Dihydrotestosterone Research Articles

MiR-423-3p inhibits CTNNBIP1/WNT preventing hyperandrogenic PCOS.

Polycystic ovary syndrome (PCOS) lacks the generally accepted diagnostic biomarkers and targeted therapy. Increasing evidence indicates that microRNAs (miRNAs) play a crucial role in PCOS. Hereby, we tested the functional implications of a novel miRNA (miR-423-3p) as a mediator in the progress of hyperandrogenic PCOS, as well as its potential as a new serum biomarker and therapeutic target for the PCOS. We found significantly decreased miR-423-3p levels in serum, granulosa cells (hGCs), and follicular fluid (FF) of PCOS patients (n = 40) compared to healthy controls (n = 30), and this decrease corroborated in PCOS-like mouse models. The receiver operating characteristic (ROC) curve analysis for circulating miR-423-3p indicated high diagnostic potential as a biomarker, with an area under the curve (AUC) of 82%. miR-423-3p influenced human granulosa cell (KGN) proliferation by directly targeting CTNNBIP1 modulated WNT signaling pathway. We further proved as mechanistic role that the elevated dihydrotestosterone (DHT) inhibited the expression of miR-423-3p via the activation of the androgen receptor, and the overexpression of miR-423-3p normalized the function of androgen-induced GCs. While we overexpressed miR-423-3p, it counteracted androgen-induced dysfunction in GCs. Antiandrogen treatment restored the reproductive phenotypes in letrozole-induced PCOS-like mice and regulated miR-423-3p expression and its downstream effects. Ovarian intrabursal injection of miR-423-3p antagomir in wildtype (WT) mice induced PCOS-like phenotypes, further underscoring its functional role. Our results demonstrated that miR-423-3p emerged as a novel mediator in hyperandrogenic PCOS progression and it holds promise as both a diagnostic biomarker and a therapeutic target.

Effect of Androgens on Human Fascia

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.

2171-LB: A Low-Dose, Portal Dihydrotestosterone Implant Has a Sustained Effect to Improve Glycemic Control and Provides Cardiovascular and Renal Protection in a Large Animal Model of Type 2 Diabetes

Introduction and Objective: In a large animal model of type 2 diabetes (T2D), we have shown that portal, GLP-1-dependent, glucose sensing is impaired and a low-dose dihydrotestosterone (DHT) implant inserted into the area of the portal sensor normalizes glucose metabolism acutely. We evaluated the capacity of portal DHT to achieve sustained remission of diabetes and its impact on cardiovascular and renal function. Methods: Three groups of six minipigs (aged 3yr) were used. In two groups, diabetes was induced (obesogenic diet plus streptozotocin 80 mg/kg, IV). In half of these, a silicon implant delivering 100μg/24H DHT was inserted laparoscopically in the region of the GLP-1r (DHT); the other half received a sham implant (Sham). The third group was fed a non-obesogenic diet (Lean). One year following implant insertion, daily glucose (CGM), fasting plasma insulin, insulin sensitivity (euglycemic hyperinsulinemic clamp), cardiovascular function (HF oscillometry, Doppler ultrasound, and gated 18 FDG PET) and glomerular filtration rate (68 Ga DOTA PET), were measured. Results: Data are presented in the table. Conclusion: In a large animal model of T2D, low-dose, portal DHT administration has sustained effects to improve both glycemic control and insulin sensitivity, and preserves cardiovascular and renal function. Disclosure C. Malbert: None. M.R. Allouche: None. M. Horowitz: None. K.L. Jones: None.

Reduced locomotor activity in an ovarian-intact rat model of PCOS induced by mild exposure to dihydrotestosterone.

Androgen excess is thought to play a crucial role in the onset and progression of polycystic ovary syndrome (PCOS), although the underlying mechanism remains unclear. Using our mild dihydrotestosterone (DHT)-exposed rat model, which more closely reproduces human PCOS phenotypes than conventional models, we examined whether the presence of ovaries is essential in the pathophysiology of PCOS induced by androgen excess. At 26 days of age, female rats were divided into two primary groups: bilaterally ovariectomized (OVX) and sham-operated (intact). Each group was further divided into PCOS (implanted with a tube filled with diluted DHT) and control (implanted with an empty tube) groups. Body weight and food intake were measured weekly. At 58 and 59 days of age, locomotor activity and body temperature were measured. At 87 days of age, brain, blood, and fat tissues were collected and analyzed. Body weight, food intake, adipocyte size, weight of visceral and subcutaneous fat, and serum leptin levels were higher in the intact-PCOS group than the intact-control group, but there were no significant differences between the OVX-PCOS and OVX-control groups. In the intact-PCOS group, compared with the intact-control group, locomotor activity was significantly lower, particularly in the light phase, and body temperature was significantly higher in the darkness phase, whereas there were no significant differences between the OVX-PCOS and OVX-control groups. The effects of androgen might depend on the estrogen milieu, suggesting that the presence of ovaries is essential in the pathophysiologic development and progression of androgen-induced PCOS.

Dihydrotestosterone-androgen receptor signaling suppresses EBV-positive gastric cancer through DNA demethylation-mediated viral reactivation.

Our Kaplan-Meier analysis reveals that gastric cancer patients with high androgen receptor (AR) expression demonstrate poorer survival outcomes compared to those with low AR expression, particularly in patients with characteristics typical of EBV-positive gastric cancer. However, the molecular mechanisms driving this seemingly contradictory relationship have remained poorly understood, as our experimental findings suggest AR signaling actually suppresses tumor growth in EBVaGC. The study utilized AR-positive EBV-infected gastric cancer cell lines treated with dihydrotestosterone (DHT) to investigate molecular pathways. Comprehensive analyses included examination of apoptosis, miRNA expression, signaling pathways, DNA methylation patterns, and viral gene expression. In vivo validation was performed using xenograft models with MKN1-EBV and SNU719 cells to assess tumor growth and immune response. DHT treatment triggered early apoptosis through upregulation of pro-apoptotic miRNAs, particularly miR-204-5p, while activating the PI3K-Akt pathway and enhancing DNA damage response through increased phosphorylation of key proteins. The treatment reduced DNMT3A expression, leading to genome-wide DNA demethylation and increased expression of both lytic (BZLF1) and latent (EBNA1, LMP1) EBV genes. Xenograft studies confirmed these findings, showing reduced tumor growth, increased lymphocyte infiltration, and enhanced viral gene expression specifically in AR-positive tumors. The study reveals that AR signaling suppresses EBV-positive gastric cancer by modulating both cellular apoptosis and EBV reactivation through epigenetic mechanisms. These findings suggest that AR agonists might have therapeutic potential in treating AR-positive EBV-associated gastric cancer.

PCOS endometrium-derived epithelial organoids as a novel model to study endometrial dysfunction.

Are we able to establish endometrium epithelial organoids (EEOs) from endometrial samples obtained from women with PCOS, and do they differ from non-PCOS EEOs? We were able to establish, for the first time, PCOS EEOs which capture endometrial abnormalities present in women with PCOS, including increased inflammation and decreased receptivity-related gene expression. Patient-derived EEOs could serve as a tool to study endometrial dysfunction, as diseased tissue-derived organoid models typically retain the disease-related traits. In PCOS, endometrial dysfunction likely contributes to subfertility and pregnancy complications, yet previous research on the endometrial epithelial compartment has been scarce and, so far, no PCOS-derived EEOs have been established. EEOs were established from endometrial biopsies from two cohorts of women with PCOS-including overweight/obese (O-PCOS, n = 4) and lean (L-PCOS, n = 4)-along with BMI-matched controls (overweight/obese control (O-Ctrl), n = 4; lean control (L-Ctrl), n = 4). EEOs were exposed to combinations of steroid hormones (β-estradiol (E2), progesterone, cAMP, and the Wnt/β-catenin signaling (WNT) inhibitor XAV-939)for 6days to simulate the proliferative or secretory phases of the menstrual cycle, with or without simultaneous androgen exposure with dihydrotestosterone (DHT). Bulk RNA-sequencing was conducted to identify variations in gene expression between PCOS and Ctrl EEOs, while reverse-transcription quantitative PCR RT-qPCR was employed to validate these results. Morphological assessment of EEOs was performed using hematoxylin and eosin staining and immunostaining. The size of EEOs was evaluated after 6days of hormonal exposure. PCOS EEOs from both BMI groups demonstrated increased inflammation-related gene expression (including increased expression of Oncostatin M Receptor (OSMR) and Intercellular Adhesion Molecule 1 (ICAM1)) and showed a reduced diameter compared to their respective control EEOs. The O-PCOS EEOs displayed an aberrant response to steroid exposure with E2 and progesterone (including reduced expression of receptivity-related genes progestagen-associated endometrial protein and leukemia inhibitory factor)as compared to control EEOs. Addition of DHT to the culture media did not affect EEO transcriptome, aligning with the minimal androgen receptor (AR) expression in the EEOs. Sequencing data are available from the corresponding author upon request. The study should be replicated with a larger number of samples and with other PCOS phenotypes apart from different weight categories. Furthermore, as this work is the first one to establish PCOS EEOs, future studies should focus on incorporating other endometrial cell types, including immune cells, in a co-culture system. This novel in vitro organoid model for PCOS captures the endometrial abnormalities present in the two weight categories of women with PCOS, thereby providing a valuable tool to gain insights into PCOS-related endometrial dysfunction. Our findings propose potential links to the increased risk of pregnancy complications in women with PCOS, such as the role of altered receptivity and implantation environment including increased inflammation, which may contribute to aberrant placentation and subsequent placental dysfunction. Jusélius Foundation, Novo Nordisk Foundation, Research Council of Finland, Horizon 2020 Marie-Curie MATER Innovative Training Network (all to T.T.P.), Fund for Scientific Research Flanders-Belgium (FWO, G0A6719N to J.V. and GO99023N to H.V.); KU Leuven Research Fund (C14/21/116 to H.V. and C14/24/152 to J.V.), University of Oulu Scholarship Foundation Grant (to L.L.), and PhD grant of China Scholarship Council (CSC, to M.W.). The authors have no conflicts of interest to declare.

Meloside A Protects Dermal Papilla Cells from DHT-Induced Damage via Androgen Receptor Modulation

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.

Hair growth stimulated by allogenic adipose-derived stem cells supplemented with ATP in a mouse model of dihydrotestosterone-induced androgenetic alopecia

BackgroundAndrogenetic alopecia (AGA), also known as male or female pattern hair loss, is the most prevalent form of alopecia worldwide. Current treatments are based on hormone drugs, topical vasodilators and hair transplants. Newer options include stem cell therapy targeted at recovering the capacity for hair follicle regeneration. This study examines the effects of intradermally administering allogenic adipose-derived stem cells (ASCs) per se or supplemented with ATP in a mouse model of dihydrotestosterone (DHT)-induced AGA.MethodsMale and female C57BL6-strain mice were treated with DHT to induce AGA and then given injections of treatment solution in a defined area of the depilated back skin, and the same injections three days later. The treatments tested were several concentrations of ASCs combined with two ATP formulations. Photographs of the treated zones were taken on days 7, 10, 14, 17 and 21 and subjected to Image J analysis. On day 21, skin samples were also obtained for histological analysis. The main outcome measure was percentage treated surface area showing hair regrowth on treatment days 17 and 21 expressed as five categories: null, poor, moderate, intense and complete (20, 40, 60, 80 and 100% respectively).ResultsThe experimental groups found to show the highest number of male individuals with intense/complete hair regrowth on day 21 were those in which mice received low dose ASCs (1 ∙ 106) combined either with liposomal ATP or non-liposomal ATP. Both these groups showed significant differences compared to controls. In females, while low dose ASC treatments and the high dose ASC + liposomal ATP treatment led to no hair regrowth improvement over the control treatment, medium dose ASC (2 × 106) + non-liposomal ATP gave rise to greater regrowth scores.ConclusionsHair regrowth was improved in all experimental groups in which male mice were administered stem cell solutions supplemented with ATP. In female mice, the highest hair regrowth scores were observed for the medium dose ASC + liposomal ATP treatment.

Androgenetic alopecia - a literature review

Introduction and Purpose: Androgenetic alopecia (AGA) is the most common form of hair loss, affecting both men and women. It involves progressive miniaturization of hair follicles due to dihydrotestosterone (DHT) and genetic factors. AGA has cosmetic and psychological impacts and is linked to systemic conditions such as cardiovascular and metabolic disorders. Although treatments like finasteride and minoxidil are FDA-approved, alternative therapies are being explored to improve outcomes and reduce side effects. This review provides an updated overview of AGA pathogenesis and emerging treatment options. Material and Methods: A comprehensive literature review was conducted, analyzing recent studies on AGA pathophysiology, genetics, and treatments. Findings on FDA-approved drugs, alternative pharmacologic therapies, mesotherapy, and low-level light therapy (LLLT) were evaluated for efficacy and safety. State of Knowledge: AGA pathogenesis includes hormonal, genetic, and environmental components. DHT binds to androgen receptors in vulnerable hair follicles, leading to miniaturization. Genetic susceptibility involves loci like AR/EDA2R. While finasteride and minoxidil remain mainstays, newer treatments—such as dutasteride, androgen receptor antagonists (e.g., spironolactone, clascoterone, pyrilutamide), mesotherapy, and low-dose oral minoxidil—show promise. LLLT, particularly red LED light (630–660 nm), stimulates hair growth and reduces inflammation. Clinical studies suggest combination therapies are more effective than monotherapy. Conclusions: AGA is complex and requires long-term management. Finasteride and minoxidil are effective, but alternative treatments like dutasteride, mesotherapy, androgen blockers, and red LED therapy offer promising results. Combination therapy appears most effective, though more research is needed to standardize protocols and confirm long-term safety.

Plumbagin ameliorates ferroptosis of ovarian granulosa cells in polycystic ovary syndrome by down-regulating SLC7A5 m6A methylation modification through inhibition of YTHDF1

Background and objectivePolycystic ovary syndrome (PCOS) is a common endocrine-metabolic disease in women of reproductive age. One of its core pathologies is ovarian granulosa cell (GC) dysfunction, and ferroptosis, as a novel cell death mode dependent on iron ions and lipid peroxidation, may be involved in the PCOS process, but the exact mechanism is unknown. Plumbagin (PLB) shows potential in PCOS treatment due to its antioxidant properties. The present study aimed to elucidate the molecular mechanisms by which PLB ameliorates mitochondrial dysfunction and ferroptosis in PCOS GCs through the YTH N6-methyladenosine RNA binding protein 1/L-type amino acid transporter 1 (YTHDF1/SLC7A5) axis.MethodsAn in vitro model of PCOS was constructed by treating KGN cells with dihydrotestosterone (DHT), and PLB treatment, YTHDF1 knockdown (si-YTHDF1), and SLC7A5 overexpression (pcDNA 3.1-SLC7A5) were intervened respectively. Cell viability was measured by cell counting kit-8. Lactate dehydrogenase (LDH) release, adenosine triphosphate (ATP) level, iron ion, and lipid peroxidation (LPO) content were detected by commercial kits. Mitochondrial membrane potential (MMP) was analyzed by JC-1 staining combined with flow cytometry. Reactive oxygen species (ROS) levels were assessed by C11-BODIPY probe, oxidative stress indicators including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase were measured by kits, and Cytochrome C, Ferritin, mitochondrial transcription factor A (TFAM), glutathione peroxidase 4 (GPX4) and SLC7A5 expression were detected by Western blot. Fluorescence in situ hybridization, RNA immunoprecipitation, and m6A quantitative real-time polymerase chain reaction verified the interaction and translational regulation of YTHDF1 and SLC7A5.ResultsDHT treatment significantly decreased KGN cell viability, MMP and ATP levels, increased LDH release, ROS, MDA, iron ions and LPO content, up-regulated Cytochrome C expression, and down-regulated Ferritin, TFAM, and GPX4 expression. Both PLB treatment and YTHDF1 knockdown significantly reversed the above changes, but YTHDF1 overexpression reversed the protective effect of PLB. YTHDF1 co-localized with SLC7A5 mRNA and enhanced its translation through m6A modification. YTHDF1 knockdown reduced SLC7A5 protein levels without affecting mRNA expression. SLC7A5 overexpression weakened the protective effect of YTHDF1 knockdown, resulting in decreased cell viability, deterioration of mitochondrial function, and increased ferroptosis.ConclusionPLB ameliorates DHT-induced mitochondrial dysfunction and ferroptosis in KGN cells by inhibiting YTHDF1 expression, and its action is dependent on the mechanism by which YTHDF1 regulates SLC7A5 translation through m6A modification. Downregulating YTHDF1 or SLC7A5 significantly enhances GC survival and function.

Usefulness topical di-hydro testosterone prior to proximal hypospadias repair in testosterone non-responders.

Usefulness topical di-hydro testosterone prior to proximal hypospadias repair in testosterone non-responders.

5α-reductase type 3 is a predictive marker for chemotherapy efficacy in breast cancer in an androgen-independent manner.

5α-reductase type 3 is a predictive marker for chemotherapy efficacy in breast cancer in an androgen-independent manner.

Bioactivity guided identification of sexual function restorative constituents of Carpolobia lutea G. Don roots in paroxetine-induced sexual dysfunction male rats.

Bioactivity guided identification of sexual function restorative constituents of Carpolobia lutea G. Don roots in paroxetine-induced sexual dysfunction male rats.

Role of UVA-driven cellular senescence via mTOR activation in dihydrotestosterone-induced hair loss in androgenetic alopecia mouse model.

Role of UVA-driven cellular senescence via mTOR activation in dihydrotestosterone-induced hair loss in androgenetic alopecia mouse model.

Toward manipulating sex hormones to modulate the adaptive antitumor immune response in liver cancer.

e16246 Background: The incidence and mortality of hepatocellular carcinoma (HCC) is three to seven times greater in men than women after accounting for known environmental risk factors. This longstanding unexplained observation hints at sex-based biological differences, which are thought to be due to male hormone signaling mediated by the transcription factor androgen receptor (AR). AR is detected in 70% of HCC and increased AR activity corresponds with worse HCC outcomes. While AR inhibition is highly effective for the treatment of prostate cancer, clinical trials to inhibit AR signaling in advanced HCC have been unsuccessful to date. Understanding the role of AR in HCC is expected to inform new therapeutic opportunities for this rapidly expanding patient population for which treatment options are currently limited. Methods: Transgenic animal development, molecular biology, RNA-sequencing, in-vitro and ex-vivo assessments. Results: A lack of human-relevant genetically engineered mouse models (GEMMs) of HCC has hindered progress in this area for decades. Therefore, guided by HCC sequencing databases, we developed a new genetically engineered mouse model of HCC using cre-LoxP technology that recapitulates the sex differences observed in human HCC. We demonstrate that AR inhibition via surgical castration suppresses liver tumors while treatment with dihydrotestosterone (DHT) results in large liver tumors in both male and female mice, making the model an ideal platform to functionally assess the role of AR and male sex hormones in a genetically defined organismal model system of HCC. We generated cell lines from these liver tumors and unexpectedly found that while they express AR, they are not overtly responsive to AR signaling manipulations ex-vivo, suggesting the outcomes associated with active AR in HCC may not be due to AR signaling in the tumor cells themselves. In support of this idea, we found that these tumor cell lines engraft and grow at the same rates in gondadectomized immunocompromised nod-scid gamma (NSG) mice with or without DHT supplementation, suggesting a non-cell-autonomous mechanism may account for the greater tumor burden in male mice. Collectively, these observations guided us in developing our central hypothesis that AR signaling suppresses the adaptive antitumor immune response to accelerate HCC progression via immune evasion. Our ongoing efforts to characterize the impact of hormonal manipulations in HCC are expected to lead to new treatments to complement and extend current standard-of-care immunotherapies for HCC. Conclusions: We developed and phenotypically characterized a new genetically engineered mouse model of HCC that recapitulates the sex differences observed in human HCC. This model will serve as a useful platform to study the role of sex hormones in adaptive antitumor immunity in HCC.

O-172 MHR Early career innovator award:Novel actions of paxillin in female reproduction and androgen excess disorders

Abstract 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 tissues. We sought to investigate the relationship between paxillin and AR in granulosa cells (GCs), where androgen actions, apoptosis, and focal adhesions are of established importance, but where the role of paxillin is unknown. We generated GC-specific paxillin knockout mice using the antimullerian hormone receptor 2-driven Cre/lox system. These mice are protected from the reproductive effects of aging and of androgen excess. Paxillin-knockout mice produced more litters than controls at age 24-28 weeks of age due to a shorter time to pregnancy and tended to have a higher ovarian follicle reserve. In a separate experiment, polycystic ovary syndrome-like phenotype was induced by chronic postnatal dihydrotestosterone (DHT) exposure, causing complete cessation of estrous cycles in littermate controls, however 33% of paxillin knockout mice continued to cycle. Mechanistically, we found 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. Depletion of paxillin in mouse GCs or in human granulosa-derived KGN cells results in a reduction of AR protein half-life by approximately one-third, independently of its mRNA expression. 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. Paxillin deletion may offer partial protection from the negative effects of androgen excess by reducing AR expression, making paxillin a novel potential target in the management of androgen-related disorders in women, such as PCOS. Paxillin may also be contributing to the age-related decline of ovarian reserve through androgen signaling or other mechanisms, such as oxidative stress.

Subcutaneous injection of genetically engineered exosomes for androgenic alopecia treatment.

Androgenetic alopecia (AGA) is a common disorder that negatively impacts quality of life but remains challenging to treat effectively. The hair loss observed in AGA is the consequence of a gradual reduction in the duration of the anagen phase concomitant of the miniaturization of the hair follicles and subsequent atrophy. This process of miniaturization is associated with abnormalities in the Dihydrotestosterone (DHT) induced dermal papilla cells (DPCs). DHT induces DPCs senescence and promotes apoptosis of vascular endothelial cells and keratinocytes via the DPCs paracrine pathway, which ultimately leads to follicular miniaturization. In this study, we developed a multifunctional exosome-based targeted delivery platform, designated as EX104, through the engineering of HEK-293 cells to express a combination of therapeutical molecules, including WNT10B, VEGFA, and FGF7. EX104 reversed the hair follicle miniaturization phenotype in DHT-induced DPCs. Furthermore, it demonstrated significant hair growth-promoting effects in the murine model of androgenetic alopecia by remodeling the follicular microenvironment and restoring miniaturized hair follicles. Topical EX104 application demonstrated comparable hair growth promotion to first-line minoxidil, while significantly outperforming it in stimulating capillary growth and follicular proliferation. EX104 represents a promising and innovative strategy for AGA management and follicular regenerative therapy.

Dihydrotestosterone and 17β-estradiol modulate TMJ osteoarthritis development and reveal sex-specific differences in pathogenesis

To investigate the effects and mechanisms of dihydrotestosterone (DHT) and 17β-estradiol on temporomandibular joint osteoarthritis (TMJ-OA) to understand sex differences and apply findings to TMJ-OA prevention and treatment. Ten-week-old male C57BL/6J mice were divided into six groups to study the effects of mechanical stress (MS), aromatase inhibitors (Ai), orchiectomy (ORX), and 17β-estradiol supplementation on TMJ-OA. Interventions included mechanical stress induction and hormone manipulations. Analyses included serum hormone levels, micro-CT, histomorphometry, immunohistochemistry, RT-qPCR for gene expression, and statistical evaluations. ORX and Ai-induced reductions in DHT and 17β-estradiol caused bone loss, including decreased BV/TV and trabecular thickness, and increased trabecular spacing. MS further reduced cartilage thickness, Safranin O-positive areas, and increased osteoclast counts. Matrix metalloproteinase-13(MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) levels were highest in MS + Ai and MS + Ai + ORX groups. In contrast, 17β-estradiol supplementation restored cartilage thickness, reduced osteoclast activity, suppressed inflammatory markers (NFκB, Gremlin 1, RelA), and increased BMP7 expression. The lower incidence of TMJ-OA in males may result from testosterone and DHT being converted to 17β-estradiol by adrenal aromatase, mitigating mechanical stress effects and protecting the temporomandibular joint via the Gremlin-1-NF-κB pathway.

Oxyresveratrol enhances hair regeneration in human dermal papilla cell and androgenetic alopecia mouse model

Alopecia, or hair loss, is a common dermatological condition caused by multiple factors. Oxyresveratrol (ORV), a compound derived from the heartwood of Artocarpus lakoocha, is recognized for its potent antioxidant properties, with recent studies highlighting its anti-inflammatory effect across various cell types. This study aims to explore the therapeutic potential of ORV in treating alopecia. We evaluated the effects of ORV on Human Follicle Dermal Papilla Cells (HFDPCs) and an androgenetic alopecia (AGA) mouse model. Oxidative stress in HFDPCs was induced using hydrogen peroxide (H2O2), and dihydrotestosterone (DHT) was used to simulate AGA in both HFDPCs and C57BL/6NJcl mice. Our finding demonstrated that ORV significantly enhanced HFDPCs proliferation. In H2O2-induced oxidative stress conditions, pretreatment with ORV decreased reactive oxygen species (ROS) levels and reduced the production of pro-inflammatory cytokine. In the AGA model, ORV inhibited β-Catenin phosphorylation in HFDPCs, thereby promoting hair growth and maintaining skin thickness, hair bulb size, and count in mice. Overall, ORV demonstrated anti-inflammatory and hair-regenerative effects in both in vitro and in vivo models of alopecia. These findings suggest that ORV is a promising candidate for the treatment of hair loss.

Androgen Receptor PROTAC ARV-110 Ameliorates Metabolic Complications in a Mouse Model of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. Hyperandrogenemia (HA) is a hallmark of PCOS and is positively associated with metabolic complications. Androgens exert their biological actions through the androgen receptor (AR), which regulates transcriptional activity. Antiandrogens are not recommended for managing metabolic complications in PCOS due to their hepatotoxicity, despite being a viable therapy to treat HA. We hypothesized that the novel AR Proteolysis Targeting Chimera (PROTAC) degrader ARV-110 would downregulate AR protein levels and actions to abolish or mitigate HA-mediated metabolic complications using a well-established HA mouse model of PCOS. Three-week-old female mice were implanted with dihydrotestosterone (DHT) or control pellets. Four weeks later, mice were treated with low- (ARV-110-L, 1 mg/kg.day) or high-dose (ARV-110-H, 10 mg/kg.day) ARV-110 for an additional 8 weeks. ARV-110 dose-dependently reduced AR protein levels in white adipose tissue (WAT), kidney, liver, and ovary. ARV-110 attenuated DHT-induced increases in body weight, fat mass, kidney mass, WAT mass, circulating leptin and antimüllerian hormone, and altered glucose homeostasis. ARV-110-H increased kidney (UACR, KIM-1, NGAL) and liver (ALT, AST, LDH) injury markers and caused severe hepatomegaly, while ARV-110-L mostly spared those deleterious effects. Unbiased proteomics analysis revealed that ARV-110-H treatment severely affected the liver proteome and dysregulated multiple signaling and metabolic canonical pathways, while only minimal effects were observed with ARV-110-L treatment. In summary, our findings underscore the potential of AR PROTACs as a novel therapeutic approach for managing metabolic complications in PCOS, provided the dosing is carefully optimized to avoid adverse effects.