Search Results (194)

Male sex and aging are risk factors for fibro-calcific aortic valve disease (FCAVD), indicating an understudied influence of sex hormones. Valvular interstitial cells (VICs) from female and male donors were isolated and exposed to pro-calcifying medium (PM), and the expression of matrix gla protein (MGP), fibronectin (FN1) and bone morphogenic protein 2 (BMP2) was analyzed. The effect of sex hormones on hydroxyapatite (HA) deposition by VICs was also analyzed. Exposure to PM increased MGP gene expression in male (n = 5, +5.8-fold, p = 0.031), and female VICs (n = 6, +4.9-fold, p = 0.004). In female VICs a +3.5-fold MGP increase accompanied the transition from the fibrotic to the calcific phase (p = 0.022 vs. males) while in male VICs the increase was delayed to the calcific phase. Female VICs upregulated FN1 (+1.8-fold, p = 0.003), while male VICs upregulated BMP2 (+3.7-fold, p = 0.05). 5α-dihydrotestosterone increased HA deposition +6.3-fold in male and +5.2-fold in female VICs (p ≤ 0.001 and p < 0.04, respectively). It further decreased BMP2 (p < 0.001) in male VICs and increased MGP in female VICs (p = 0.087). Female VICs decreased HA deposition when exposed to progesterone (−2.4-fold, p = 0.037 vs. PM) and estrogen (−2.0-fold, p = 0.072). In summary, VICs show donor-sex-specific gene expression which is modifiable by 5α-dihydrotestosterone. This needs to be considered when designing in vitro regulatory studies. Full article

Prostate-specific membrane antigen (PSMA) targeting agents have been the cornerstone of advanced prostate cancer (PCa) management in theranostics due to their high sensitivity for detecting and treating metastatic disease. However, approximately one-third of metastatic castration-resistant PCa (mCRPC) lesions may exhibit low or absent PSMA expression due to tumor heterogeneity, prior androgen deprivation therapy, or loss of androgen receptor expression, subsequently altering their response to PSMA-targeted therapy. The molecular and biological mechanisms underlying PSMA downregulation remain elusive but may include neuroendocrine differentiation or epithelial-to-mesenchymal transition (EMT). This review addresses this knowledge gap by examining recent preclinical and clinical evidence on novel radiotracers with the potential to provide alternative strategies beyond PSMA for imaging and treating PCa. The diagnostic performance and therapeutic potential of three emerging radiotracer classes are discussed, including gastrin-releasing peptide receptor (GRPR) ligands, androgen receptor (AR) ligands, and amino acid analogs. This article further highlights the complementary roles of these radiotracers along with their utility in specific patient populations, such as those with low prostate-specific antigen (PSA), biochemical recurrence (BCR), or confirmed PSMA-negative disease. For instance, GRPR-targeted radiotracers have achieved sensitivity of up to 88% and specificity of up to 90% for detecting primary tumors in PCa. The radiolabeled androgen agonist, fluorine-18 (¹⁸F)-fluoro-5α-dihydrotestosterone (FDHT), has demonstrated 98% true-positive rate in predicting lesions on positron emission tomography (PET) scans of mCRPC patients. On the other hand, the synthetic amino acid analog ¹⁸F-fluciclovine demonstrated a lesion detection rate of 84% for PSA levels at or above 5, and 62.5% for PSA levels ranging from 0.7 to less than 1. This review concludes with future directions on the paradigm of multi-tracer and dual-targeting strategies, which can effectively address challenges associated with PCa tumor heterogeneity and facilitate personalized approaches in theranostics. Full article

Background/Objectives: Androgenetic alopecia (AGA) is the most common hair loss disorder in dermatological practice. Its primary pathogenesis involves the conversion of testosterone to dihydrotestosterone (DHT) by type II 5α-reductase upon reaching dermal papilla cells (DPCs). DHT impairs DPCs’ activity and inhibits hair growth. Although the FDA-approved drugs finasteride and minoxidil show certain efficacy, they are also associated with severe side effects. This study aims to explore the effects of Terminalia chebula fruit extract (TCFE) on hair growth and its underlying molecular mechanisms. Methods: We investigated the therapeutic potential of TCFE in hair follicle regeneration, employing a multi-level experimental approach combining in vitro analyses of DPCs, in vivo animal models of AGA, and ex vivo cultures of human hair follicles and scalp tissue. Results: First, RNA-seq analysis and RT-PCR validation revealed that TCFE treatment activated the Wnt and TGF-β3 signaling pathways in DPCs, particularly upregulating the AKR1C gene family, which is involved in DHT metabolism. TCFE also potently inhibited type II 5α-reductase activity and mitigated DHT-induced damage to DPCs. In an AGA mouse model, TCFE reversed the AGA phenotype with efficacy comparable to finasteride. However, unlike finasteride, TCFE specifically enhanced the expression of AKR1C1 and AKR1C3, indicating a distinct mechanism. Finally, in ex vivo organ cultures, TCFE suppressed hair follicle cell apoptosis, promoted proliferation, and thereby stimulated hair growth. Conclusions: These findings suggest that TCFE is a promising natural treatment for AGA, likely acting through multiple mechanisms, including Wnt pathway activation, 5α-reductase inhibition, and enhanced DHT degradation. Full article

Age-related impaired wounds often become infected with bacteria, leading to substantial mortality and morbidity in the elderly. The decline in androgen levels with increasing age is believed to exacerbate inflammation during wound infections. Despite its well-documented anti-inflammatory activities in wound repair, little is known about the effect of age-related androgen deprivation on bacterial phagocytosis in impaired chronic wounds. The aim of this study was to investigate the effect of age-related testosterone deprivation on the phagocytic functions of THP-1 monocyte-derived macrophages to eliminate Gram-positive and Gram-negative bacteria in vitro. Host–pathogen interaction experiments were conducted to quantify the macrophage-mediated clearance of two common wound-associated bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, under in vitro environments that model testosterone levels representative of those found in elderly males, healthy young adults and testosterone replacement therapy (TRT). Testosterone and its metabolite 5α-dihydrotestosterone (DHT) significantly dampened the macrophage-mediated phagocytosis of both MRSA and P. aeruginosa in a dose-dependent manner (p < 0.05). Blockade of the androgen receptor (AR) using enzalutamide confirmed that testosterone mediates bacterial clearance through binding to the AR. Blocking the conversion of testosterone to DHT through stimulation of macrophages with the 5-α-reductase inhibitor finasteride reversed the testosterone-mediated effects on bacterial clearance, which confirmed that testosterone could potentially dampen the innate phagocytic responses in macrophages through conversion to DHT. Novel findings in this study suggest that the selective manipulation of the AR and/or blockade of testosterone–DHT conversion may provide effective therapeutic treatments to combat wound infections in the elderly. Full article

Purpose: Androgenetic alopecia (AGA) is a common, chronic, non-cicatricial dermatological condition characterized by progressive miniaturization of hair follicles. Although AGA is a benign disorder, it has a considerable impact on patients’ quality of life and psychological health. The current treatment options often demonstrate limited efficacy and are frequently associated with undesirable side effects. This study aimed to co-mill two natural compounds, quercetin (QT) and glycyrrhizic acid (GL), to develop follicle-targeted nanocrystals (NCs), thereby enhancing local accumulation, improving the pathological follicular microenvironment associated with AGA, and promoting hair regrowth. Methods: QT nanocrystals (QT-NCs) were fabricated using a top–down wet media milling technique with GL as a bioactive stabilizer. The resulting QT-NCs were characterized regarding their particle size, crystallinity, morphology, and stability. The skin permeation properties of the QT-NCs were further evaluated in vitro, and their therapeutic efficacy was assessed in a dihydrotestosterone (DHT)-induced AGA mouse model. Results: The QT-NCs exhibited an irregular structure with a particle size ranging from 200 to 300 nm, demonstrating uniform dimensions and excellent storage stability. In vitro permeation studies revealed a 2.27-fold increase in cumulative penetration and a 2.47-fold enhancement in skin retention compared to raw QT. In the DHT-induced AGA mouse model, QT-NCs significantly reduced local DHT levels while concurrently modulating the follicular microenvironment, resulting in markedly improved therapeutic outcomes. Notably, when co-administered, QT and GL demonstrated synergistic pharmacological effects, suggesting potential combinatory benefits. Conclusions: This study presents the first demonstration of QT-NCs for AGA treatment, establishing a novel therapeutic strategy with substantial potential for clinical translation. Full article

Background/Objectives: Benign prostatic hyperplasia (BPH) is a prevalent urological disorder in aging men, characterized by the enlargement of prostate epithelial and stromal cells, which leads to lower urinary tract symptoms. Paeonol, a bioactive compound derived from Moutan Cortex (Paeonia suffruticosa), exhibits multiple pharmacological properties; however, its therapeutic potential in BPH remains unclear. This study aimed to elucidate the mechanisms of paeonol in BPH treatment using network pharmacology and in vivo experiments. Methods: Network pharmacology and molecular docking were conducted to identify potential targets of paeonol against BPH. For the in vivo study, testosterone-induced BPH rat models were employed, and efficacy was evaluated through prostate weight assessment, histological examination, and the quantitative real-time polymerase chain reaction (qRT-PCR) analysis of prostate tissues. Results: In silico analysis revealed key signaling pathways involved in apoptosis, proliferation, phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt), and inflammation. Paeonol administration significantly reduced prostate weight, volume, and histological hyperplasia in BPH rats. qRT-PCR analysis demonstrated that paeonol may suppress dihydrotestosterone production by inhibiting 5α-reductase 2 (5AR2) and the androgen receptor (AR), while also downregulating local growth factors, alpha serine/threonine-protein kinase (Akt1), nuclear factor-κB (NF-κB), and glutathione reductase (GR) expression. Conclusions: These findings provide novel insights into the multitargeted therapeutic potential of paeonol in BPH by inhibiting 5AR and AR and suppressing proliferation via NF-κB and Akt pathway modulation. Full article

Background/Objectives: Androgenetic alopecia suppresses hair follicle growth. This occurs via dihydrotestosterone (DHT), which inhibits key molecular pathways such as Wnt/β-catenin and Sonic Hedgehog (SHH) signaling. Exosomes derived from plant callus cultures are promising biomaterials for targeted delivery and regenerative medicine. This study aimed to investigate the protective effects of hemp seed callus-derived exosomes (E40) against DHT-induced inhibition of feather follicle development in a chicken embryo model. Methods: E40 exosomes were isolated and purified from the calli of germinated hemp seeds. A DHT-induced feather loss model was established by injecting chicken embryos on embryonic day 7 (E7) with DHT (50 ng/mL), with or without co-administration of E40 (40 µg/mL). On embryonic day 12 (E12), feather length, density, and expression of molecular markers were analyzed. The methods included FISH, Western blotting, and quantitative analysis of PTCH1, AR, SHH, SMO, GLI1, Wnt, β-catenin, BMP4, and Noggin. Results: DHT treatment significantly reduced feather length and density. It also downregulated SHH and Wnt/β-catenin markers, upregulating BMP4 and androgen receptor expression. Co-treatment with E40 restored feather length and density to levels comparable to controls and significantly recovered the expression of SHH, SMO, GLI1, Wnt, and β-catenin. E40 also suppressed DHT-induced BMP4 upregulation by approximately 30% and reduced androgen receptor expression. Conclusions: These results suggest that hemp seed-derived exosomes (E40) effectively mitigate DHT-induced feather follicle inhibition by modulating critical signaling pathways and immune-related markers, supporting their potential application as a nanocarrier-based therapeutic strategy for alopecia management. Full article

Androgenetic alopecia (AGA) is a common progressive hair loss disorder driven by elevated dihydrotestosterone (DHT) levels, leading to follicular miniaturization. This study investigated sulforaphane-rich broccoli sprout extract (BSE) as a potential oral therapy for AGA. BSE exhibited dose-dependent proliferative and migratory effects on keratinocytes, dermal fibroblasts, and dermal papilla cells, showing greater in vitro activity than sulforaphane (SFN) and minoxidil under the tested conditions, while maintaining low cytotoxicity. In a testosterone-induced AGA mouse model, oral BSE significantly accelerated hair regrowth, with 20 mg/kg achieving 99% recovery by day 15, alongside increased follicle length, density, and hair weight. Mechanistically, BSE upregulated hepatic and dermal DHT-metabolizing enzymes (Akr1c21, Dhrs9) and activated Wnt/β-catenin signaling in the skin, suggesting dual actions via androgen metabolism modulation and follicular regeneration. Pharmacokinetic analysis revealed prolonged SFN plasma exposure following BSE administration, and in silico docking showed strong binding affinities of key BSE constituents to Akr1c2 and β-catenin. No systemic toxicity was observed in liver histology. These findings indicate that BSE may serve as a safe, effective, and multitargeted natural therapy for AGA. Further clinical studies are needed to validate its efficacy in human populations. Full article

The inhibition of steroid 5-alpha reductase (S5AR), a key mechanism for managing dihydrotestosterone-dependent conditions, has been demonstrated in teak (Tectona grandis L.f.) leaf extracts. Our recent clinical study confirmed the effectiveness of a hair growth formulation containing teak leaf extract in males with androgenic alopecia. However, significant variability in S5AR inhibitory activity among teak leaf samples from different regions underscores the need for quality control of raw materials. This study applied a metabolomics approach to investigate the influence of leaf age, harvesting period, and geographic origin on chemical composition and S5AR inhibitory activity, as well as to identify active S5AR inhibitors. Geographic origin emerged as the primary determinant of variations in chemical profiles and S5AR inhibitory activity. Using orthogonal partial least squares analysis, six diterpenoid S5AR inhibitors were identified, including four compounds reported for the first time as S5AR inhibitors: rhinocerotinoic acid, 7-oxo-8-labden-15-oic acid, 8-hydroxy-labd-13-en-15-oic acid, and a novel diterpene, 7-hydroxy-labd-8,13-dien-15-oic acid. These findings highlight the potential of metabolomics as a powerful tool for discovering bioactive compounds and optimizing raw material selection. By prioritizing proven geographic sources, consistent bioactivity can be achieved, supporting the therapeutic potential of teak leaves in managing S5AR-related conditions. Full article

Androgens are emerging as important regulators of connective tissue remodeling, but current knowledge about their role in human fascia is still limited. This study examined the expression of the androgen receptor (AR) in human deep fascia and investigated the effects of dihydrotestosterone (DHT) on collagen production by fascial fibroblasts. Fascia lata and thoracolumbar fascia samples were collected from four adult donors (two male and two female). AR expression was assessed by immunohistochemistry and immunocytochemistry. Fascial fibroblasts were treated in vitro for 24 h with DHT at concentrations reflecting physiological levels: 0.4 ng/mL (female), 4 ng/mL (male average), and 10 ng/mL (high male dose). Collagen content was quantified using Picrosirius Red staining, and collagen I and III were evaluated using immunocytochemistry and image analysis, and were compared to an untreated control group. AR was detected in all samples. Low-dose DHT (0.4 ng/mL) significantly increased collagen I (4.80 ± 1.75%) and decreased collagen III (3.32 ± 0.46%) compared to controls (2.09 ± 0.91% and 10.46 ± 0.53%, respectively; p < 0.05). Higher DHT doses induced smaller or no significant changes in collagen subtype expression (e.g., 10 ng/mL: 2.03 ± 0.81% for collagen I, 8.49 ± 1.85% for collagen III). The results demonstrated that human fascia is hormonally responsive via AR, with DHT modulating matrix composition in a dose-dependent manner. The distinct effects at male and female levels may help explain gender differences in fascial stiffness and pain. Full article

Androgenetic alopecia (AGA) is associated with dihydrotestosterone (DHT)-induced apoptosis in human dermal papilla cells (HDPCs) via androgen receptor (AR) upregulation. This study aimed to evaluate the potential of Cucumis melo var. makuwa leaf extract (CLE) to attenuate these DHT-mediated effects in HDPCs. HDPCs were treated with CLE, and DHT-induced apoptosis and AR expression were assessed. High-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC–ESI–MS) identified Meloside A as the principal bioactive constituent within CLE. CLE significantly attenuated DHT-induced apoptosis in HDPCs, demonstrating a 57.74% reduction at 1000 ppm. Mechanistically, Meloside A inhibited DHT-stimulated AR nuclear translocation and reduced AR protein expression. Furthermore, Meloside A decreased the expression of downstream target genes at 100 ppm, showing a 16.27% reduction in IL-6, a 26.55% reduction in TGF-β1, and a 35.38% reduction in DKK-1. Additionally, Meloside A significantly inhibited ROS generation within DHT-stimulated HDPCs by 45.45% at 100 ppm. These findings suggest that Meloside A, isolated from CLE, exerts anti-AGA effects by modulating AR nuclear translocation and gene expression. This highlights its potential as a therapeutic agent for AGA and provides a basis for developing novel therapeutic strategies for hair loss. Full article

Androgenetic alopecia (AGA) is a prevalent form of non-scarring hair loss, affecting approximately 32.13% of the population. Seborrheic alopecia is the most frequently observed among its various types, contributing to over 25% of hair loss cases in men. Identifying effective natural compounds or therapeutic agents that stimulate hair growth remains a key research focus. Platycladus orientalis L., known for its medicinal properties, shows potential in promoting hair darkening and regeneration, although its mechanisms remain unclear. In this study, Fr2 of Platycladus orientalis L. was found to significantly enhance hair growth in mice. Similarly, (7E)-7,8-Dehydroheliobuphthalmin (DHHB) was successfully isolated and purified for the first time through a combination of medium-pressure liquid chromatography and two-dimensional high-performance liquid chromatography. In an alopecia areata (AGA) model using dermal papilla cells (DPCs), DHHB was found to significantly promote cell proliferation and differentiation by down-regulating the expression of androgen receptor (AR) proteins, and activating the Wnt/β-catenin signaling pathway, as compared with the dihydrotestosterone-induced model group. These results indicate that DHHB is a major bioactive compound in Platycladus orientalis L. and represents a promising candidate for promoting hair growth. Full article

Background: Polycystic ovary syndrome (PCOS) is a common female endocrine disorder characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. While canonical androgens like testosterone (T) and dihydrotestosterone (DHT) are well studied in PCOS pathophysiology, the role of 11-ketotestosterone (11KT) remains unclear. This study investigates the differential effects of these androgens on folliculogenesis, ovulation, and steroidogenesis using in vivo and in vitro models. Methods: Four-week-old female C57BL/6 mice received T, DHT, or 11KT for six weeks. The assessments included body weight, estrous cyclicity, serum hormone profiles, ovarian histology, and follicle classification. In parallel, large preantral follicles were cultured with each androgen to evaluate follicle growth, antrum formation, and ovulation capacity. Androgen receptor (AR) signaling and steroidogenic function were analyzed using western blotting, RT-qPCR, and luciferase reporter assays. Results: The DHT-treated mice exhibited increased weight gain, whereas 11KT-treated mice showed reduced weight gain. T and DHT disrupted the estrous cycle, while 11KT prolonged diestrus. All androgen treatments led to ovarian morphological changes, including follicular arrest and cystic features. In vitro, all androgens enhanced follicle growth, but only T and DHT inhibited ovulation. The AR expression was elevated across all androgen-treated groups, but only DHT significantly activated AR and CYP19A1 promoters. Conclusions: 11KT induces a distinct and milder PCOS-like phenotype compared to classical androgens, promoting follicle growth with minimal impact on ovulation or steroidogenic disruption. These findings underscore the heterogeneity of PCOS and suggest that different androgen profiles may drive diverse clinical phenotypes. By elucidating the distinct roles of different androgens, this may lead to better stratification of PCOS phenotypes based on predominant androgen types for more precise diagnosis and individualized management. Full article

Hair loss is often associated with oxidative stress and mitochondrial dysfunction in human follicle dermal papilla cells (HFDPCs), resulting in impaired cellular function and follicle degeneration. Thus, many studies have been conducted on natural plants aimed at inhibiting hair loss. This study investigated the therapeutic potential of exosomes derived from the rhizomes of Iris germanica L. (Iris-exosomes) in HFDPCs damaged by dihydrotestosterone (DHT). Iris-exosomes significantly reduced reactive oxygen species (ROS) levels, restoring mitochondrial membrane potential and ATP production, thereby mitigating oxidative stress and improving mitochondrial function. These effects occurred alongside enhanced cellular processes critical for hair follicle regeneration, including increased cell migration, alkaline phosphatase (ALP) activity, and three-dimensional (3D) spheroid formation, which replicates the follicle-like microenvironment and promotes inductive potential. Furthermore, Iris-exosomes stimulated the Wnt/β-catenin signaling pathway by enhancing glycogen synthase kinase-3β (GSK-3β), AKT, and extracellular signal-regulated kinase (ERK), leading to β-catenin stabilization and nuclear translocation, thereby supporting the expression of genes essential for hair growth. Taken together, these findings suggest that Iris-exosomes can be promising ingredients for alleviating hair loss. Full article

Hair loss, a prevalent condition affecting individuals across various demographics, is associated with hormonal imbalances, oxidative stress, inflammation, and environmental factors. This study evaluated the anti-hair loss potential of the water-soluble fraction of Rhus semialata gall extract (WRGE) and its primary component, Penta-O-Galloyl-β-D-Glucose (PGG), through both in vitro and clinical studies. WRGE was obtained using a standardized extraction process, and PGG was identified via HPLC-DAD and HRESIMS/MS techniques. Human dermal papilla cells (HDPCs) are specialized fibroblasts that can regulate the hair growth cycle and hair follicle growth. HDPCs are widely used in research focused on anti-hair loss. In this study, the anti-hair loss effects of WRGE and PGG on HDPCs were confirmed. WRGE and PGG enhance cell proliferation in HDPCs. These results are associated with the activation of the Wnt/β-catenin signaling pathway and the upregulation of hair growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and fibroblast growth factor (FGF). Furthermore, WRGE and PGG significantly inhibited dihydrotestosterone (DHT)-mediated DKK-1 secretion and H₂O₂-medicated cytotoxicity. Clinical trials further validated these results, demonstrating significant improvements in hair density and visual hair appearance scores in participants treated with WRGE compared to a placebo group. These results collectively suggest that WRGE and PGG may serve as promising natural agents for the prevention and treatment of hair loss by targeting multiple biological pathways, including the regulation of hair growth factors, oxidative stress, and hormonal imbalances. Full article