia...
ETHNOPHARMACOLOGICAL RELEVANCE
Androgenic alopecia (AGA) is the most prevalent form of hair loss in clinical practice and affects the physical and psychological well-being of adolescents. Paeonia lactiflora Pallas (PL), which is widely used in traditional Chinese medicine, enhances blood function and promotes hair growth, and ellagic acid (EA), a polyphenol in PL extract, shows strong antioxidant, anti-aging, and anti-inflammatory properties and also plays a role in the treatment of various skin conditions. However, its role and mechanism of action in AGA remain unclear.
AIM OF THE STUDY
To determine whether EA can rescue slow hair regeneration by regulating dihydrotestosterone (DHT)-induced ferroptosis in AGA mice and clarify the effect of EA on DHT-induced ferroptosis in dermal papilla cells (DPCs).
MATERIALS AND METHODS
Male C57BL/6 mice were used to establish a DHT-induced AGA mouse model, whereas DPCs were used to establish a DHT-induced cellular model. Thereafter, we investigated the therapeutic mechanism of action of EA via immunofluorescence, western blot analysis, immunohistochemistry, electron microscopy, and molecular docking.
RESULTS
EA stimulated hair regeneration in mice and reversed DHT-induced increases in iron content, lipid peroxidation, and DHT-induced mitochondrial dysfunction by activating the Wnt/β-catenin signaling pathway. Further, β-catenin knockdown suppressed the inhibitory effect of EA on DHT-induced ferroptosis in DPCs.
CONCLUSION
EA inhibits DHT-induced ferroptosis and promotes hair regrowth in mice by activating the Wnt/β-catenin signaling pathway. Thus, it has potential for use as a treatment option for AGA.
Topics: Animals; Male; Mice; Alopecia; beta Catenin; Dihydrotestosterone; Ellagic Acid; Ferroptosis; Hair; Mice, Inbred C57BL; Regeneration; Wnt Signaling Pathway
PubMed: 38685364
DOI: 10.1016/j.jep.2024.118227 -
Nutrients Apr 2024Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate, associated with lower urinary tract symptoms (LUTSs). Taraxaci Herba (TH), commonly...
Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate, associated with lower urinary tract symptoms (LUTSs). Taraxaci Herba (TH), commonly known as dandelion, has traditionally been utilized in East Asia to treat symptoms related to LUTSs. Based on this traditional use, our study aimed to explore the inhibitory effects of TH on BPH progression using a testosterone propionate-induced rat model. To induce BPH, male Sprague Dawley rats were castrated and injected subcutaneously with testosterone propionate (3 mg/kg/day) for 28 days. Concurrently, TH extract was administered orally at doses of 100 and 300 mg/kg/day throughout the four-week period of testosterone propionate injections. The TH extract significantly reduced both the absolute and relative weights of the prostate, along with histopathological changes in the gland. Moreover, it lowered serum levels of testosterone and dihydrotestosterone and reduced the expression of the androgen receptor in the prostate. Additionally, the TH extract modulated the protein expressions of Bax and Bcl-2, which are key regulators of apoptosis in prostate cells. Collectively, our findings suggest that TH inhibits BPH development partially by modulating androgen signaling and inducing apoptosis within the prostate.
Topics: Male; Animals; Prostatic Hyperplasia; Testosterone Propionate; Rats, Sprague-Dawley; Prostate; Plant Extracts; Rats; Apoptosis; Disease Models, Animal; Testosterone; Receptors, Androgen; Dihydrotestosterone; bcl-2-Associated X Protein; Proto-Oncogene Proteins c-bcl-2
PubMed: 38674879
DOI: 10.3390/nu16081189 -
The Journal of Steroid Biochemistry and... Jul 2024Mud crab (Scylla paramamosain) has become an important mariculture crab along the southeast coast of China due to its strong adaptability, delicious taste, and rich...
Mud crab (Scylla paramamosain) has become an important mariculture crab along the southeast coast of China due to its strong adaptability, delicious taste, and rich nutrition. Several vertebrate steroid hormones and their synthesis-related genes and receptors have been found in crustaceans, but there are few reports on their synthesis process and mechanism. 3-beta-hydroxysteroid dehydrogenase (HSD3B) is a member of the Short-chain Dehydrogenase/Reductase (SDR) family, and an indispensable protein in vertebrates' steroid hormone synthesis pathway. In this study, the SpHsd3b gene sequence was obtained from the transcriptome data of S. paramamosain, and its full-length open reading frame (ORF) was cloned. The spatial and temporal expression pattern of SpHsd3b was performed by quantitative real-time PCR (qRT-PCR). SpHsd3b dsRNA interference (RNAi) and HSD3B inhibitor (trilostane) were used to analyze the function of SpHSD3B. The results showed that the SpHsd3b gene has an 1113 bp ORF encoding 370 amino acids with a 3β-HSD domain. SpHSD3B has lower homology with HSD3B of vertebrates and higher homology with HSD3B of crustaceans. SpHsd3b was expressed in all examined tissues in mature crabs, and its expression was significantly higher in the testes than in the ovaries. SpHsd3b expression level was highest in the middle stage of testicular development, while its expression was higher in the early and middle stages of ovarian development. RNAi experiment and trilostane injection results showed that SpHSD3B had regulatory effects on several genes related to gonadal development and steroid hormone synthesis. 15-day trilostane suppression could also inhibit ovarian development and progesterone level of hemolymph. According to the above results, crustaceans may have steroid hormone synthesis pathways like vertebrates, and the Hsd3b gene may be involved in the gonadal development of crabs. This study provides further insight into the function of genes involved in steroid hormone synthesis in crustaceans.
Topics: Animals; Brachyura; Female; Male; Phylogeny; Amino Acid Sequence; 3-Hydroxysteroid Dehydrogenases; Ovary; Cloning, Molecular; RNA Interference; Dihydrotestosterone
PubMed: 38670516
DOI: 10.1016/j.jsbmb.2024.106529 -
The Science of the Total Environment Jul 2024Pentachlorophenol (PCP), a typical environmental endocrine disruptor and a new persistent organic pollutant, has been extensively used as a pesticide worldwide. Although...
Pentachlorophenol (PCP), a typical environmental endocrine disruptor and a new persistent organic pollutant, has been extensively used as a pesticide worldwide. Although its use has been restricted for decades, PCP remains prevalent in both the environment and human bodies. Despite the known endocrine-disrupting and exogenous hormonal effects of PCP, few epidemiological studies examined such impact, especially among sensitive populations and during critical periods. Based on a prospective birth cohort in Wuhan, China, we collected maternal (first trimester; 13.0 ± 1.02 gestational weeks) and infant urine samples (1.16 ± 0.22 months postpartum) from 720 mother-infant pairs. We aimed to examine the association of PCP exposure during early pregnancy with maternal and infant urinary sex steroid hormones, including estrogens (estrone, E1; estradiol, E2; estriol, E3), progestogens (progesterone, P4; pregnenolone, P5; 17α-OH-Progesterone, 17OHP4; 17α-OH-Pregnenolone, 17OHP5), and androgens (testosterone, Testo; dihydrotestosterone, DHT; dehydroepiandrosterone, DHEA; androstenedione, A4). Additionally, gonadotropins [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)] were measured in infant urine. Detection frequencies of all the sex steroid hormones in the maternal urine samples (>99 %) were higher than those in the infants' [most ≥80 %, except for E1 (3.36 %) and E2 (21.4 %)]. Maternal urinary PCP concentration was found to be significantly related with increased maternal sex steroid hormone concentrations; each interquartile increase in PCP concentration was positively related with percent change of the hormones (%Δ) ranging from 26.6 % to 48.5 %. On the other hand, maternal PCP exposure was associated with significantly increased P4 in male infants [%Δ (95 % confidence interval): 10.5 (0.56, 21.4)] but slightly decreased P4 in female infants [-11.9 (-21.8, 0.68)]. In addition, maternal PCP exposure was significantly associated with decreased FSH [%Δ (95 % CI): -9.90 (-17.0, -2.18)] and LH [-8.44 (-16.0, -0.19)] in the female infants, but not in the male infants. Sensitivity analyses, excluding infertility related treatment, pregnancy complications, preterm birth, or low birth weight, showed generally consistent results. Our findings implied that maternal/prenatal PCP exposure might disrupt the homeostasis of maternal and infant reproductive hormones. However, further studies are needed to confirm the findings.
Topics: Humans; Female; Pregnancy; Pentachlorophenol; China; Maternal Exposure; Adult; Endocrine Disruptors; Infant; Male; Infant, Newborn; Environmental Pollutants; Gonadal Steroid Hormones; Cohort Studies; Prospective Studies
PubMed: 38670355
DOI: 10.1016/j.scitotenv.2024.172723 -
Molecular Medicine Reports Jun 2024Polycystic ovary syndrome (PCOS) is a globally prevalent gynecological disorder among women of childbearing age. The present study aimed to investigate the role of...
Polycystic ovary syndrome (PCOS) is a globally prevalent gynecological disorder among women of childbearing age. The present study aimed to investigate the role of tenascin C (TNC) in PCOS and its potential mechanisms. Fasting blood glucose and serum insulin, the homeostasis model assessment of insulin resistance and the serum hormone levels were determined in PCOS rats. In addition, H&E staining was used for assessing pathology. In addition, the effects of TNC on oxidative stress and inflammation response in PCOS rat and cell models was assessed. Furthermore, the roles of TNC on KGN cell proliferation and apoptosis were determined employing EdU assay and flow cytometry. TLR4/NF‑κB pathway‑related proteins were measured using western blotting, immunofluorescence and immunohistochemistry. It was found that the mRNA and protein expression was upregulated in PCOS rats and in KGN cells induced by dihydrotestosterone (DHT). Knockdown of TNC relieved the pathological characteristics and the endocrine abnormalities of PCOS rats. Knockdown of TNC inhibited ovarian cell apoptosis, oxidative stress and inflammation in PCOS rats. Knockdown of TNC reversed the DHT‑induced reduction in cell proliferation and increase in apoptosis in KGN cells. Furthermore, knockdown of TNC alleviated oxidative stress and inflammatory responses induced by DHT in KGN cells. Additionally, knockdown of TNC inhibited the toll‑like receptor 4 (TLR4)/NF‑κB signaling pathway in PCOS rats and DHT‑treated KGN cells. In conclusion, knockdown of TNC could ameliorate PCOS in both rats and a cell model by inhibiting cell apoptosis, oxidative stress and inflammation via the suppression of the TLR4/NF‑κB signaling pathway.
Topics: Polycystic Ovary Syndrome; Female; Animals; Toll-Like Receptor 4; Signal Transduction; NF-kappa B; Rats; Tenascin; Cell Proliferation; Oxidative Stress; Apoptosis; Disease Models, Animal; Rats, Sprague-Dawley; Insulin Resistance; Humans; Cell Line
PubMed: 38666538
DOI: 10.3892/mmr.2024.13230 -
The Journal of Neuroscience : the... Jun 2024Aggression is a crucial behavior that impacts access to limited resources in different environmental contexts. Androgens synthesized by the gonads promote aggression...
Aggression is a crucial behavior that impacts access to limited resources in different environmental contexts. Androgens synthesized by the gonads promote aggression during the breeding season. However, aggression can be expressed during the non-breeding season, despite low androgen synthesis by the gonads. The brain can also synthesize steroids ("neurosteroids"), including androgens, which might promote aggression during the non-breeding season. Male song sparrows, , are territorial year-round and allow the study of seasonal changes in the steroid modulation of aggression. Here, we quantified steroids following a simulated territorial intrusion (STI) for 10 min in wild adult male song sparrows during the breeding and non-breeding seasons. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we examined 11 steroids: pregnenolone, progesterone, corticosterone, dehydroepiandrosterone, androstenedione, testosterone, 5α-dihydrotestosterone, 17β-estradiol, 17α-estradiol, estriol, and estrone. Steroids were measured in blood and 10 microdissected brain regions that regulate social behavior. In both seasons, STI increased corticosterone in the blood and brain. In the breeding season, STI had no rapid effects on androgens or estrogens. Intriguingly, in the non-breeding season, STI increased testosterone and androstenedione in several behaviorally relevant regions, but not in the blood, where androgens remained non-detectable. Also in the non-breeding season, STI increased progesterone in the blood and specific brain regions. Overall, rapid socially modulated changes in brain steroid levels are more prominent during the non-breeding season. Brain steroid levels vary with season and social context in a region-specific manner and suggest a role for neuroandrogens in aggression during the non-breeding season.
Topics: Animals; Male; Seasons; Aggression; Androgens; Brain; Sparrows; Territoriality; Songbirds
PubMed: 38658166
DOI: 10.1523/JNEUROSCI.1095-23.2024 -
Water Research Jun 2024The safety of municipal sewage sludge has raised great concerns because of the accumulation of large-scale endocrine disrupting chemicals in the sludge during wastewater...
The safety of municipal sewage sludge has raised great concerns because of the accumulation of large-scale endocrine disrupting chemicals in the sludge during wastewater treatment. The presence of contaminants in sludge can cause secondary pollution owing to inappropriate disposal mechanisms, posing potential risks to the environment and human health. Effect-directed analysis (EDA), involving an androgen receptor (AR) reporter gene bioassay, fractionation, and suspect and nontarget chemical analysis, were applied to identify causal AR agonists in sludge; 20 of the 30 sludge extracts exhibited significant androgenic activity. Among these, the extracts from Yinchuan, Kunming, and Shijiazhuang, which held the most polluted AR agonistic activities were prepared for extensive EDA, with the dihydrotestosterone (DHT)-equivalency of 2.5 - 4.5 ng DHT/g of sludge. Seven androgens, namely boldione, androstenedione, testosterone, megestrol, progesterone, and testosterone isocaproate, were identified in these strongest sludges together, along with testosterone cypionate, first reported in sludge media. These identified androgens together accounted for 55 %, 87 %, and 52 % of the effects on the sludge from Yinchuan, Shijiazhuang, and Kunming, respectively. This study elucidates the causative androgenic compounds in sewage sludge and provides a valuable reference for monitoring and managing androgens in wastewater treatment.
Topics: Sewage; China; Androgens; Water Pollutants, Chemical; Endocrine Disruptors; Receptors, Androgen
PubMed: 38657313
DOI: 10.1016/j.watres.2024.121652 -
Beneficial Microbes Nov 2023Benign prostatic hyperplasia (BPH) can cause urethral compression, bladder stone formation, and renal function damage, which may endanger the life of patients....
Benign prostatic hyperplasia (BPH) can cause urethral compression, bladder stone formation, and renal function damage, which may endanger the life of patients. Therefore, we aimed to develop plant-based preparations for BPH treatment with no side effects. In this study, the Lactiplantibacillus plantarum 322Hp, Lactobacillus acidophilus 322Ha, and Limosilactobacillus reuteri 322Hr were used to ferment rape pollen. The fermented rape pollen was subsequently converted into fermented rape pollen powder (FRPP) through vacuum freeze-drying technology. After fermenting and drying, the bioactive substances and antioxidant capacity of FRPP were significantly higher than those of unfermented rapeseed pollen, and FRPP had a longer storage duration, which can be stored for over one year. To investigate the therapeutic effect of FRPP on BPH, a BPH rat model was established by hypodermic injection of testosterone propionate. The BPH rats were treated differently, with the model group receiving normal saline, the positive control group receiving finasteride, and the low, medium, and high dose FRPP group receiving FRPP at doses of 0.14 g/kg/d, 0.28 g/kg/d, and 0.56 g/kg/d, respectively. The results indicate that medium dose FRPP reduced the levels of hormone such as testosterone, dihydrotestosterone, and oestradiol in rats with BPH by about 32%, thus bringing the prostate tissue of BPH rats closer to normal. More importantly, medium dose FRPP treatment had a significant effect on the composition of gut microbiota in rats with BPH, increasing the levels of beneficial genera (such as Coprococcus and Jeotgalicoccus), and decreasing the levels of harmful pathogens (such as Turicibacter and Clostridiaceae_Clostridium) in the gut. This study showed that medium dose FRPP reduced the hormone level and regulated the unbalanced gut microbiota in BPH rats, thereby alleviating BPH.
Topics: Male; Animals; Pollen; Gastrointestinal Microbiome; Rats; Prostatic Hyperplasia; Powders; Fermentation; Rats, Sprague-Dawley; Disease Models, Animal; Testosterone; Dihydrotestosterone; Brassica rapa; Prostate; Brassica napus; Lactobacillus plantarum; Testosterone Propionate; Hormones
PubMed: 38656098
DOI: 10.1163/18762891-20230039 -
ACS Chemical Neuroscience May 2024Neuroactive steroids are a group of steroid molecules that are involved in the regulation of functions of the nervous system. The nervous system is not only the site of...
Neuroactive steroids are a group of steroid molecules that are involved in the regulation of functions of the nervous system. The nervous system is not only the site of their action, but their biosynthesis can also occur there. Neuroactive steroid levels depend not only on the physiological state of an individual (person's sex, age, diurnal variation, etc.), but they are also affected by various pathological processes in the nervous system (some neurological and psychiatric diseases or injuries), and new knowledge can be gained by monitoring these processes. The aim of our research was to develop and validate a comprehensive method for the simultaneous determination of selected steroids with neuroactive effects in human serum. The developed method enables high throughput and a sensitive quantitative analysis of nine neuroactive steroid substances (pregnenolone, progesterone, 5α-dihydroprogesterone, allopregnanolone, testosterone, 5α-dihydrotestosterone, androstenedione, dehydroepiandrosterone, and epiandrosterone) in 150 μL of human serum by ultrahigh-performance liquid chromatography with tandem mass spectrometry. The correlation coefficients above 0.999 indicated that the developed analytical procedure was linear in the range of 0.90 nmol/L to 28.46 μmol/L in human serum. The accuracy and precision of the method for all analytes ranged from 83 to 118% and from 0.9 to 14.1%, respectively. This described method could contribute to a deeper understanding of the pathophysiology of various diseases. Similarly, it can also be helpful in the search for new biomarkers and diagnostic options or therapeutic approaches.
Topics: Humans; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Neurosteroids; Steroids; Male; Reproducibility of Results
PubMed: 38655788
DOI: 10.1021/acschemneuro.3c00824