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1.
Behav Neurol ; 2021: 5346507, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594430

RESUMO

Epidemiological studies have suggested that traumatic stress increases vulnerability to various mental disorders, such as dementia and psychiatric disorders. While women are more vulnerable than men to depression and anxiety, it is unclear whether endogenous estrogens are responsible for the underlying sex-specific mechanisms. In this study, the aromatase gene heterozygous (Ar+/-) mice were used as an endogenous estrogen deficiency model and age- and sex-matched wild type mice (WT) as controls to study the predator odor 2,3,5-trimethyl-3-thiazoline- (TMT-) induced short- and long-term cognitive and social behavior impairments. In addition, the changes in brain regional neurotransmitters and their associations with TMT-induced changes in behaviors were further investigated in these animals. Our results showed TMT induced immediate fear response in both Ar+/- and WT mice regardless of sexes. TMT induced an acute impairment of novel object recognition memory and long-term social behavior impairment in WT mice, particularly in females, while Ar+/- mice showed impaired novel object recognition in both sexes and TMT-elevated social behaviors, particularly in males. TMT failed to induce changes in the prepulse inhibition (PPI) test in both groups. TMT resulted in a slight increase of DOPAC/DA ratio in the cortex and a significant elevation of this ratio in the striatum of WT mice. In addition, the ratio of HIAA/5-HT was significantly elevated in the cortex of TMT-treated WT mice, which was not found in TMT-treated Ar+/- mice. Taken together, our results indicate that TMT exposure can cause cognitive and social behavior impairments as well as change catecholamine metabolism in WT mice, and endogenous estrogen deficiency might desensitize the behavioral and neurochemical responses to TMT in Ar+/- mice.


Assuntos
Medo , Odorantes , Animais , Aromatase/genética , Comportamento Animal , Cognição , Estrogênios , Feminino , Humanos , Masculino , Camundongos , Comportamento Social
2.
Am J Case Rep ; 22: e932722, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34615846

RESUMO

BACKGROUND Anovulation consists in the lack of oocyte release during the menstrual cycle, leading to an irregular menstrual cycle. Untreated chronic anovulation is one of the major causes of female infertility and can induce hypoestrogenism. Different etiological factors can contribute to anovulation; therefore, the clinical approaches to manage this condition should take into account the specific patient characteristics. Oral ovulation-inducing agents are first-line treatments for most anovulatory patients. Drugs used include selective estrogen receptor modulators (SERMs) such as clomiphene citrate and aromatase inhibitors (AIs) such as letrozole. The latter, in particular, halts the estrogen biosynthesis by blocking the activity of steroidogenic enzyme aromatase, which catalyzes the conversion of androgens to estrogens. Similarly, d-chiro-inositol (DCI) modulates the activity of aromatase by reducing the corresponding gene expression, and DCI supplementation was successfully used to induce ovulation in anovulatory PCOS patients. Here, we report the use of DCI to induce ovulation in non-PCOS anovulatory oligomenorrheic women. CASE REPORT Two young non-PCOS anovulatory oligomenorrheic women received treatment with high-dose (1200 mg) DCI for 6 weeks. Based on an initial evaluation, both patients had normal hormone levels and were non-insulin-resistant. Ovulation assessment was based on the increment of progesterone and LH levels, as well as on the endometrial thickening. Also, the treatment with DCI resulted in a reduction of testosterone levels relative to baseline values. CONCLUSIONS After the 6-week treatment with 1200 mg DCI, ovulation was restored in both women, as confirmed by increased progesterone and LH and endometrial thickening.


Assuntos
Aromatase , Inositol , Indução da Ovulação , Síndrome do Ovário Policístico , Feminino , Humanos , Inositol/uso terapêutico , Ovulação , Síndrome do Ovário Policístico/tratamento farmacológico
3.
Eur J Neurosci ; 54(9): 7072-7091, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34535925

RESUMO

Estrogens support major brain functions including cognition, reproduction, neuroprotection and sensory processing. Neuroestrogens are synthesized within some brain areas by the enzyme aromatase and can rapidly modulate local circuit functions, yet the cellular physiology and sensory-response profiles of aromatase neurons are essentially unknown. In songbirds, social and acoustic stimuli drive neuroestrogen elevations in the auditory forebrain caudomedial nidopallium (NCM). In both males and females, neuroestrogens rapidly enhance NCM auditory processing and auditory learning. Estrogen-producing neurons in NCM may therefore exhibit distinguishing profiles for sensory-activation and intrinsic electrophysiology. Here, we explored these questions using both immunocyctochemistry and electrophysiological recordings. Immunoreactivity for aromatase and the immediate early gene EGR1, a marker of activity and plasticity, were quantified in NCM of song-exposed animals versus silence-exposed controls. Using whole-cell patch clamp recordings from NCM slices, we also documented the intrinsic excitability profiles of aromatase-positive and aromatase-negative neurons. We observed that a subset of aromatase neurons were significantly activated during song playback, in both males and females, and in both hemispheres. A comparable population of non-aromatase-expressing neurons were also similarly driven by song stimulation. Membrane properties (i.e., resting membrane potential, rheobase, input resistance and multiple action potential parameters) were similarly indistinguishable between NCM aromatase and non-aromatase neurons. Together, these findings demonstrate that aromatase and non-aromatase neurons in NCM are indistinct in terms of their intrinsic electrophysiology and responses to song. Nevertheless, such similarities in response properties may belie more subtle differences in underlying conductances and/or computational roles that may be crucial to their function.


Assuntos
Córtex Auditivo , Tentilhões , Animais , Aromatase/genética , Aromatase/metabolismo , Córtex Auditivo/metabolismo , Estradiol , Feminino , Masculino , Neurônios/metabolismo , Prosencéfalo/metabolismo , Vocalização Animal
4.
Anim Sci J ; 92(1): e13617, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34405917

RESUMO

Granulosa cells (GCs) play an important role in the development of follicles. In this study, we investigate the impact of heat stress at 41°C and 43°C on duck GCs' proliferation and steroids secretion. And, the transcriptomic responses to heat treatment were examined using RNA-sequencing analysis. Digital gene expression profiling was used to screen and identify differentially expressed genes (fold change ≥ 2 and Q value < 0.05). Further, the differential expression genes (DEGs) were classified into GO categories and KEGG pathways. The results show that duck GCs blocked in the G1 phase were increased on exposure to heat stress. Meanwhile, the expression of proliferative genes, which were essential for the transition from G1 to S phase, was inhibited. At the same time, heat stress inhibited the estradiol synthesis of GCs by decreasing CYP11A1 and CYP19A1 gene expression. A total of 241 DEGs including 181 upregulated and 60 downregulated ones were identified. Transcriptome result shows that heat shock protein and CXC chemokines gene were significantly activated during heat stress. While collagenases (MMP1 and MMP13) and strome lysins (MMP3) were downregulated. And, the hedgehog signaling pathway may be a prosurvival adaptive response under heat stress. These results offer a basis for better understanding the molecular mechanism underlying lay-eggs-less in ducks under heat stress.


Assuntos
Proliferação de Células/genética , Patos/fisiologia , Estradiol/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Expressão Gênica , Células da Granulosa/fisiologia , Resposta ao Choque Térmico/genética , Resposta ao Choque Térmico/fisiologia , Ovulação/fisiologia , Animais , Aromatase/genética , Aromatase/metabolismo , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Regulação para Baixo , Feminino , Células da Granulosa/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas Hedgehog/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
5.
Reprod Domest Anim ; 56(10): 1349-1357, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34342069

RESUMO

Kisspeptin, upstream of the hypothalamic-pituitary-gonadal axis, play an essential role in the reproductive process. In the present study, the effect of different types of kisspeptin, including goldfish (Carassius auratus) kiss1 kisspeptin (Kiss1), human kisspeptin (Hkiss) and their combination (Kiss1+H) on the reproductive-related genes (kiss1, Kissr and Cyp19) of adult female goldfish was investigated in comparison with Ovaprim (a synthetic GnRH hormone). Kiss1 and Hkiss were synthesized using a solid-phase synthesis approach. Peptides were injected at a dose of 100 µg/kg body weight. The brain and ovarian tissues of samples were separated for histological studies 24 hr post-injection. The expression of the kiss1, Kissr and Cyp19 genes was measured by RT-PCR. The results showed a significant increase in expression of the reproductive-related genes. Histological analysis revealed higher number of mature oocytes in kisspeptin treated groups compare to other ones. In conclusion, Hkiss and Kiss1+H are the most effective peptides in oocyte maturation and expression of reproductive-related genes. In addition, it seems that kisspeptins in other domestic animals can be used to stimulate the hypothalamus-pituitary-gonadal axis.


Assuntos
Carpa Dourada/fisiologia , Kisspeptinas/farmacologia , Oócitos/efeitos dos fármacos , Animais , Aromatase/genética , Encéfalo/metabolismo , Domperidona/farmacologia , Combinação de Medicamentos , Feminino , Expressão Gênica/efeitos dos fármacos , Carpa Dourada/genética , Carpa Dourada/metabolismo , Hormônio Liberador de Gonadotropina/farmacologia , Ovário/metabolismo
6.
Genet Test Mol Biomarkers ; 25(7): 486-495, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34280004

RESUMO

Objective: Breast cancer (BC), the most prevalent cancer in women, has been associated with several genetic factors, including the CYP19A1 rs700519 polymorphism; however, the conclusions have not been consistent. This case-control study and meta-analysis aimed to further assess the relationship between the CYP19A1 rs700519 polymorphism and BC susceptibility. Materials and Methods: We conducted a case-control study to assess the relationship of the CYP19A1 rs700519 polymorphism with the risk and prognosis of BC. Subsequently, we performed a meta-analysis of the case-control studies. Results: In the case-control study, we found a significant negative relationship between the rs700519 AA genotype and risk (χ2 = 7.503, p < 0.01) and disease-free survival rates (hazard rate = 0.400, 95% confidence interval [CI] = 0.181-0.883, p < 0.01) of patients with BC, especially in postmenopausal hormone receptor-positive (HR+) patients. Nine case-control studies were included in the meta-analysis. The CYP19A1 rs700519 polymorphism was significantly associated with BC susceptibility in the dominant (odds ratio [OR] = 0.95, 95% CI = 0.90-1.00, p = 0.05) and allelic models (OR = 0.84, 95% CI = 0.75-0.93, p < 0.01), but not in the recessive model. Sensitivity analysis revealed that the study results were stable, whereas the funnel plot revealed some publication bias. Conclusions: The CYP19A1 rs700519 polymorphism is related to breast tumorigenesis.


Assuntos
Aromatase/genética , Neoplasias da Mama/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Citocromo P-450 CYP1A1/genética , Suscetibilidade a Doenças , Intervalo Livre de Doença , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Fatores de Risco
7.
Sci Rep ; 11(1): 13772, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215832

RESUMO

Our present knowledge on interrelation between morphology/ultrastructure of mitochondria of the Leydig cell and its steroidogenic function is far from satisfactory and needs additional studies. Here, we analyzed the effects of blockade of androgen receptor, triggered by exposure to flutamide, on the expression of steroidogenic proteins (1) and ultrastructure of Leydig cells' constituents (2). We demonstrated that increase in the expression level of steroidogenic (StAR, CYP11A1, 3ß-HSD, and CYP19A1) proteins (and respective mRNAs) in rat testicular tissue as well as elevation of intratesticular sex steroid hormone (testosterone and estradiol) levels observed in treated animals correspond well to morphological alterations of the Leydig cell ultrastructure. Most importantly, up-regulation of steroidogenic proteins' expression apparently correlates with considerable multiplication of Leydig cell mitochondria and subsequent formation of local mitochondrial networks. Interestingly, we showed also that the above-mentioned processes were associated with elevated transcription of Drp1 and Mfn2 genes, encoding proteins implicated in mitochondrial dynamics. Collectively, our studies emphasize the importance of mitochondrial homeostasis to the steroidogenic function of Leydig cells.


Assuntos
Aromatase/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Hidroxiesteroide Desidrogenases/genética , Receptores Androgênicos/genética , Animais , Flutamida/farmacologia , Regulação da Expressão Gênica no Desenvolvimento , Hormônios Esteroides Gonadais/biossíntese , Hormônios Esteroides Gonadais/genética , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/biossíntese , Hormônio Luteinizante/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/ultraestrutura , Ratos , Receptores Androgênicos/metabolismo , Esteroides/biossíntese , Esteroides/metabolismo , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Testosterona/biossíntese , Testosterona/metabolismo
8.
Molecules ; 26(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34279404

RESUMO

Herein, we present the synthesis and crystal structures determination of five 4-(1-phenyl-1H-1,2,3-triazol-4-yl)phenol derivatives containing halogen atoms, 6a-e, which may be used as an excellent mimic of steroids in the drug development process. Good quality crystals obtained for all of the synthesized compounds allowed the analysis of their molecular structures. Subsequently, the determined crystal structures were used to calculate the Hirshfeld surfaces for each of the synthesized compounds. Furthermore, results of our docking studies indicated that synthesized derivatives are able to bind effectively to the active sites of selected enzymes and receptors involved in the hormone biosynthesis and signaling pathways, analogously to the native steroids.


Assuntos
Inibidores da Aromatase/síntese química , Simulação de Acoplamento Molecular , Triazóis/síntese química , Aromatase/química , Aromatase/metabolismo , Inibidores da Aromatase/farmacologia , Domínio Catalítico , Cristalização , Halogênios/química , Fenóis/química , Ligação Proteica , Triazóis/farmacologia
9.
Bioorg Chem ; 113: 105017, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34091288

RESUMO

Breast cancer, emerging malignancy is common among women due to overexpression of estrogen. Estrogens are biosynthesized from androgens by aromatase, a cytochrome P450 enzyme complex, and play a pivotal role in stimulating cell proliferation. Therefore, deprivation of estrogen by blocking aromatase is considered as the effective way for the inhibition and treatment of breast cancer. In recent years, various non-steroidal heterocyclic functionalities have been extensively developed and studied for their aromatase inhibition activity. This review provides information about the structural-activity relationship of heterocycles (Type II) towards aromatase. This aids the medicinal chemist around the significance of different heterocyclic moieties and helps to design potent aromatase inhibitors.


Assuntos
Inibidores da Aromatase/química , Aromatase/metabolismo , Compostos Heterocíclicos/química , Aromatase/química , Inibidores da Aromatase/metabolismo , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Desenho de Fármacos , Estrogênios/metabolismo , Feminino , Compostos Heterocíclicos/metabolismo , Compostos Heterocíclicos/uso terapêutico , Humanos , Relação Estrutura-Atividade
10.
Sci Rep ; 11(1): 12942, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34155264

RESUMO

Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disorder in pre-menopausal women having complex pathophysiology. Several candidate genes have been shown to have association with PCOS. CYP19 gene encodes a key steroidogenic enzyme involved in conversion of androgens into estrogens. Previous studies have reported contradictory results with regard to association of SNP rs2414096 in CYP19 gene with PCOS and hyperandrogenism in different ethnic populations. Present study was aimed to investigate the impact of SNP rs2414096 polymorphism of CYP19 gene on susceptibility of PCOS and hyperandrogenism in Kashmiri women. Further we also studied the genotypic-phenotypic association for various clinical and biochemical parameters of this polymorphism. Case control study. 394 PCOS cases diagnosed on the basis of Rotterdam criteria and age matched 306 healthy women. We found a significant differences in genotypic frequency (χ2 = 18.91, p < 0.05) as well as allele frequency (OR 0.63, CI 0.51-0.78, χ2 = 17.66, p < 0.05) between PCOS women and controls. The genotype-phenotype correlation analysis showed a significant difference in FG score (p = 0.047) and alopecia (p = 0.045) between the three genotypes. Also, the androgen excess markers like DHEAS (p < 0.001), Androstenedione (p < 0.001), Testosterone (p < 0.001) and FAI (p = 0.005) were significantly elevated in GG genotype and showed a significant difference in additive model in PCOS women. rs2414096 polymorphism of CYP19 gene is associated with the risk of PCOS as well as with clinical and biochemical markers of hyperandrogenism, hence suggesting its role in clinical manifestations of PCOS in Kashmiri women.


Assuntos
Alelos , Aromatase/genética , Predisposição Genética para Doença , Hiperandrogenismo/genética , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único , Adulto , Biomarcadores , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Hiperandrogenismo/diagnóstico , Modelos Genéticos , Razão de Chances , Síndrome do Ovário Policístico/diagnóstico , Fatores de Risco , Fatores Sexuais , Adulto Jovem
11.
J Enzyme Inhib Med Chem ; 36(1): 1334-1345, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34139914

RESUMO

Recent findings suggested several allosteric pockets on human aromatase that could be utilised for the development of new modulators able to inhibit this enzyme in a new mechanism. Herein, we applied an integrated in-silico-based approach supported by in-vitro enzyme-based and cell-based validation assays to select the best leads able to target these allosteric binding sites from a small library of plant-derived natural products. Chrysin, apigenin, and resveratrol were found to be the best inhibitors targeting the enzyme's substrate access channel and were able to produce a competitive inhibition with IC50 values ranged from 1.7 to 15.8 µM. Moreover, they showed a more potent antiproliferative effect against ER+ (MCF-7) than ER- one (MDA-MB-231) cell lines. On the other hand, both pomiferin and berberine were the best hits for the enzyme's haem-proximal cavity producing a non-competitive inhibition (IC50 15.1 and 21.4 µM, respectively) and showed selective antiproliferative activity towards MCF-7 cell lines.


Assuntos
Aromatase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Regulação Alostérica , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos
12.
Clinics (Sao Paulo) ; 76: e2846, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34133482

RESUMO

Breast cancer is the most frequently diagnosed malignant neoplasm in women and is considered a multifactorial disease of unknown etiology. One of the major risk factors is genetic alteration. Changes in CYP19A1 gene expression levels have been associated with increased risk and increased aggressiveness of breast cancer. Increased CYP19A1 gene expression and/or aromatase activity are among the major regulatory events for intratumoral production of estrogens in breast malignant tissues. This systematic review aimed to investigate the influence of CYP19A1 gene expression levels in women with breast cancer. The research was carried out using the PubMed, Scopus, and Web of Science databases. Searches were conducted between February 2 and May 15, 2019. Inclusion criteria were studies published between 2009 and 2019, English language publications, and human studies addressing the gene expression of CYP19A1 in breast cancer. A total of 6.068 studies were identified through PubMed (n=773), Scopus (n=2,927), and the Web of Science (n=2,368). After selecting and applying the inclusion and exclusion criteria, six articles were included in this systematic review. This systematic review provides evidence that increased or decreased levels of CYP19A1 gene expression may be related to pathological clinical factors of disease, MFS, OS, DFS, WATi, markers of metabolic function, concentrations of E1, FSH, and in the use of multiple exons 1 of the CYP19A1 gene in breast cancer.


Assuntos
Neoplasias da Mama , Aromatase/genética , Neoplasias da Mama/genética , Estrogênios , Feminino , Expressão Gênica , Humanos , RNA Mensageiro
13.
Aquat Toxicol ; 237: 105876, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34120034

RESUMO

Bisphenol A (BPA) is used to produce plastic and plastic derived products in multitude of daily utensils, being one of the industrial compounds most widely used. This endocrine disrupting chemical (EDCs) is a well-known environmental pollutant released into the aquatic environment from industrial wastewater, sewage sludge or landfill leachate. Aromatases are considered potential targets of EDCs with characteristics that make them suitable biomarkers of exposure to their effects. The main objective of our study was to evaluate the expression of cyp19a aromatase as a toxicological endpoint after BPA exposure through the identification and assessment of alterations of the main cells responsible for cyp19a1a and cyp19a1b expression in the zebrafish ovary and brain using different concentrations of BPA in water. Immunohistochemistry was used to analyze the expression of these enzymes in female zebrafish exposed and not exposed to different concentrations of BPA (1, 10, 100 and 1000 µg / L) in water (n = 6/group) for 14 days. The results obtained in this study showed that the cyp19a aromatase system, involved in the synthesis of steroid compounds, is specially located in distinct oocyte stages in the ovary (cyp19a1a) and in radial glial cells of the brain (cyp19a1b). An overexpression of these aromatases was observed after BPA exposure in zebrafish, peaking from a concentration of 10 µg/L and showing to be good biomarkers of exposure to identify the early effects of low BPA concentrations. To our knowledge, this study is the first to localize and quantify the expression of cyp19a1a and cyp19a1b in the cells of brain and ovary after fish exposure to different BPA concentrations in water.


Assuntos
Disruptores Endócrinos , Poluentes Químicos da Água , Animais , Aromatase/genética , Aromatase/metabolismo , Compostos Benzidrílicos/toxicidade , Encéfalo/metabolismo , Disruptores Endócrinos/toxicidade , Feminino , Ovário , Fenóis , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
14.
J Genet ; 1002021.
Artigo em Inglês | MEDLINE | ID: mdl-34187970

RESUMO

The human aromatase protein encoded by CYP19A1 gene is the principle enzyme involved in the biogenesis of oestrogen in adipose tissues. An excessive exposure to endogenous oestrogen is regarded as an important determinant in the risk of breast cancer. Thus, in the present study we have used multiple computational methods to identify the most deleterious nonsynonymous SNPs in CYP19A1 gene that caused probable genotypic-phenotypic alterations susceptible to breast cancer malignancy. In this study, a total of 338 nsSNPs were screened using 12 in silico tools including SIFT, PROVEAN, PolyPhene-2, SNAP2, I Mutant 3.0, MuPro, mCSM, PhD SNP, SNP&GO, P-Mut, Dr Cancer, and, CScape. Additionally the structural and functional consequences of missense mutations were validated using Consurf, ModPred, SOPMA, and, HOPE server tools. Of the 338 nsSNPs subjected to functional, protein stability, disease associated, and, cancer susceptible analysis, 14 variants were predicted to be highly deleterious mutants. Further, structural and molecular studies suggested 10 variants (R435H, Y77C, Y81C, E302K, E210K; and L451P, G49D, G131D, L204W and D309) to have various deformities and caused structural disturbances of the protein. Through the combination of multiple computational tools and strategized analysis, we report seven novel high risk nsSNPs of human aromatase enzyme in association with the pathogenesis of human breast cancer.


Assuntos
Aromatase/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Neoplasias da Mama/patologia , Biologia Computacional , Simulação por Computador , Feminino , Humanos , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genética , Software
15.
Am J Mens Health ; 15(3): 15579883211017033, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34036824

RESUMO

Abnormal aromatase (CYP19A1) expression may participate in prostate cancer (PCa) carcinogenesis. However, the results of studies on the CYP19A1 gene polymorphisms and PCa are conflicting. This meta-analysis aimed to systematically evaluate the associations between the CYP19A1 Arg264Cys polymorphism and the (TTTA)n repeat polymorphism and PCa. Electronic databases (PubMed, EmBase, ScienceDirect, and Cochrane Library) were comprehensively searched to identify eligible studies. The strength of the association between the Arg264Cys polymorphism and PCa was assessed by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) in allelic, dominant, recessive, homozygous, and heterozygous genetic models. To analyze the impact of the (TTTA)n repeat polymorphism, we sequentially took the N-repeat allele (where N equals 7,8,10,11,12, and 13) as the minor allele and the sum of all the other alleles as the major allele. The ORs and 95% CIs were calculated in the allelic model; this analysis was performed individually for each repeat number. Pooled estimates of nine studies addressing the Arg264Cys polymorphism indicated that this polymorphism was not associated with PCa risk in the overall population or in the Caucasian or Asian subgroups. The 8-repeat allele in the (TTTA)n repeat polymorphism increased PCa risk in the overall population (OR = 1.34, 95% CI = 1.14-1.58, p = .001) and in the subgroup with population-based (PB) controls (OR = 1.41, 95% CI = 1.13-1.74, p = .002) as well as in the subgroup using capillary electrophoresis to identify this polymorphism (OR = 1.34, 95% CI = 1.09-1.65, p = .006).The meta-analysis indicated that the CYP19A1 (TTTA)n repeat polymorphism, but not the Arg264Cys polymorphism, may affect PCa risk.


Assuntos
Aromatase , Neoplasias da Próstata , Alelos , Aromatase/genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo Genético , Neoplasias da Próstata/genética
16.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946947

RESUMO

The cation channel TRPV2 is known to be expressed by murine macrophages and is crucially involved in their functionality. Macrophages are frequent cells of the mouse testis, an immune-privileged and steroid-producing organ. TRPV2 expression by testicular macrophages and possible changes associated with age or inflammation have not been investigated yet. Therefore, we studied testes of young adult and old wild-type (WT) and AROM+ mice, i.e., transgenic mice overexpressing aromatase. In these animals, inflammatory changes are described in the testis, involving active macrophages, which increase with age. This is associated with impaired spermatogenesis and therefore AROM+ mice are a model for male infertility associated with sterile inflammation. In WT animals, testicular TRPV2 expression was mapped to interstitial CD206+ and peritubular MHC II+ macrophages, with higher levels in CD206+ cells. Expression levels of TRPV2 and most macrophage markers did not increase significantly in old mice, with the exception of CD206. As the number of TRPV2+ testicular macrophages was relatively small, their possible involvement in testicular functions and in aging in WT mice remains to be further studied. In AROM+ testis, TRPV2 was readily detected and levels increased significantly with age, together with macrophage markers and TNF-α. TRPV2 co-localized with F4/80 in macrophages and further studies showed that TRPV2 is mainly expressed by unusual CD206+MHC II+ macrophages, arising in the testis of these animals. Rescue experiments (aromatase inhibitor treatment and crossing with ERαKO mice) restored the testicular phenotype and also abolished the elevated expression of TRPV2, macrophage and inflammation markers. This suggests that TRPV2+ macrophages of the testis are part of an inflammatory cascade initiated by an altered sex hormone balance in AROM+ mice. The changes in testis are distinct from the described alterations in other organs of AROM+, such as prostate and spleen. When we monitored TRPV2 levels in another immune-privileged organ, namely the brain, we found that levels of TRPV2 were not elevated in AROM+ and remained stable during aging. In the adrenal, which similar to the testis produces steroids, we found slight, albeit not significant increases in TRPV2 in both AROM+ and WT mice, which were associated with age. Thus, the changes in the testis are specific for this organ.


Assuntos
Canais de Cálcio/fisiologia , Macrófagos/metabolismo , Orquite/metabolismo , Canais de Cátion TRPV/fisiologia , Testículo/metabolismo , Glândulas Suprarrenais/metabolismo , Fatores Etários , Animais , Aromatase/genética , Encéfalo/metabolismo , Canais de Cálcio/biossíntese , Canais de Cálcio/genética , Modelos Animais de Doenças , Genótipo , Infertilidade Masculina/metabolismo , Lectinas Tipo C/análise , Masculino , Lectinas de Ligação a Manose/análise , Camundongos , Camundongos Transgênicos , NADPH Oxidase 2/biossíntese , NADPH Oxidase 2/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Superfície Celular/análise , Espermatogênese , Canais de Cátion TRPV/biossíntese , Canais de Cátion TRPV/genética , Fator de Necrose Tumoral alfa/biossíntese
17.
Biol Direct ; 16(1): 8, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902660

RESUMO

Human aromatase is a member of the cytochrome P450 superfamily, involved in steroid hormones biosynthesis. In particular, it converts androgen into estrogens being therefore responsible for the correct sex steroids balance. Due to its capacity in producing estrogens it has also been considered as a promising target for breast cancer therapy. Two single-nucleotide polymorphisms (R264C and R264H) have been shown to alter aromatase activity and they have been associated to an increased or decreased risk for estrogen-dependent pathologies. Here, the effect of these mutations on the protein dynamics is investigated by UV/FTIR and time resolved fluorescence spectroscopy. H/D exchange rates were measured by FTIR for the three proteins in the ligand-free, substrate- and inhibitor-bound forms and the data indicate that the wild-type enzyme undergoes a conformational change leading to a more compact tertiary structure upon substrate or inhibitor binding. Indeed, the H/D exchange rates are decreased when a ligand is present. In the variants, the exchange rates in the ligand-free and -bound forms are similar, indicating that a structural change is lacking, despite the single amino acid substitution is located in the peripheral shell of the protein molecule. Moreover, the fluorescence lifetimes data show that the quenching effect on tryptophan-224 observed upon ligand binding in the wild-type, is absent in both variants. Since this residue is located in the catalytic pocket, these findings suggest that substrate entrance and/or retention in the active site is partially compromised in both mutants. A contact network analysis demonstrates that the protein structure is organized in two main clusters, whose connectivity is altered by ligand binding, especially in correspondence of helix-G, where the amino acid substitutions occur. Our findings demonstrate that SNPs resulting in mutations on aromatase surface modify the protein flexibility that is required for substrate binding and catalysis. The cluster analysis provides a rationale for such effect, suggesting helix G as a possible target for aromatase inhibition.


Assuntos
Aromatase/genética , Polimorfismo Genético , Espectrometria de Fluorescência , Aromatase/metabolismo , Catálise , Domínio Catalítico , Humanos , Ligação Proteica
19.
BMC Cancer ; 21(1): 391, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836687

RESUMO

BACKGROUND: Astrocytoma is a common type of central nervous system tumor. In this study, we investigated the correlation between ST6GAL1 and CYP19A1 polymorphisms and the risk and prognosis of astrocytoma. METHODS: A total of 365 astrocytoma patients and 379 healthy controls were genotyped using the Agena MassARRAY system. The correlation between ST6GAL1 and CYP19A1 variants and astrocytoma risk was calculated using logistic regression. The survival rate of patients with astrocytoma was analyzed to evaluate prognosis. RESULTS: We found that the ST6GAL1-rs2239611 significantly decreased the risk of astrocytoma in the codominant model (p = 0.044) and dominant model (p = 0.049). In stratified analyses, CYP19A1-rs2255192 might be associated with a higher risk of astrocytoma among the low-grade subgroup under recessive (p = 0.034) and additive (p = 0.030) models. However, CYP19A1-rs4646 had a risk-decreasing effect on the high-grade subgroup in the codominant model (p = 0.044). The results of Cox regression analysis showed that the CYP19A1-rs2239611 and -rs1042757 polymorphisms were significantly correlated with the prognosis of astrocytoma. CONCLUSION: Our results suggest that ST6GAL1 and CYP19A1 genes may be a potential biomarker of genetic susceptibility and prognosis to astrocytoma in the Chinese Han population.


Assuntos
Regiões 3' não Traduzidas , Antígenos CD/genética , Aromatase/genética , Astrocitoma/epidemiologia , Astrocitoma/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Sialiltransferases/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Astrocitoma/mortalidade , Astrocitoma/terapia , Estudos de Casos e Controles , China/epidemiologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Fatores de Risco , Análise de Sobrevida
20.
Molecules ; 26(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803091

RESUMO

Although melatonin has been extensively studied in animal reproduction, the mechanism of melatonin in puberty remains elusive. This study was designed to explore the effect of intraperitoneal administration of melatonin on puberty onset in female mice. The injection of melatonin into postnatal days 10 mice at a dose of 15 mg/kg accelerated the puberty onset in mice. Mechanistically, there was no difference in physical growth and serum Leptin levels after melatonin administration. Meanwhile, the serum levels of reproductive hormones involved in hypothalamic-pituitary-ovarian axis, such as FSH and estrogen level in serum were increased. The mRNA levels of GnRH and GnRHr were not affected by melatonin, while the expressions of FSHß in pituitary and Cyp19a1 in ovary were significantly up-regulated. In addition, melatonin still promoted FSH synthesis after ovariectomy. Furthermore, the enhanced activity of ERK1/2 signaling verified that the expression of FSHß increased in pituitary. We confirmed that melatonin promoted the FSH synthesis in pituitary, thereby increased serum estrogen levels and ultimately accelerated puberty onset. However, these effects of melatonin may be pharmacological due to the high dose. This study would help us to understand the functions of melatonin in pubertal regulation comprehensively.


Assuntos
Hormônio Foliculoestimulante/metabolismo , Melatonina/farmacologia , Maturidade Sexual/efeitos dos fármacos , Animais , Aromatase/metabolismo , China , Estrogênios/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Injeções Intraperitoneais , Leptina/metabolismo , Hormônio Luteinizante/metabolismo , Melatonina/metabolismo , Camundongos , Ovário/efeitos dos fármacos , Hipófise/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Receptores LHRH/metabolismo , Maturidade Sexual/fisiologia
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