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Molecules (Basel, Switzerland) Feb 2024β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer's disease...
β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer's disease therapeutic, due to its medicinal properties. The effects of NMN on the growth of mouse hair were observed after hair removal. The results indicated that NMN can reverse the state of hair follicle atrophy, hair thinning, and hair sparsity induced by dihydrotestosterone (DHT), compared to that of minoxidil. In addition, the action mechanisms of NMN promoting hair growth in cultured human dermal papilla cells (HDPCs) treated with DHT were investigated in detail. The incubation of HDPCs with DHT led to a decrease in cell viability and the release of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1Beta (IL-1β) and tumor necrosis factor Alpha (TNF-α). It was found that NMN can significantly lower the release of inflammatory factors induced by DHT in HDPCs. HDPCs cells are protected from oxidative stress damage by NMN, which inhibits the NF-κB p65 inflammatory signaling pathway. Moreover, the levels of androgen receptor (AR), dickkopf-1 (DKK-1), and β-catenin in the HDPCs were assessed using PCR, indicating that NMN can significantly enhance the expression of VEGF, reduced IL-6 levels and suppress the expression of AR and DKK-1, and notably increase β-catenin expression in DHT-induced HDPCs.
Topics: Animals; Mice; Humans; beta Catenin; Nicotinamide Mononucleotide; Interleukin-6; Hair; Hair Follicle; Dihydrotestosterone; Cell Proliferation; Oxidative Stress
PubMed: 38398550
DOI: 10.3390/molecules29040798 -
Heliyon Feb 2024Androgenetic alopecia (AGA) is the most common form of hair loss. Studies have suggested a potential link to metabolic disorders, but with conflicting results. To...
BACKGROUND
Androgenetic alopecia (AGA) is the most common form of hair loss. Studies have suggested a potential link to metabolic disorders, but with conflicting results. To elucidate the lipidomics profile and sex-specific variations in AGA, while exploring correlation between AGA and metabolic syndrome (MetS).
METHODS
The AGA patients (n = 83) and healthy controls (n = 84) were collected in the study. The lipid profiles were analyzed using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Serum levels of important factors associated with AGA, namely dihydrotestosterone (DHT), prostaglandin D (PGD) and transforming growth factor-β1 (TGF-β1) were quantified using ELISA.
RESULTS
Compared with controls, AGA patients had a higher probability of MetS (26.51% vs 11.9%, < 0.05). Fifty-one differentially expressed lipids were identified in AGA. The kind of triglyceride (TG) were significantly increased, while phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), and phosphatidylserine (PS) exhibited remarkable decrease. PC (16:2/21:6), PC (34:4p), PE (41:7), PE (44:12), PG (40:9), PI (32:2) and TG (15:0/18:1/18:1) were identified as potential biomarkers of AGA with the highest specificity. The levels of DHT, PGD and TGF-β1 were significantly elevated in AGA. All seven lipids showed significant correlations with DHT, PC (34:4p) and TG (15:0/18:1/18:1) were significantly associated with PGD, TGF-β1 displayed exclusively correlation with TG (15:0/18:1/18:1) (all < 0.05). Furthermore, these lipids were also significantly linked to systolic blood pressure and BMI, while some of them also showed significant associations with total cholesterol and HDL-C. In subgroups, forty-two differentially expressed lipids were identified in male AGA vs male control and eighty-one in female AGA vs female control. PC (16:2/21:6) was the only specific lipids common to both sexes.
CONCLUSIONS
Aberrant lipid metabolism was observed in AGA, with distinct lipidomic profiles between male and female AGA. The potential biomarkers were closely related to DHT, PGD, TGF-β1 and MetS-related indicators. It provides the foundation for revealing the mechanisms of AGA.
PubMed: 38390155
DOI: 10.1016/j.heliyon.2024.e26204 -
ACS Omega Feb 2024The stereoselective reduction of the steroidal 4-ene-3-ketone moiety (enone) affords the 5β-steroid backbone that is a key structural element of biologically important...
The stereoselective reduction of the steroidal 4-ene-3-ketone moiety (enone) affords the 5β-steroid backbone that is a key structural element of biologically important neuroactive steroids. Neurosteroids have been currently studied as novel and potent central nervous system drug-like compounds for the treatment of, e.g., postpartum depression. As a green methodology, we studied the palladium-catalyzed hydrogenation of steroidal 4-ene-3-ketones in the presence of ionic liquids derived from natural carboxylic acids. The hydrogenation proceeds with improved 5β-selectivity in the presence of tetrabutylammonium carboxylates as additives compared to the exclusive use of an organic solvent. Under optimal conditions, using tetrabutylammonium d-mandelate, the reduction of testosterone led to 5β-dihydrotestosterone in high yield and stereoselectivity and no byproduct formation was observed. Moreover, the catalyst could be recycled. The presence of additional substituents on the steroid backbone showed a significant effect on the 5β-selectivity.
PubMed: 38371788
DOI: 10.1021/acsomega.3c08963 -
BioRxiv : the Preprint Server For... Feb 2024the most frequent cause of skin infections, is more common in men than women and selectively colonizes the skin during inflammation. Yet, the specific cues that drive...
UNLABELLED
the most frequent cause of skin infections, is more common in men than women and selectively colonizes the skin during inflammation. Yet, the specific cues that drive infection in these settings remain unclear. Here we show that the host androgens testosterone and dihydrotestosterone promote pathogenesis and skin infection. Without the secretion of these hormones, skin infection is limited. Testosterone activates virulence in a concentration dependent manner through stimulation of the quorum sensing system, with the capacity to circumvent other inhibitory signals in the environment. Taken together, our work defines a previously uncharacterized inter-kingdom signal between the skin and the opportunistic pathogen and identifies the mechanism of sex-dependent differences in skin infection.
ONE-SENTENCE SUMMARY
Testosterone promotes pathogenesis through activation of the quorum sensing system.
PubMed: 38370751
DOI: 10.1101/2024.02.10.579753 -
BioRxiv : the Preprint Server For... Feb 2024Gonadal steroids play a modulatory role in cocaine use disorders, and are responsible for many sex differences observed in the behavioral response to cocaine. In...
Gonadal steroids play a modulatory role in cocaine use disorders, and are responsible for many sex differences observed in the behavioral response to cocaine. In females, it is well established that estradiol enhances the behavioral response to cocaine. In males, we have recently shown that testosterone enhances sensitization to cocaine but its mechanism of action remains to be elucidated. The current study investigated the contribution of DHT, a non-aromatizable androgen, and of estradiol, in regulating cocaine-induced sensitization in male rats. Gonadectomized (GDX) male rats treated with estradiol sensitized to repeated cocaine administration, while GDX rats treated with DHT did not, implicating estradiol in cocaine sensitization. Furthermore, intact male rats treated with the antiestrogen ICI 182,780 did not show sensitization to repeated cocaine. This study demonstrates the pivotal role of estradiol in cocaine-induced neuroplasticity and neuroadaptations in the rodent brain.
PubMed: 38370714
DOI: 10.1101/2024.02.07.579327 -
BMC Genomics Feb 2024Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease in children and adolescents, but its etiology remains largely...
Adrenarche-accompanied rise of adrenal sex steroid precursors prevents NAFLD in Young Female rats by converting into active androgens and inactivating hepatic Srebf1 signaling.
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease in children and adolescents, but its etiology remains largely unknown. Adrenarche is a critical phase for hormonal changes, and any disturbance during this period has been linked to metabolic disorders, including obesity and dyslipidemia. However, whether there is a causal linkage between adrenarche disturbance and the increasing prevalence of NAFLD in children remains unclear.
RESULTS
Using the young female rat as a model, we found that the liver undergoes a transient slowdown period of growth along with the rise of adrenal-derived sex steroid precursors during adrenarche. Specifically blocking androgen actions across adrenarche phase using androgen receptor antagonist flutamide largely increased liver weight by 47.97% and caused marked fat deposition in liver, thus leading to severe NAFLD in young female rats. Conversely, further administrating nonaromatic dihydrotestosterone (DHT) into young female rats across adrenarche phase could effectively reduce liver fat deposition. But, administration of the aromatase inhibitor, formestane across adrenarche had minimal effects on hepatic de novo fatty acid synthesis and liver fat deposition, suggesting adrenal-derived sex steroid precursors exert their anti-NAFLD effects in young females by converting into active androgens rather than into active estrogens. Mechanistically, transcriptomic profiling and integrated data analysis revealed that active androgens converted from the adrenal sex steroid precursors prevent NAFLD in young females primarily by inactivating hepatic sterol regulatory element-binding transcription factor 1 (Srebf1) signaling.
CONCLUSIONS
We firstly evidenced that adrenarche-accompanied rise of sex steroid precursors plays a predominant role in preventing the incidence of NAFLD in young females by converting into active androgens and inactivating hepatic Srebf1 signaling. Our novel finding provides new insights into the etiology of NAFLD and is crucial in developing effective prevention and management strategies for NAFLD in children.
Topics: Animals; Child; Female; Humans; Rats; Adrenarche; Androgens; Liver; Non-alcoholic Fatty Liver Disease; Steroids; Sterol Regulatory Element Binding Protein 1
PubMed: 38369486
DOI: 10.1186/s12864-024-10107-6 -
Journal of Pharmaceutical Analysis Jan 2024The occurrence of benign prostate hyperplasia (BPH) was related to disrupted sex steroid hormones, and metformin (Met) had a clinical response to sex steroid...
The occurrence of benign prostate hyperplasia (BPH) was related to disrupted sex steroid hormones, and metformin (Met) had a clinical response to sex steroid hormone-related gynaecological disease. However, whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear. Here, our clinical study showed that along with prostatic epithelial cell (PEC) proliferation, sex steroid hormones were dysregulated in the serum and prostate of BPH patients. As the major contributor to dysregulated sex steroid hormones, elevated dihydrotestosterone (DHT) had a significant positive relationship with the clinical characteristics of BPH patients. Activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor (AR)-mediated Yes-associated protein (YAP1)-TEA domain transcription factor (TEAD4) heterodimers. Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells. Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.
PubMed: 38352949
DOI: 10.1016/j.jpha.2023.08.012 -
ACS Omega Feb 2024Three new pimarane diterpenoids, libertellenones U-W (-), together with libertellenone C () and myrocin A () were isolated from an EtOAc-extract of culture medium. The...
Three new pimarane diterpenoids, libertellenones U-W (-), together with libertellenone C () and myrocin A () were isolated from an EtOAc-extract of culture medium. The chemical structures of the new compounds were elucidated using MS, NMR, and CD spectroscopic data. Benign prostatic hyperplasia (BPH), the abnormal and pathological proliferation of epithelial and stromal cells in prostatic tissues, is a common disease in middle-aged and elderly men. In this study, the anti-BPH effects of myrocin A () were evaluated using BPH-1 and WPMY-1 cells. Treatment with myrocin A () exerted antiproliferative effects in BPH-1 and dihydrotestosterone (DHT)-stimulated WPMY-1 cells. In BPH, treatment with myrocin A () significantly suppressed the mRNA levels of androgen receptor () and its downstream targets nuclear receptor coactivator 1 (), proliferating cell nuclear antigen () and kallikrein-related peptidase 3 (). Additionally, DHT-stimulated WPMY-1 cells demonstrated an upregulated mRNA levels of , , and . However, treatment with myrocin A () resulted in suppression of the mRNA levels. Moreover, myrocin A () docked computationally into the binding site of the androgen receptor (-5.5 kcal/mol).
PubMed: 38343945
DOI: 10.1021/acsomega.3c07930 -
Genome Biology Feb 2024The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors...
BACKGROUND
The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employ an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease.
RESULTS
The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer.
CONCLUSIONS
AR and GATA3 interact to transcriptionally regulate luminal epithelial cell differentiation in breast cancer regardless of ER status. This interaction facilitates the tumor suppressor function of AR and mechanistically explains why AR expression is associated with less proliferative, more differentiated breast tumors and better overall survival in breast cancer.
Topics: Female; Humans; Breast Neoplasms; Cell Line, Tumor; Epithelial Cells; GATA3 Transcription Factor; Jumonji Domain-Containing Histone Demethylases; Phenotype; Proteomics; Receptors, Androgen
PubMed: 38317241
DOI: 10.1186/s13059-023-03161-y -
Clinical Cancer Research : An Official... Apr 2024Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only...
PURPOSE
Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies.
EXPERIMENTAL DESIGN
Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments.
RESULTS
We identified ERBB3 OE in diverse patient populations with CSPC, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low dihydrotestosterone and stable expression of androgen receptor (AR) transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy resensitized therapy-resistant prostate cancer cell lines to enzalutamide.
CONCLUSIONS
In diverse patient populations with CSPC, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Androgens; Neoplasm Recurrence, Local; Receptors, Androgen; Nitriles; Biomarkers; Castration; Drug Resistance, Neoplasm; Cell Line, Tumor; Receptor, ErbB-3; Benzamides; Phenylthiohydantoin
PubMed: 38306015
DOI: 10.1158/1078-0432.CCR-23-2161