-
Molecular and Cellular Endocrinology Aug 2023Histone deacetylase 1 (HDAC1) is known to participate in the molecular etiology of polycystic ovary syndrome (PCOS). However, its role in granulosa cell (GC) pyroptosis...
Histone deacetylase 1 (HDAC1) is known to participate in the molecular etiology of polycystic ovary syndrome (PCOS). However, its role in granulosa cell (GC) pyroptosis remains unclear. This study sought to investigate the mechanism of HDAC1 in PCOS-induced GC pyroptosis through histone modification. Clinical serum samples and the general data of study subjects were collected. PCOS mouse models were established using dehydroepiandrosterone and cell models were established in HGL5 cells using dihydrotestosterone. Expressions of HDAC1, H19, miR-29a-3p, and NLR family pyrin domain containing 3 (NLRP3) and pyroptosis-related proteins and levels of hormones and inflammatory cytokines were determined. Ovarian damage was observed by hematoxylin-eosin staining. Functional rescue experiments were conducted to verify the role of H19/miR-29a-3p/NLRP3 in GC pyroptosis in PCOS. HDAC1 and miR-29a-3p were downregulated whereas H19 and NLRP3 were upregulated in PCOS. HDAC1 upregulation attenuated ovarian damage and hormone disorders in PCOS mice and suppressed pyroptosis in ovarian tissues and HGL5 cells. HDAC1 inhibited H3K9ac on the H19 promoter and H19 competitively bound to miR-29a-3p to improve NLRP3 expression. Overexpressed H19 or NLRP3 or inhibited miR-29a-3p reversed the inhibition of GC pyroptosis by HDAC1 upregulation. Overall, HDAC1 suppressed GC pyroptosis in PCOS through deacetylation to regulate the H19/miR-29a-3p/NLRP3 axis.
Topics: Humans; Female; Mice; Animals; Pyroptosis; MicroRNAs; NLR Family, Pyrin Domain-Containing 3 Protein; Polycystic Ovary Syndrome; Histone Deacetylase 1; Histone Code; Granulosa Cells
PubMed: 37207962
DOI: 10.1016/j.mce.2023.111950 -
Science Translational Medicine Mar 2024Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in...
Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females. Male human PTECs showed increased glucose and glutamine fluxes to the TCA cycle, whereas female human PTECs showed increased pyruvate content. The male human PTEC phenotype was enhanced by dihydrotestosterone and mediated by the transcription factor HNF4A and histone demethylase KDM6A. In mice where sex chromosomes either matched or did not match gonadal sex, male gonadal sex contributed to the kidney metabolism differences between males and females. A blood metabolomics analysis in a cohort of adolescents with or without diabetes showed increased TCA cycle metabolites in males. In a second cohort of adults with diabetes, females without DKD had higher serum pyruvate concentrations than did males with or without DKD. Serum pyruvate concentrations positively correlated with the estimated glomerular filtration rate, a measure of kidney function, and negatively correlated with all-cause mortality in this cohort. In a third cohort of adults with CKD, male sex and diabetes were associated with increased plasma TCA cycle metabolites, which correlated with all-cause mortality. These findings suggest that differences in male and female kidney metabolism may contribute to sex-dependent outcomes in DKD.
Topics: Adolescent; Adult; Humans; Female; Male; Animals; Mice; Diabetic Nephropathies; Sex Characteristics; Pyruvates; Renal Insufficiency, Chronic; Glucose; Kidney; Diabetes Mellitus
PubMed: 38446901
DOI: 10.1126/scitranslmed.abm2090 -
Applied Biochemistry and Biotechnology Dec 2023Polycystic ovarian syndrome (PCOS) is an endocrine syndrome in women of reproductive age. Berberine (BBR) is a Chinese herbal monomer that exhibits many pharmacological...
Polycystic ovarian syndrome (PCOS) is an endocrine syndrome in women of reproductive age. Berberine (BBR) is a Chinese herbal monomer that exhibits many pharmacological properties related to PCOS treatment. This study aims to analyze the effect of BBR on a cell model of PCOS and the underlying mechanism. Human ovarian granulosa (KGN) cells were treated with dihydrotestosterone (DHT) to mimic a PCOS cell model. The RNA expression of circ_0097636, miR-186-5p, and sirtuin3 (SIRT3) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was detected by western blotting. Cell viability was analyzed by CCK-8 assay. Cell proliferation and apoptosis were investigated by 5-ethynyl-2'-deoxyuridine (EdU) assay and flow cytometry assay, respectively. The levels of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) were analyzed by enzyme-linked immunosorbent assays (ELISAs). Fe concentration was assessed by an iron assay kit. Oxidative stress was assessed by detecting reactive oxygen species (ROS) level and malondialdehyde (MDA) level using commercial kits. The association of miR-186-5p with circ_0097636 and SIRT3 was identified by dual-luciferase reporter assay and RNA pull-down assay. Circ_0097636 expression was downregulated in the follicular fluid of PCOS patients and DHT-treated KGN cells when compared with control groups. BBR treatment partially relieved the DHT-induced inhibitory effect on cell proliferation and promoted effects on cell apoptosis, inflammation, ferroptosis, and oxidative stress in KGN cells. Additionally, circ_0097636 bound to miR-186-5p, and SIRT3 was identified as a target gene of miR-186-5p in KGN cells. BBR treatment ameliorated DHT-induced KGN cell injury by upregulating circ_0097636 and SIRT3 expression and downregulating miR-186-5p expression. Moreover, circ_0097636 overexpression protected KGN cells from DHT-induced injury by increasing SIRT3 expression. BBR ameliorated DHT-induced KGN cell injury and ferroptosis by regulating the circ_0097636/miR-186-5p/SIRT3 pathway.
PubMed: 38153651
DOI: 10.1007/s12010-023-04825-y -
Scientific Reports Dec 2023Androgenetic alopecia (AGA), also known as male pattern baldness, is a common hair loss condition influenced by genetic and hormonal factors. Variations in gene...
Androgenetic alopecia (AGA), also known as male pattern baldness, is a common hair loss condition influenced by genetic and hormonal factors. Variations in gene expression and androgen responsiveness have been observed between the frontal and occipital regions of AGA patients. However, obtaining and cultivating frontal hair follicles is challenging. Therefore, no matched frontal and occipital dermal papilla (DP) cell lines have been reported yet. This study aimed to establish matched immortalized human frontal and occipital scalp DP cell lines from AGA patients. Simian virus 40 large T antigen (SV40T-Ag) and human telomerase reverse transcriptase (hTERT) were introduced into primary human DP cells. The obtained cell lines were characterized by assessing their gene expression patterns, androgen receptor (AR) levels, and the presence of 5-alpha reductase (5αR). Additionally, we examined their response to dihydrotestosterone (DHT) and evaluated cell viability. The conditioned medium from the frontal DP cell line inhibited human hair follicle growth, leading to reduced keratinocyte proliferation and increased apoptosis. Furthermore, when the cells were cultured in a 3D environment mimicking in vivo conditions, the 3D cultured frontal DP cell line exhibited weaker sphere aggregation than the occipital DP cell line due to the increased expression of matrix metalloproteinase 1 (MMP1), MMP3, and MMP9. Additionally, the expression of DP signature genes was inhibited in the 3D cultured frontal DP cell line. These matched frontal and occipital DP cell lines hold significant potential as valuable resources for research on hair loss. Their establishment allows us to investigate the differences between frontal and occipital DP cells, contributing to a better understanding of the molecular mechanisms underlying AGA. Furthermore, these cell lines may be valuable for developing targeted therapeutic approaches for hair loss conditions.
Topics: Humans; Male; Scalp; Alopecia; Androgens; Hair Follicle; Cell Line
PubMed: 38049592
DOI: 10.1038/s41598-023-48942-4 -
Journal of Cosmetic and Laser Therapy :... Jun 2024We aimed to determine the efficacy of the various available oral, topical, and procedural treatment options for hair loss in individuals with androgenic alopecia. Using...
We aimed to determine the efficacy of the various available oral, topical, and procedural treatment options for hair loss in individuals with androgenic alopecia. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review of the National Library of Medicine was performed. Overall, 141 unique studies met our inclusion criteria. We demonstrate that many over the counter (e.g. topical minoxidil, supplements, low-level light treatment), prescription (e.g. oral minoxidil, finasteride, dutasteride), and procedural (e.g. platelet-rich plasma, fractionated lasers, hair transplantation) treatments successfully promote hair growth, highlighting the superiority of a multifaceted and individualized approach to management.
PubMed: 38852607
DOI: 10.1080/14764172.2024.2362126 -
Gynecological Endocrinology : the... Dec 2023To investigate the underling mechanisms of liver dysfunction in patients with polycystic ovary syndrome (PCOS). PCOS patients were enrolled according to the Amsterdam...
To investigate the underling mechanisms of liver dysfunction in patients with polycystic ovary syndrome (PCOS). PCOS patients were enrolled according to the Amsterdam criteria while PCOS animal model was established by dihydrotestosterone (DHEA) sustained release tablet implantation on its neck. Further liver damage and iron overload were detected by HE and Prussian blue staining. The liver related enzymes, mRNA and protein levels of hepcidin and GPX4 were tested by ELISA, qRT-PCR and Western blot. RNA interference and miR-761 transfection were routinely performed while the regulation of miR-761 on hepcidin and GPX4 was confirmed by luciferase reporter gene analysis. We found that a part of PCOS patients and animal model had unexplained liver damage, which is independent of nonalcoholic fatty liver disease (NAFLD) and accompanied by increased ferrum (Fe) deposition. Besides, the expression of hepcidin and GPX4 that is important effector proteins for ferroptosis was down regulated in liver, showing the importance of iron metabolism in this unexplained liver damage. Based on the miR-761-hepcidin/GPX4 axis, we systematically studied the effects of miR-761 on ferroptosis and Fe deposition, which further influence the phenotype and liver function of PCOS model. From both and levels, changes in PCOS disease phenotype and ferroptosis were observed through hierarchical antagonism or overexpression of miR-761, hepcidin and GPX4. our results provide a novel explanation for unexplained liver damage in PCOS and a potential therapeutic target.
Topics: Animals; Female; Humans; Ferroptosis; Hepcidins; Iron; Iron Overload; Liver Diseases; MicroRNAs; Polycystic Ovary Syndrome; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 36657482
DOI: 10.1080/09513590.2023.2166483 -
Journal of Cosmetic Dermatology Mar 2024Hair loss occurs due to various biological and environmental causes, which can have psychosocial consequences. The Wnt/β-catenin signaling is well-known for its role in...
BACKGROUND
Hair loss occurs due to various biological and environmental causes, which can have psychosocial consequences. The Wnt/β-catenin signaling is well-known for its role in hair growth and regeneration, as it induces the proliferation and differentiation of hair cells. When the leucine-rich G protein-coupled receptor 5 (Lgr5) interacts with the R-spondins, the frizzled receptor (FZD), a Wnt receptor, becomes stabilized, resulting in an increased β-catenin activity.
AIM
We investigated whether the octapeptide that binds to Lgr5 enhances proliferation and differentiation of human primary hair cells through the activation of Wnt/β-catenin signaling.
METHODS
The binding affinity of the octapeptide to Lgr5 was evaluated using surface plasmon resonance (SPR). We confirmed changes in proliferation and related factors like β-catenin activation and growth factors (GFs) expression in human hair follicle dermal papilla cells (HHFDPCs). Additionally, we observed the proliferation and the expression of differentiation markers in human hair follicle outer root sheath cells (HHFORSCs), human hair follicle germinal matrix cells (HHFGMCs), and human hair follicle stem cells (HHFSCs). We used three-dimensional HHFDPC spheroid culture treated with dihydrotestosterone (DHT) to create in vitro conditions that mimic androgenetic alopecia, and we studied the effects of octapeptide on Wnt expression and HHFSC differentiation.
RESULTS
The binding of the octapeptide to Lgr5 was confirmed using SPR analysis. In HHFDPCs, treatment with octapeptide resulted in a concentration-dependent increase in proliferation. We also observed increased nuclear translocation of β-catenin and increased expression of its downstream targets. HHFDPCs treated with octapeptide exhibited increased expression of growth factors and phosphorylation of Akt and ERK. In addition, we confirmed that octapeptide increased proliferation and induced differentiation in HHFORSCs, HHFGMCs, and HHFSCs. Under the HHFDPC spheroid culture conditions, we found that octapeptide restored the inhibition of Wnt-5a and Wnt-10b expressions by DHT. In HHFSCs treated with HHFDPC spheroid culture media, we observed that octapeptide recovered the inhibition of differentiation by DHT.
CONCLUSION
We found that octapeptides activated the Wnt/β-catenin signaling and induced the proliferation and differentiation of human primary hair cells by acting as an exogenous ligand for Lgr5. In addition, octapeptides recovered inhibited hair regeneration characters by DHT in androgenetic alopecia-mimic in vitro model. These findings suggest that octapeptides may be a promising therapeutic option for treating hair loss.
Topics: Humans; beta Catenin; Hair Follicle; Hair; Receptors, G-Protein-Coupled; Wnt Signaling Pathway; Dihydrotestosterone; Alopecia; Intercellular Signaling Peptides and Proteins; Cell Proliferation
PubMed: 37905348
DOI: 10.1111/jocd.16036 -
The Journal of Endocrinology Sep 2023Since the discovery in 1968 that dihydrotestosterone (DHT) is a major mediator of androgen action, a convincing body of evidence has accumulated to indicate that the...
Since the discovery in 1968 that dihydrotestosterone (DHT) is a major mediator of androgen action, a convincing body of evidence has accumulated to indicate that the major pathway of DHT formation is the 5α-reduction of circulating testosterone in androgen target tissues. However, we now know that DHT can also be formed in peripheral tissues by the oxidation of 5α-androstane-3α,17β-diol (adiol). This pathway is responsible for the formation of the male phenotype. We discuss the serendipitous discovery in the tammar wallaby of an alternate pathway by which adiol is formed in the testes, secreted into plasma and converted in peripheral tissues to DHT. This alternate pathway is responsible for virilisation of the urogenital system in this species and is present in the testes at the onset of male puberty of all mammals studied so far. This is the first clear-cut function for steroid 5α-reductase 1 in males. Unexpectedly, the discovery of this pathway in this Australian marsupial has had a major impact in understanding the pathophysiology of aberrant virilisation in female newborns. Overactivity of the alternate pathway appears to explain virilisation in congenital adrenal hyperplasia CAH, in X-linked 46,XY disorders of sex development. It also appears to be important in polycystic ovarian syndrome (PCOS) since PCOS ovaries have enhanced the expression of genes and proteins of the alternate pathway. It is now clear that normal male development in marsupials, rodents and humans requires the action of both the classic and the alternate (backdoor) pathways.
Topics: Infant, Newborn; Humans; Animals; Male; Female; Androgens; Australia; Testosterone; Dihydrotestosterone; Macropodidae; Virilism
PubMed: 37343228
DOI: 10.1530/JOE-22-0296 -
Endocrinology Sep 2023Hyperandrogenemia and polycystic ovary syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and...
Hyperandrogenemia and polycystic ovary syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and this study examines how neuronal Ar in the central nervous system mediates metabolism under normal and increased androgen conditions in female mice. The neuron-specific ARKO mouse (SynARKO) was created from female (Ar fl/wt; synapsin promoter driven Cre) and male (Ar fl/y) mice. A glucose tolerance test revealed impaired glucose tolerance that was partially alleviated in the SynARKO-dihydrotestosterone (DHT) mice compared with Con-DHT mice after 4 months of DHT treatment. Heat production and food intake was higher in Con-DHT mice than in Con-veh mice; these effects were not altered between SynARKO-veh and SynARKO-DHT mice, indicating that excess androgens may partially alter calorie intake and energy expenditure in females via the neuronal Ar. The pAkt/Akt activity was higher in the hypothalamus in Con-DHT mice than in Con-veh mice, and this effect was attenuated in SynARKO-DHT mice. Western blot studies show that markers of inflammation and microglia activation, such as NF-kB p-65 and IBA1, increased in the hypothalamus of Con-DHT mice compared with Con-veh. These studies suggest that neuronal Ar mediates the metabolic impacts of androgen excess in females.
PubMed: 37738624
DOI: 10.1210/endocr/bqad141 -
The Journal of Clinical Endocrinology... Jan 2024Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear.
BACKGROUND
Arteries from boys with hypospadias demonstrate hypercontractility and impaired vasorelaxation. The role of sex hormones in these responses in unclear.
AIMS
We compared effects of sex steroids on vascular reactivity in healthy boys and boys with hypospadias.
METHODS
Excess foreskin tissue was obtained from 11 boys undergoing hypospadias repair (cases) and 12 undergoing routine circumcision (controls) (median age [range], 1.5 [1.2-2.7] years) and small resistance arteries were isolated. Vessels were mounted on wire myographs and vascular reactivity was assessed in the absence/presence of 17β-estradiol, dihydrotestosterone (DHT), and testosterone.
RESULTS
In controls, testosterone and 17β-estradiol increased contraction (percent of maximum contraction [Emax]: 83.74 basal vs 125.4 after testosterone, P < .0002; and 83.74 vs 110.2 after estradiol, P = .02). 17β-estradiol reduced vasorelaxation in arteries from controls (Emax: 10.6 vs 15.6 to acetylcholine, P < .0001; and Emax: 14.6 vs 20.5 to sodium nitroprusside, P < .0001). In hypospadias, testosterone (Emax: 137.9 vs 107.2, P = .01) and 17β-estradiol (Emax: 156.9 vs 23.6, P < .0001) reduced contraction. Androgens, but not 17β-estradiol, increased endothelium-dependent and endothelium-independent vasorelaxation in cases (Emax: 77.3 vs 51.7 with testosterone, P = .02; and vs 48.2 with DHT to acetylcholine, P = .0001; Emax: 43.0 vs 39.5 with testosterone, P = .02; and 39.6 vs 37.5 with DHT to sodium nitroprusside, P = .04).
CONCLUSION
In healthy boys, testosterone and 17β-estradiol promote a vasoconstrictor phenotype, whereas in boys with hypospadias, these sex hormones reduce vasoconstriction, with androgens promoting vasorelaxation. Differences in baseline artery function may therefore be sex hormone-independent and the impact of early-life variations in androgen exposure on vascular function needs further study.
Topics: Male; Humans; Infant; Nitroprusside; Acetylcholine; Hypospadias; Testosterone; Estradiol; Androgens; Dihydrotestosterone
PubMed: 37672642
DOI: 10.1210/clinem/dgad525