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1.
Syst Biol Reprod Med ; 70(1): 289-298, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39361820

RESUMO

Cryptorchidism, a condition where the testis fails to fully descend into the scrotum during development, is associated with elevated environmental temperatures and pressures, leading to male infertility and germ cell tumors. Factors such as oxidative stress and high temperatures contribute to infertility in cryptorchidism. This study aims to explore how external pressure affects Sertoli cells and discover new mechanisms affecting spermatogenesis in cryptorchidism. Sertoli cells were subjected to various pressure levels (0 mmHg, 25 mmHg, 50 mmHg, 100 mmHg) and durations (0 h, 2 h, 4 h) using an enzyme-linked immunosorbent assay (ELISA) to measure androgen binding protein (ABP) and inhibin B (INH B) secretion. Cell morphology changes were observed using immunofluorescence; apoptosis rates were measured with terminal-deoxynucleotidyl transferase mediated nick end labelling (TUNEL) assay and flow cytometry; ultrastructural variations were examined via transmission electron microscopy; and the expression of apoptosis-related proteins (Fas, FasL, caspase 3, and caspase 8) was analyzed through immunohistochemistry, real-time polymerase chain reaction (real-time PCR), and western blotting. The results showed that elevated pressure suppressed ABP and INH B secretion from Sertoli cells. Structural changes were observed under pressure, including cytoskeleton loosening and nuclear fragmentation. Apoptosis rates increased with higher pressure levels. Ultrastructural analysis revealed chromatin changes, apoptotic bodies, and mitochondrial alterations. Increased expressions of Fas and FasL were detected, along with elevated levels of caspase 3 and caspase 8. The caspase 8 inhibitor blocked pressure-induced apoptosis and caspase 3 activation, while the cytochrome C inhibitor did not show the same effect. Our findings suggested that external pressure induces apoptosis of Sertoli cells via the Fas/FasL signaling pathway, potentially contributing to male infertility associated with cryptorchidism.


Assuntos
Apoptose , Proteína Ligante Fas , Células de Sertoli , Transdução de Sinais , Receptor fas , Masculino , Células de Sertoli/metabolismo , Proteína Ligante Fas/metabolismo , Animais , Receptor fas/metabolismo , Pressão , Ratos Sprague-Dawley , Ratos , Inibinas/metabolismo , Espermatogênese , Criptorquidismo/patologia , Criptorquidismo/metabolismo , Células Cultivadas
2.
Cell Rep Med ; 5(10): 101783, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39383870

RESUMO

Sperm production depends on proper Sertoli-germ cell interaction, and we hypothesized that receptor activator of nuclear factor κB ligand (RANKL) activity in Sertoli cells may influence spermatogenesis. Treatment with the RANKL inhibitor denosumab, normally used to treat osteoporosis, increased testicular weight, inhibin B, and germ cell proliferation in ex vivo testis cultures and in vivo in a humanized RANKL mouse. The effect on germ cell proliferation was positively associated with baseline serum concentrations of anti-müllerian hormone (AMH). In accordance, denosumab increased germ cell proliferation in ex vivo human testis cultures with low/moderate but not severe impairment of Sertoli cell function. In a placebo-controlled randomized clinical trial, denosumab had no effect on semen quality but increased sperm concentration in a subgroup of infertile men with serum AMH ≥38 pmol/L at baseline. In conclusion, high serum AMH may increase the probability of a beneficial response to denosumab treatment in infertile men, thus suggesting a possible venue for precision medicine in male infertility.


Assuntos
Denosumab , Infertilidade Masculina , Ligante RANK , Células de Sertoli , Espermatogênese , Masculino , Humanos , Denosumab/farmacologia , Denosumab/uso terapêutico , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Espermatogênese/efeitos dos fármacos , Infertilidade Masculina/tratamento farmacológico , Animais , Ligante RANK/metabolismo , Camundongos , Hormônio Antimülleriano/sangue , Proliferação de Células/efeitos dos fármacos , Adulto , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Inibinas/sangue , Inibinas/metabolismo
3.
Int J Mol Sci ; 25(18)2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39337600

RESUMO

Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts with numerous partners. Here, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual carrying an ACMG-categorized 'pathogenic' NR5A1/SF-1 variant in comparison to the healthy carrier father. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in NR1H2 and INHA associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the AR and INHA gene promoters were found. Transactivation studies showed that wild-type NR5A1/SF-1 regulates INHA and AR gene expression, while the NR5A1/SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate AR gene transcription; however, the NR1H2 variant showed normal activity. This study expands the NR5A1/SF-1 network of interacting partners, while not solving the exact interplay of different variants that might be involved in revealing the observed DSD phenotype. It also illustrates that understanding complex genetics in DSDs is challenging.


Assuntos
Inibinas , Receptores Androgênicos , Fator Esteroidogênico 1 , Humanos , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Inibinas/metabolismo , Inibinas/genética , Masculino , Transtorno 46,XY do Desenvolvimento Sexual/genética , Feminino , Sequenciamento do Exoma , Regiões Promotoras Genéticas
4.
Sci Rep ; 14(1): 13802, 2024 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-38877312

RESUMO

Sodium-glucose cotransporter (SGLT) 2 inhibition is a well-known target for the treatment of type 2 diabetes, renal disease and chronic heart failure. The protein SGLT2 is encoded by SLC5A2 (Solute Carrier Family 5 Member 2), which is highly expressed in renal cortex, but also in the testes where glucose uptake may be essential for spermatogenesis and androgen synthesis. We postulated that in healthy males, SGLT2 inhibitor therapy may affect gonadal function. We examined the impact on gonadal and steroid hormones in a post-hoc analysis of a double-blind, randomized, placebo-controlled research including 26 healthy males who were given either placebo or empagliflozin 10 mg once daily for four weeks. After one month of empagliflozin, there were no discernible changes in androgen, pituitary gonadotropin hormones, or inhibin B. Regardless of BMI category, the administration of empagliflozin, a highly selective SGLT2 inhibitor, did not alter serum androgen levels in men without diabetes. While SGLT2 is present in the testes, its inhibition does not seem to affect testosterone production in Leydig cells nor inhibin B secretion by the Sertoli cells.


Assuntos
Compostos Benzidrílicos , Glucosídeos , Inibidores do Transportador 2 de Sódio-Glicose , Masculino , Humanos , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Adulto , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Método Duplo-Cego , Testículo/metabolismo , Testículo/efeitos dos fármacos , Testosterona/sangue , Inibinas/sangue , Inibinas/metabolismo , Pessoa de Meia-Idade , Transportador 2 de Glucose-Sódio/metabolismo , Androgênios/metabolismo , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Células de Sertoli/metabolismo , Células de Sertoli/efeitos dos fármacos
5.
J Assist Reprod Genet ; 41(6): 1637-1642, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38557803

RESUMO

PURPOSE: To determine correlations between chemicals in follicular fluid (FF) and follicular reproductive hormone levels. METHODS: The analysis was part of a larger cohort study to determine associations between exposure to EDCs and in vitro fertilization (IVF) outcomes. FF was aspirated from a single leading follicle per participant. Demographics and data on exposure to EDCs were self-reported by the participants using a questionnaire. The concentrations of estradiol (E2), progesterone (PG), anti-Mullerian hormone (AMH), and inhibin B, as well as that of 12 phthalate metabolites and 12 phenolic chemicals were measured in each FF sample. Multivariate linear regression model was used to identify the drivers of hormone levels based on participant's age, BMI, smoking status, and chemical exposure for the monitored chemicals detected in more than 50% of the samples. Benjamini-Hochberg false discovery rate (FDR) correction was applied on the resulting p values (q value). RESULTS: FF samples were obtained from 72 women (mean age 30.9 years). Most of the phthalates and phenolic substances monitored (21/24, 88%) were identified in FF. Ten compounds (7 phthalate metabolites, 3 phenols) were found in more than 50% of samples. In addition, there were positive associations between E2 levels and mono-n-butyl phthalate (MnBP) (beta = 0.01) and mono-isobutyl phthalate (MiBP) (beta = 0.03) levels (q value < 0.05). CONCLUSION: Higher concentrations of several phthalate metabolites, present among others in personal care products, were associated with increased E2 levels in FF. The results emphasize the need to further investigate the mechanisms of action of such EDCs on hormonal cyclicity and fertility in women.


Assuntos
Hormônio Antimülleriano , Disruptores Endócrinos , Estradiol , Fertilização in vitro , Líquido Folicular , Ácidos Ftálicos , Progesterona , Humanos , Líquido Folicular/metabolismo , Líquido Folicular/química , Feminino , Adulto , Disruptores Endócrinos/análise , Ácidos Ftálicos/metabolismo , Ácidos Ftálicos/análise , Estradiol/análise , Estradiol/metabolismo , Progesterona/análise , Progesterona/metabolismo , Hormônio Antimülleriano/metabolismo , Inibinas/metabolismo , Fenóis/análise
6.
J Oral Pathol Med ; 53(4): 266-274, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38531807

RESUMO

BACKGROUND: Inhibin A and N6-methyladenosine methylation modifications participate in oral squamous cell carcinoma development. However, the N6-methyladenosine modification of Inhibin A in oral squamous cell carcinoma has not been revealed. This study reveals a key gene "Inhibin A" that may affect the tumorigenesis of oral squamous cell carcinoma and its molecular mechanisms on N6-methyladenosine methyltransferase KIAA1429-mediated N6-methyladenosine methylation modification. METHODS: Bioinformatics analysis and quantitative real-time polymerase chain reaction identified the potential regulatory genes in oral squamous cell carcinoma. We examined the changes in the proliferation (Cell Counting Kit-8 assay), migration (transwell migration assay), and invasion (transwell invasion assays) of oral squamous cell carcinoma cells. We performed a xenograft tumor experiment to validate the role of Inhibin A in oral squamous cell carcinoma in vivo. The interactions between Inhibin A and KIAA1429 were analyzed using bioinformatics, methylated RNA immunoprecipitation-qPCR, quantitative real-time polymerase chain reaction, and Western blotting experiments. RESULTS: Inhibin A had the highest expression in patients with oral squamous cell carcinoma. Inhibin A silencing impaired the ability of oral squamous cell carcinoma cells to proliferate, migrate, and invade, as well as limited the tumorous growth of oral squamous cell carcinoma cells in vivo. Bioinformatics analysis showed that Inhibin A expression positively interacted with KIAA1429 expression in The Cancer Genome Atlas database. The levels were also upregulated in our clinical samples. Furthermore, KIAA1429 silencing repressed the N6-methyladenosine level of Inhibin A in oral squamous cell carcinoma. CONCLUSIONS: Inhibin A promotes the tumorigenesis of oral squamous cell carcinoma by KIAA1429-mediated N6-methyladenosine modification. This study adds to our current knowledge of the molecular mechanisms underlying oral squamous cell carcinoma malignancy.


Assuntos
Adenina , Carcinoma de Células Escamosas , Inibinas , Neoplasias Bucais , Humanos , Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Transformação Celular Neoplásica , Neoplasias de Cabeça e Pescoço , Inibinas/metabolismo , Neoplasias Bucais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
7.
J Interferon Cytokine Res ; 43(11): 518-530, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37819735

RESUMO

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes can protect lung tissues against sepsis, but its related mechanism remains elusive. BMSCs were primed with or without lipopolysaccharide (LPS) before extracting exosomes. The isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. LPS-stimulated macrophages were cocultured with exosomes for 24 h, followed by enzyme-linked immunosorbent assay, flow cytometry, and molecular experiments. Bioinformatics and luciferase assay were employed to investigate the interaction between miR-150-3p and inhibin subunit beta A (INHBA). MiR-150-3p expression was increased in exosomes in a proinflammatory environment. Exosomes suppressed proinflammatory polarization by downregulating IL-6, IL-1ß, iNOS, and CD86, as well as promoted anti-inflammatory polarization by upregulating IL-10, ARG-1, and CD206 in LPS-stimulated macrophages. Such effects were more pronounced by LPS-primed exosomes, which was reversed in the absence of miR-150-3p. MiR-150-3p targeted INHBA. INHBA silencing decreased CD86 expression and increased CD206 expression in macrophages, but these effects were reversed by exosomal miR-150-3p inhibition. Proinflammatory BMSC-derived exosomal miR-150-3p suppressed proinflammatory polarization and promoted anti-inflammatory polarization of alveolar macrophages to attenuate LPS-induced sepsis by targeting INHBA.


Assuntos
Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Sepse , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Macrófagos Alveolares/metabolismo , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/metabolismo , Sepse/genética , Anti-Inflamatórios/metabolismo , Inibinas/metabolismo , Exossomos/genética , Exossomos/metabolismo
8.
PLoS Genet ; 19(9): e1010954, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37713421

RESUMO

As an oocyte-specific growth factor, bone morphogenetic protein 15 (BMP15) plays a critical role in controlling folliculogenesis. However, the mechanism of BMP15 action remains elusive. Using zebrafish as the model, we created a bmp15 mutant using CRISPR/Cas9 and demonstrated that bmp15 deficiency caused a significant delay in follicle activation and puberty onset followed by a complete arrest of follicle development at previtellogenic (PV) stage without yolk accumulation. The mutant females eventually underwent female-to-male sex reversal to become functional males, which was accompanied by a series of changes in secondary sexual characteristics. Interestingly, the blockade of folliculogenesis and sex reversal in bmp15 mutant could be partially rescued by the loss of inhibin (inha-/-). The follicles of double mutant (bmp15-/-;inha-/-) could progress to mid-vitellogenic (MV) stage with yolk accumulation and the fish maintained their femaleness without sex reversal. Transcriptome analysis revealed up-regulation of pathways related to TGF-ß signaling and endocytosis in the double mutant follicles. Interestingly, the expression of inhibin/activin ßAa subunit (inhbaa) increased significantly in the double mutant ovary. Further knockout of inhbaa in the triple mutant (bmp15-/-;inha-/-;inhbaa-/-) resulted in the loss of yolk granules again. The serum levels of estradiol (E2) and vitellogenin (Vtg) both decreased significantly in bmp15 single mutant females (bmp15-/-), returned to normal in the double mutant (bmp15-/-;inha-/-), but reduced again significantly in the triple mutant (bmp15-/-;inha-/-;inhbaa-/-). E2 treatment could rescue the arrested follicles in bmp15-/-, and fadrozole (a nonsteroidal aromatase inhibitor) treatment blocked yolk accumulation in bmp15-/-;inha-/- fish. The loss of inhbaa also caused a reduction of Vtg receptor-like molecules (e.g., lrp1ab and lrp2a). In summary, the present study provided comprehensive genetic evidence that Bmp15 acts together with the activin-inhibin system in the follicle to control E2 production from the follicle, Vtg biosynthesis in the liver and its uptake by the developing oocytes.


Assuntos
Proteína Morfogenética Óssea 15 , Inibinas , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Feminino , Masculino , Ativinas/genética , Proteína Morfogenética Óssea 15/genética , Proteína Morfogenética Óssea 15/metabolismo , Inibinas/genética , Inibinas/metabolismo , Mutação , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
9.
Zhonghua Gan Zang Bing Za Zhi ; 31(3): 288-292, 2023 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-37137855

RESUMO

Objective: To investigate the effect and role of the hepatitis B virus (HBV) on the expression of inhibin (PHB) in the proliferation and survival of hepatocellular carcinoma (HCC) cells. Methods: The expression of PHB in 13 pairs of HBV-infected livers, normal livers and HepG2.2.15 and HepG2 cells was detected by real-time fluorescent quantitative PCR and Western blot. Liver tissues were collected from seven patients with chronic hepatitis B before and after antiviral (tenofovir) treatment, and the expression of PHB was detected by RT-PCR and Western blot. HepG2.2.15 cells were transfected with Pcmv6-AC-GFP-PHB, and control vectors were collected. DNA content was analyzed by flow cytometry. The proliferation level of each cell group was detected using the EdU cell proliferation assay. HepG2.2.15 cells transfected with Pcmv6-AC-GFP-PHB and the control vector were cultured in serum-free medium for 6 days. Apoptosis was measured at the indicated time points using fluorescence-activated cell sorting (FACS)-based Annexin-V/PI double staining. Results: Compared with normal liver tissue, the expression of PHB in HBV-infected liver tissue was down-regulated (P < 0.01). Compared with HepG2 cells, the expression of PHB in HepG2.2.15 cells was significantly decreased (P < 0.01). The expression level of PHB in liver tissue after antiviral treatment (tenofovir) was significantly higher than that before treatment (P < 0.01). Compared with the control vector, the proliferation rate of HepG2.2.15 cells transfected with Pcmv6-AC-GFP-PHB was significantly lower than that of the control vector, and the apoptosis rate of HepG2.2.15 cells transfected with the Pcmv6-AC-GFP-PHB vector was significantly higher than the control vector (P < 0.01). Conclusion: HBV down-regulates the expression of inhibin to promote the proliferation and survival of hepatocellular carcinoma cells.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Vírus da Hepatite B/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Inibinas/metabolismo , Células Hep G2 , Tenofovir , Proliferação de Células , Antivirais/metabolismo
10.
J Endocrinol ; 258(1)2023 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-37194642

RESUMO

Although originally characterised as proteins involved in the control of reproductive function, activins, and to a lesser degree inhibins, are also important regulators of homeostasis in extragonadal tissues. Accordingly, disrupted inhibin/activin expression can have detrimental effects not only on fertility and fecundity but also on the regulation of muscle, fat and bone mass. Indeed, only recently, two complementary mouse models of inhibin designed to lack bioactivity/responsiveness revealed that inhibin A/B deficiency during pregnancy restricts embryo and fetal survival. Conversely, hyper-elevated levels of activin A/B, as are frequently observed in patients with advanced cancers, can not only promote gonadal tumour growth but also cancer cachexia. As such, it is not surprising that inhibin/activin genetic variations or altered circulating levels have been linked to reproductive disorders and cancer. Whilst some of the detrimental health effects associated with disrupted inhibin/activin levels can be attributed to accompanied changes in circulating follicle-stimulating hormone (FSH) levels, there is now abundant evidence that activins, in particular, have fundamental FSH-independent tissue homeostatic roles. Increased understanding of inhibin/activin activity, garnered over several decades, has enabled the development of targeted therapies with applications for both reproductive and extra-gonadal tissues. Inhibin- or activin-targeted technologies have been shown not just to enhance fertility and fecundity but also to reduce disease severity in models of cancer cachexia. Excitingly, these technologies are likely to benefit human medicine and be highly valuable to animal breeding and veterinary programmes.


Assuntos
Ativinas , Neoplasias , Gravidez , Camundongos , Feminino , Animais , Humanos , Caquexia/etiologia , Hormônio Foliculoestimulante/metabolismo , Inibinas/genética , Inibinas/metabolismo , Neoplasias/complicações
11.
Int J Mol Sci ; 24(8)2023 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-37108077

RESUMO

Inhibins suppress the FSH production in pituitary gonadotrope cells by robustly antagonizing activin signaling by competitively binding to activin type II receptors (ACTR II). The binding of inhibin A to ACTR II requires the presence of its co-receptor, namely, betaglycan. In humans, the critical binding site for betaglycan to inhibin A was identified on the inhibin α subunit. Through conservation analysis, we found that a core 13-amino-acid peptide sequence within the betaglycan-binding epitope on human inhibin α subunit is highly conserved across species. Based on the tandem sequence of such a conserved 13-amino-acid betaglycan-binding epitope (INHα13AA-T), we developed a novel inhibin vaccine and tested its efficacy in promoting female fertility using the female rat as a model. Compared with placebo-immunized controls, INHα13AA-T immunization induced a marked (p < 0.05) antibody generation, enhanced (p < 0.05) ovarian follicle development, and increased ovulation rate and litter sizes. Mechanistically, INHα13AA-T immunization promoted (p < 0.05) pituitary Fshb transcription and increased (p < 0.05) serum FSH and 17ß-estradiol concentrations. In summary, active immunization against INHα13AA-T potently increased FSH levels, ovarian follicle development, ovulation rate and litter sizes, thus causing super-fertility in females. Therefore, immunization against INHα13AA is a promising alternative to the conventional approach of multiple ovulation and super-fertility in mammals.


Assuntos
Ativinas , Inibinas , Ratos , Feminino , Humanos , Animais , Inibinas/metabolismo , Receptores de Ativinas , Peptídeos , Imunização , Vacinação , Hormônio Foliculoestimulante/farmacologia , Fertilidade , Aminoácidos , Mamíferos/metabolismo
12.
Circulation ; 147(24): 1809-1822, 2023 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-37096577

RESUMO

BACKGROUND: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers. METHODS: Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues. RESULTS: Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; P=0.037 and 1.263 [95% CI, 1.049-1.520]; P=0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; P=0.001 and 1.365 [95% CI, 1.185-1.573]; P<0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; P=0.009) and 0.17 (95% CI, 0.06-0.45; P<0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; P=0.019) and 0.27 (95% CI, 0.09-0.78, P=0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin. CONCLUSIONS: These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.


Assuntos
Folistatina , Hipertensão Arterial Pulmonar , Humanos , Folistatina/metabolismo , Inibinas/metabolismo , Ativinas/metabolismo , Pulmão/metabolismo
13.
Placenta ; 136: 35-41, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37028223

RESUMO

Activin A is a two-subunit protein belonging to the transforming growth factor ß superfamily. First discovered almost three decades ago, it has since been implicated in diverse physiological roles, ranging from wound repair to reproduction. After 30 years of research, altered activin A levels are now understood to be associated with the development of various diseases, making activin A a potential therapeutic target. In pregnancy, the placenta and fetal membranes are major producers of activin A, with significantly enhanced serum concentrations now recognised as a contributor to numerous gestational disorders. Evidence now suggests that circulating levels of activin A may be clinically relevant in the early detection of pregnancy complications, including miscarriage and preeclampsia. This review aims to summarise our current understanding of activin A as a potential diagnostic marker in common pregnancy pathologies.


Assuntos
Inibinas , Complicações na Gravidez , Gravidez , Feminino , Humanos , Inibinas/metabolismo , Ativinas/metabolismo , Reprodução/fisiologia , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/etiologia
14.
Theriogenology ; 202: 10-20, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36878034

RESUMO

Inhibin (INH) is a glycoprotein hormone secreted by the gonads that inhibit the synthesis and secretion of follicle-stimulating hormone (FSH). Increasing evidence indicates that INH plays a significant role in the development of the reproductive system including follicle development, ovulation rate, corpus luteum formation and ablation, steroid hormone synthesis and spermatogenesis, subsequently affecting the reproductive capacity of animals such as litter size and egg production. There are currently three main views on how INH inhibits FSH synthesis and secretion: influencing the activity of adenylate cyclase, the expression of follicle-stimulating hormone receptor or gonadotropin-releasing hormone receptor, and the competition system of inhibin-activin. This review discusses the current findings on the structure, function, and mechanism of action of INH in the reproductive system of animals.


Assuntos
Inibinas , Hormônio Luteinizante , Feminino , Masculino , Animais , Inibinas/metabolismo , Hormônio Luteinizante/metabolismo , Hormônio Foliculoestimulante/farmacologia , Ativinas , Gônadas/metabolismo
15.
Int J Mol Sci ; 24(4)2023 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-36834742

RESUMO

Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of the pulmonary vasculature that is associated with high mortality and morbidity rates. Although significant progress has been made in understanding PAH and its diagnosis and treatment, numerous unanswered questions remain regarding pulmonary vascular remodeling, a major factor contributing to the increase in pulmonary arterial pressure. Here, we discuss the role of activins and inhibins, both of which belong to the TGF-ß superfamily, in PAH development. We examine how these relate to signaling pathways implicated in PAH pathogenesis. Furthermore, we discuss how activin/inhibin-targeting drugs, particularly sotatercep, affect pathophysiology, as these target the afore-mentioned specific pathway. We highlight activin/inhibin signaling as a critical mediator of PAH development that is to be targeted for therapeutic gain, potentially improving patient outcomes in the future.


Assuntos
Inibinas , Hipertensão Arterial Pulmonar , Humanos , Inibinas/metabolismo , Ativinas/metabolismo , Fator de Crescimento Transformador beta/metabolismo
16.
Hum Reprod ; 38(4): 686-700, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36762771

RESUMO

STUDY QUESTION: Which substances and signal transduction pathways are potentially active downstream to the effect of FSH and LH in the regulation of human oocyte maturation in vivo? SUMMARY ANSWER: The regulation of human oocyte maturation appears to be a multifactorial process in which several different signal transduction pathways are active. WHAT IS KNOWN ALREADY: Many studies in animal species have provided insight into the mechanisms that govern the final maturation of oocytes. Currently, these studies have identified several different mechanisms downstream to the effects of FSH and LH. Some of the identified mechanisms include the regulation of cAMP/cGMP levels in oocytes involving C-type natriuretic peptide (CNP), effects of epidermal growth factor (EGF)-related peptides such as amphiregulin (AREG) and/or epiregulin (EREG), effect of TGF-ß family members including growth differentiation factor 9 (GDF9) and morphogenetic protein 15 (BMP15), activins/inhibins, follicular fluid meiosis activating sterol (FF-MAS), the growth factor midkine (MDK), and several others. However, to what extent these pathways and mechanisms are active in humans in vivo is unknown. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 50 women undergoing fertility treatment in a standard antagonist protocol at a university hospital affiliated fertility clinic in 2016-2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: We evaluated the substances and signalling pathways potentially affecting human oocyte maturation in follicular fluid (FF) and granulosa cells (GCs) collected at five time points during the final maturation of follicles. Using ELISA measurement and proteomic profiling of FF and whole genome gene expression in GC, the following substances and their signal transduction pathways were collectively evaluated: CNP, the EGF family, inhibin-A, inhibin-B, activins, FF-MAS, MDK, GDF9, and BMP15. MAIN RESULTS AND THE ROLE OF CHANCE: All the evaluated substances and signal transduction pathways are potentially active in the regulation of human oocyte maturation in vivo except for GDF9/BMP15 signalling. In particular, AREG, inhibins, and MDK were significantly upregulated during the first 12-17 h after initiating the final maturation of follicles and were measured at significantly higher concentrations than previously reported. Additionally, the genes regulating FF-MAS synthesis and metabolism were significantly controlled in favour of accumulation during the first 12-17 h. In contrast, concentrations of CNP were low and did not change during the process of final maturation of follicles, and concentrations of GDF9 and BMP15 were much lower than reported in small antral follicles, suggesting a less pronounced influence from these substances. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: Although GC and cumulus cells have many similar features, it is a limitation of the current study that information for the corresponding cumulus cells is not available. However, we seldom recovered a cumulus-oocyte complex during the follicle aspiration from 0 to 32 h. WIDER IMPLICATIONS OF THE FINDINGS: Delineating the mechanisms governing the regulation of human oocyte maturation in vivo advances the possibility of developing a platform for IVM that, as for most other mammalian species, results in healthy offspring with good efficacy. Mimicking the intrafollicular conditions during oocyte maturation in vivo in small culture droplets during IVM may enhance oocyte nuclear and cytoplasmic maturation. The primary outlook for such a method is, in the context of fertility preservation, to augment the chances of achieving biological children after a cancer treatment by subjecting oocytes from small antral follicles to IVM. Provided that aspiration of oocytes from small antral follicles in vivo can be developed with good efficacy, IVM may be applied to infertile patients on a larger scale and can provide a cheap alternative to conventional IVF treatment with ovarian stimulation. Successful IVM has the potential to change current established techniques for infertility treatment. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the University Hospital of Copenhagen, Rigshospitalet, the Independent Research Fund Denmark (grant number 0134-00448), and the Interregional EU-sponsored ReproUnion network. There are no conflicts of interest to be declared.


Assuntos
Fator de Crescimento Epidérmico , Proteômica , Animais , Criança , Humanos , Feminino , Fator de Crescimento Epidérmico/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Estudos Prospectivos , Técnicas de Maturação in Vitro de Oócitos/métodos , Oócitos/metabolismo , Peptídeo Natriurético Tipo C/farmacologia , Hormônio Foliculoestimulante/metabolismo , Inibinas/metabolismo , Ativinas/metabolismo , Mamíferos
17.
Am J Physiol Cell Physiol ; 324(2): C428-C437, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36622068

RESUMO

Activins and inhibins are unique members of the transforming growth factor-ß (TGFß) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.


Assuntos
Inibinas , Neoplasias Ovarianas , Humanos , Feminino , Inibinas/genética , Inibinas/metabolismo , Ativinas/genética , Ativinas/metabolismo , Neoplasias Ovarianas/genética , Transdução de Sinais , Sistema Endócrino/metabolismo
18.
Endocrinology ; 164(3)2023 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-36718082

RESUMO

Inhibins are transforming growth factor-ß family heterodimers that suppress follicle-stimulating hormone (FSH) secretion by antagonizing activin class ligands. Inhibins share a common ß chain with activin ligands. Follistatin is another activin antagonist, known to bind the common ß chain of both activins and inhibins. In this study, we characterized the antagonist-antagonist complex of inhibin A and follistatin to determine if their interaction impacted activin A antagonism. We isolated the inhibin A:follistatin 288 complex, showing that it forms in a 1:1 stoichiometric ratio, different from previously reported homodimeric ligand:follistatin complexes, which bind in a 1:2 ratio. Small angle X-ray scattering coupled with modeling provided a low-resolution structure of inhibin A in complex with follistatin 288. Inhibin binds follistatin via the shared activin ß chain, leaving the α chain free and flexible. The inhibin A:follistatin 288 complex was also shown to bind heparin with lower affinity than follistatin 288 alone or in complex with activin A. Characterizing the inhibin A:follistatin 288 complex in an activin-responsive luciferase assay and by surface plasmon resonance indicated that the inhibitor complex readily dissociated upon binding type II receptor activin receptor type IIb, allowing both antagonists to inhibit activin signaling. Additionally, injection of the complex in ovariectomized female mice did not alter inhibin A suppression of FSH. Taken together, this study shows that while follistatin binds to inhibin A with a substochiometric ratio relative to the activin homodimer, the complex can dissociate readily, allowing both proteins to effectively antagonize activin signaling.


Assuntos
Folistatina , Glicoproteínas , Feminino , Camundongos , Animais , Glicoproteínas/metabolismo , Inibinas/metabolismo , Ativinas/metabolismo , Ligantes , Hormônio Foliculoestimulante/metabolismo
19.
Theriogenology ; 197: 198-208, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36525859

RESUMO

Activin/inhibin is an important factor for the fecundity of Hu sheep, and it is involved in follicular development in ovaries. Inhibin subunit beta A (INHBA) participates in the synthesis of activin A and inhibin A. In this study, we also noted a positive correlation between INHBA level and the secretion of both activin A and inhibin A in culture medium. Nevertheless, both knockdown and overexpression of INHBA downregulated the expression of Inhibin Subunit Alpha (INHA). Based on RNA-Sequencing, we further examined the effect and molecular mechanism of INHBA knockdown in GCs on mRNA expression. A total of 1,687 differentially expressed genes (DEGs) were identified (Fold change ≥ 2; False-discovory-rates (FDR) ≤ 0.01), of which 602 genes were upregulated and 1,087 genes were downregulated in the INHBA interference group compared with the control groups. Gene Ontology (GO) enrichment indicated that these DEGs were mainly involved in the regulation of cell cycle, protein serine/threonine kinase activity, and actin cytoskeleton reorganization. Moreover, DEGs were significantly enriched in 40 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including P53, progesterone-mediated oocyte maturation, and PI3K-AKT signaling pathways. We also noted a positive correlation between INHBA level and many PI3K/Akt/mTOR pathway-related genes at the gene or/and protein expression. Overall, this study may contribute to a better understanding of the roles of INHBA on GCs of prolific sheep, as well as the molecular effect of low INHBA expression on GCs, clarifying some reproductive failures.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Feminino , Animais , Ovinos/genética , RNA-Seq/veterinária , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibinas/metabolismo , Células da Granulosa/fisiologia
20.
PLoS Genet ; 18(12): e1010318, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36520929

RESUMO

Growth differentiation factor 9 (GDF9) was the first oocyte-specific growth factor identified; however, most information about GDF9 functions comes from studies in the mouse model. In this study, we created a mutant for Gdf9 gene (gdf9-/-) in zebrafish using TALEN approach. The loss of Gdf9 caused a complete arrest of follicle development at primary growth (PG) stage. These follicles eventually degenerated, and all mutant females gradually changed to males through sex reversal, which could be prevented by mutation of the male-promoting gene dmrt1. Interestingly, the phenotypes of gdf9-/- could be rescued by simultaneous mutation of inhibin α (inha-/-) but not estradiol treatment, suggesting a potential role for the activin-inhibin system or its signaling pathway in Gdf9 actions. In gdf9-null follicles, the expression of activin ßAa (inhbaa), but not ßAb (inhbab) and ßB (inhbb), decreased dramatically; however, its expression rebounded in the double mutant (gdf9-/-;inha-/-). These results indicate clearly that the activation of PG follicles to enter the secondary growth (SG) requires intrinsic factors from the oocyte, such as Gdf9, which in turn works on the neighboring follicle cells to trigger follicle activation, probably involving activins. In addition, our data also support the view that estrogens are not involved in follicle activation as recently reported.


Assuntos
Fator 9 de Diferenciação de Crescimento , Peixe-Zebra , Camundongos , Feminino , Animais , Masculino , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Fator 9 de Diferenciação de Crescimento/genética , Fator 9 de Diferenciação de Crescimento/metabolismo , Inibinas/genética , Inibinas/metabolismo , Folículo Ovariano/metabolismo , Ativinas/genética , Ativinas/metabolismo
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