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1.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445256

RESUMO

Recent data demonstrate the anabolic effect of oxytocin on bone. Bone cells express oxytocin receptors. Oxytocin promotes osteoblasts differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxytocin is synthetized by osteoblasts, and this synthesis is stimulated by estrogen. Animal studies demonstrate a direct action of oxytocin on bone, as the systemic administration of oxytocin prevents and reverses the bone loss induced by estrogen deficiency. Although oxytocin is involved in bone formation in both sexes during development, oxytocin treatment has no effect on male osteoporosis, underlining the importance of estrogen that amplifies its local autocrine and paracrine secretion. There are few human data showing a decrease in the oxytocin serum level in anorexia nervosa independently of estrogen and in amenorrheic women associated with impaired bone microarchitecture; in post-menopausal women a higher oxytocin serum level is associated with higher bone density, but not in osteoporotic men. Oxytocin displays many effects that may be beneficial in the management of osteoporosis, cardiovascular diseases, cognitive disorders, breast cancer, diabetes and body fat gain, all age-related diseases affecting elderly women, opening exciting therapeutic perspectives, although the issue is to find a single route, dosage and schedule able to reach all these targets.


Assuntos
Comunicação Autócrina , Densidade Óssea , Osso e Ossos/metabolismo , Ocitocina/metabolismo , Comunicação Parácrina , Caracteres Sexuais , Amenorreia/metabolismo , Animais , Anorexia Nervosa/metabolismo , Osso e Ossos/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Estrogênios/deficiência , Estrogênios/metabolismo , Feminino , Humanos , Masculino , Osteoporose Pós-Menopausa/metabolismo
2.
Commun Biol ; 4(1): 948, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373576

RESUMO

The preoptic area (POA) is one of the most evolutionarily conserved regions of the vertebrate brain and contains subsets of neuropeptide-expressing neurons. Here we found in the teleost medaka that two neuropeptides belonging to the secretin family, pituitary adenylate cyclase-activating polypeptide (Pacap) and vasoactive intestinal peptide (Vip), exhibit opposite patterns of sexually dimorphic expression in the same population of POA neurons that project to the anterior pituitary: Pacap is male-biased, whereas Vip is female-biased. Estrogen secreted by the ovary in adulthood was found to attenuate Pacap expression and, conversely, stimulate Vip expression in the female POA, thereby establishing and maintaining their opposite sexual dimorphism. Pituitary organ culture experiments demonstrated that both Pacap and Vip can markedly alter the expression of various anterior pituitary hormones. Collectively, these findings show that males and females use alternative preoptic neuropeptides to regulate anterior pituitary hormones as a result of their different estrogen milieu.


Assuntos
Estrogênios/metabolismo , Proteínas de Peixes/metabolismo , Neuropeptídeos/metabolismo , Oryzias/metabolismo , Hormônios Hipofisários/metabolismo , Área Pré-Óptica/metabolismo , Animais , Feminino , Masculino , Caracteres Sexuais
3.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360877

RESUMO

The triad of noise-generated, drug-induced, and age-related hearing loss is the major cause of acquired sensorineural hearing loss (ASNHL) in modern society. Although these three forms of hearing loss display similar underlying mechanisms, detailed studies have revealed the presence of sex differences in the auditory system both in human and animal models of ASNHL. However, the sexual dimorphism of hearing varies among noise-induced hearing loss (NIHL), ototoxicity, and age-related hearing loss (ARHL). Importantly, estrogen may play an essential role in modulating the pathophysiological mechanisms in the cochlea and several reports have shown that the effects of hormone replacement therapy on hearing loss are complex. This review will summarize the clinical features of sex differences in ASNHL, compare the animal investigations of cochlear sexual dimorphism in response to the three insults, and address how estrogen affects the auditory organ at molecular levels.


Assuntos
Cóclea/metabolismo , Estrogênios/metabolismo , Perda Auditiva Neurossensorial/metabolismo , Animais , Cóclea/patologia , Feminino , Humanos , Masculino , Caracteres Sexuais
4.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445662

RESUMO

Acute myocardial infarction (MI) is associated with an intense inflammatory response that is critical for cardiac repair but is also involved in the pathogenesis of adverse cardiac remodeling, i.e., the set of size, geometry, and structure changes that represent the structural substrate for the development of post-MI heart failure. Deciphering the pathophysiological mechanisms underlying cardiac repair after MI is, therefore, critical to favorably regulate cardiac wound repair and to prevent development of heart failure. Catecholamines and estrogen play an active role in regulating the inflammatory response in the infarcted area. For example, stress-induced catecholamines alter recruitment and trafficking of leukocytes to the heart. Additionally, estrogen affects rate of cardiac rupture during the acute phase of MI, as well as infarct size and survival in animal models of MI. In this review, we will summarize the role of ß-adrenergic receptors and estrogen in cardiac repair after infarction in preclinical studies.


Assuntos
Estrogênios/metabolismo , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/complicações , Receptores Adrenérgicos beta/metabolismo , Remodelação Ventricular , Animais , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos
5.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445474

RESUMO

Otolaryngology (also known as ear, nose, and throat (ENT)) diseases can be significantly affected by the level of sex hormones, which indicates that sex differences affect the manifestation, pathophysiology, and outcomes of these diseases. Recently, increasing evidence has suggested that proinflammatory responses in ENT diseases are linked to the level of sex hormones. The sex hormone receptors are present on a wide variety of immune cells; therefore, it is evident that they play crucial roles in regulating the immune system and hence affect the disease progression of ENT diseases. In this review, we focus on how sex hormones, particularly estrogens, regulate ENT diseases, such as chronic rhinosinusitis, vocal fold polyps, thyroid cancer, Sjögren's syndrome, and head and neck cancers, from the perspectives of inflammatory responses and specialized proresolving mediator-driven resolution. This paper aims to clarify why considering sex differences in the field of basic and medical research on otolaryngology is a key component to successful therapy for both males and females in the future.


Assuntos
Estrogênios/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Inflamação/patologia , Rinite/patologia , Sinusite/patologia , Síndrome de Sjogren/patologia , Neoplasias da Glândula Tireoide/patologia , Animais , Progressão da Doença , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Inflamação/metabolismo , Otolaringologia , Rinite/metabolismo , Fatores Sexuais , Sinusite/metabolismo , Síndrome de Sjogren/metabolismo , Neoplasias da Glândula Tireoide/metabolismo
6.
Int J Mol Sci ; 22(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34281260

RESUMO

Males have a higher risk for cardiovascular diseases (CVDs) than females. Ambient fine particulate matter (PM) exposure increases CVD risk with increased reactive oxygen species (ROS) production and oxidative stress. Endothelial progenitor cells (EPCs) are important to vascular structure and function and can contribute to the development of CVDs. The aims of the present study were to determine if sex differences exist in the effect of PM exposure on circulating EPCs in mice and, if so, whether oxidative stress plays a role. Male and female C57BL/6 mice (8-10 weeks old) were exposed to PM or a vehicle control for six weeks. ELISA analysis showed that PM exposure substantially increased the serum levels of IL-6 and IL-1ß in both males and females, but the concentrations were significantly higher in males. PM exposure only increased the serum levels of TNF-α in males. Flow cytometry analysis demonstrated that ROS production was significantly increased by PM treatment in males but not in females. Similarly, the level of circulating EPCs (CD34+/CD133+ and Sca-1+/Flk-1+) was significantly decreased by PM treatment in males but not in females. Antioxidants N-acetylcysteine (NAC) effectively prevented PM exposure-induced ROS and inflammatory cytokine production and restored circulating EPC levels in male mice. In sharp contrast, circulating EPC levels remained unchanged in female mice with PM exposure, an effect that was not altered by ovariectomy. In conclusion, PM exposure selectively decreased the circulating EPC population in male mice via increased oxidative stress without a significant impact on circulating EPCs in females independent of estrogen.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Material Particulado/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Citocinas/sangue , Células Progenitoras Endoteliais/patologia , Estrogênios/metabolismo , Feminino , Mediadores da Inflamação/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores Sexuais
7.
Biomed Pharmacother ; 139: 111658, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243627

RESUMO

According to recent statistics, Lung Cancer (LC) is one of the most frequently diagnosed tumor types, representing nearly 12% of all global cancer cases. Moreover, in recent years, an increased mortality rate and incidence of this cancer were observed, especially among nonsmokers. Lung cancer patients are often characterized by poor prognosis and low survival rates, which encourages the scientific community to investigate the biochemical and molecular processes leading to the development of this malignancy. Furthermore, the mechanisms of LC formation and progression are not yet fully elucidated due to their high complexity, as well as a multitude of environmental, genetic, and molecular factors involved. Even though LC's association with exposure to cigarette smoke is indisputable, current research provides evidence that the development of this cancer can also be affected by the presence of estrogens and their interaction with several tobacco smoke components. Hence, the main goal of this brief review was to investigate reports of a possible synergy between 17ß estradiol (E2), the most biologically active estrogen, and benzo(a)pyrene (BaP), a strongly carcinogenic compound produced as a result of incomplete tobacco combustion. The literature sources demonstrate a possible carcinogenic synergy between estrogens, especially E2, and BaP, a toxic tobacco smoke component. Therefeore, the combined effect of disturbed estrogen production in cancer cells, as well as the molecular influence exerted by BaP, could explain the increased aggressiveness and rate of LC development. Summarizing, the synergistic effect of these risk factors is an interesting area of further research.


Assuntos
Benzo(a)pireno/toxicidade , Estrogênios/metabolismo , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Fumar/efeitos adversos , Animais , Carcinógenos/toxicidade , Estradiol/metabolismo , Humanos , Fumaça/efeitos adversos , Tabaco/toxicidade
8.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299239

RESUMO

Estrogens are steroid hormones that play a crucial role in the regulation of the reproductive and non-reproductive system physiology. Among non-reproductive systems, the nervous system is mainly affected by estrogens due to their antioxidant, anti-apoptotic, and anti-inflammatory activities, which are mediated by membranous and nuclear estrogen receptors, and also by non-estrogen receptor-associated estrogen actions. Neuronal viability and functionality are also associated with the maintenance of mitochondrial functions. Recently, the localization of estrogen receptors, especially estrogen receptor beta, in the mitochondria of many types of neuronal cells is documented, indicating the direct involvement of the mitochondrial estrogen receptor beta (mtERß) in the maintenance of neuronal physiology. In this study, cell lines of N2A cells stably overexpressing a mitochondrial-targeted estrogen receptor beta were generated and further analyzed to study the direct involvement of mtERß in estrogen neuroprotective antioxidant and anti-apoptotic actions. Results from this study revealed that the presence of estrogen receptor beta in mitochondria render N2A cells more resistant to staurosporine- and H2O2-induced apoptotic stimuli, as indicated by the reduced activation of caspase-9 and -3, the increased cell viability, the increased ATP production, and the increased resistance to mitochondrial impairment in the presence or absence of 17-ß estradiol (E2). Thus, the direct involvement of mtERß in antioxidant and anti-apoptotic activities is documented, rendering mtERß a promising therapeutic target for mitochondrial dysfunction-associated degenerative diseases.


Assuntos
Receptor beta de Estrogênio/metabolismo , Mitocôndrias/metabolismo , Neuroblastoma/metabolismo , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Estradiol/farmacologia , Receptor beta de Estrogênio/genética , Estrogênios/metabolismo , Estrogênios/farmacologia , Peróxido de Hidrogênio/metabolismo , Camundongos , Mitocôndrias/fisiologia , Células-Tronco Neurais/metabolismo , Neuroblastoma/genética , Neurônios/metabolismo , Neurônios/fisiologia , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptores de Estrogênio/metabolismo
9.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299224

RESUMO

Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias da Mama , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/fisiologia , Estrogênios/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Interleucina-6/metabolismo , Células MCF-7 , Monócitos/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Receptores de Estrogênio/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281183

RESUMO

Cryptorchidism in horses is a commonly occurring malformation. The molecular basis of this pathology is not fully known. In addition, the origins of high intratesticular estrogen levels in horses remain obscure. In order to investigate the role of the G-protein-coupled membrane estrogen receptor (GPER) and establish histological and biochemical cryptorchid testis status, healthy and cryptorchid horse testes were subjected to scanning electron microscopy analysis, histochemical staining for total protein (with naphthol blue black; NBB), acid content (with toluidine blue O; TBO), and polysaccharide content (with periodic acid-Schiff; PAS). The expression of GPER was analyzed by immunohistochemistry and Western blot. GPER-mediated intracellular cAMP and calcium (Ca2+) signaling were measured immunoenzymatically or colorimetrically. Our data revealed changes in the distribution of polysaccharide content but not the protein and acid content in the cryptorchid testis. Polysaccharides seemed to be partially translocated from the interstitial compartment to the seminiferous tubule compartment. Moreover, the markedly decreased expression of GPER and GPER downstream molecules, cAMP and Ca2+, suggests their potential role in testis pathology. Increased estrogen levels in cryptorchid conditions may be linked to disturbed GPER signaling. We postulate that GPER is a prominent key player in testis development and function and may be used as a new biomarker of horse testis in health and disease.


Assuntos
Criptorquidismo/veterinária , Doenças dos Cavalos/metabolismo , Receptores de Estrogênio/metabolismo , Testículo/metabolismo , Animais , Western Blotting/métodos , Criptorquidismo/metabolismo , Estrogênios/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Cavalos , Imuno-Histoquímica/métodos , Masculino , Microscopia Eletrônica de Varredura/métodos , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
11.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069498

RESUMO

Tamoxifen is the most widely used selective modulator of estrogen receptors (SERM) and the first strategy as coadjuvant therapy for the treatment of estrogen-receptor (ER) positive breast cancer worldwide. In spite of such success, tamoxifen is not devoid of undesirable effects, the most life-threatening reported so far affecting uterine tissues. Indeed, tamoxifen treatment is discouraged in women under risk of uterine cancers. Recent molecular design efforts have endeavoured the development of tamoxifen derivatives with antiestrogen properties but lacking agonistic uterine tropism. One of this is FLTX2, formed by the covalent binding of tamoxifen as ER binding core, 7-nitrobenzofurazan (NBD) as the florescent dye, and Rose Bengal (RB) as source for reactive oxygen species. Our analyses demonstrate (1) FLTX2 is endowed with similar antiestrogen potency as tamoxifen and its predecessor FLTX1, (2) shows a strong absorption in the blue spectral range, associated to the NBD moiety, which efficiently transfers the excitation energy to RB through intramolecular FRET mechanism, (3) generates superoxide anions in a concentration- and irradiation time-dependent process, and (4) Induces concentration- and time-dependent MCF7 apoptotic cell death. These properties make FLTX2 a very promising candidate to lead a novel generation of SERMs with the endogenous capacity to promote breast tumour cell death in situ by photosensitization.


Assuntos
Antagonistas de Estrogênios/química , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Neoplasias da Mama/metabolismo , Moduladores de Receptor Estrogênico/farmacologia , Estrogênios/metabolismo , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Simulação de Dinâmica Molecular , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Útero/metabolismo
12.
Am J Pathol ; 191(9): 1490-1498, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34102108

RESUMO

Insulin resistance results when peripheral tissues, including adipose, skeletal muscle, and liver, do not respond appropriately to insulin, causing the ineffective uptake of glucose. This represents a risk factor for the development of type 2 diabetes mellitus. Along with abdominal obesity, hypertension, high levels of triglycerides, and low levels of high-density lipoproteins, insulin resistance is a component of a condition known as the metabolic syndrome, which significantly increases the risk of developing cardiometabolic disorders. Accumulating evidence shows that biological sex has a major influence in the development of cardiometabolic disturbances, with females being more protected than males. This protection appears to be driven by female sex hormones (estrogens), as it tends to disappear with the onset of menopause but can be re-established with hormone replacement therapy. This review evaluates current knowledge on the protective role of estrogens in the relevant pathways associated with insulin resistance. The importance of increasing our understanding of sex as a biological variable in cardiometabolic research to promote the development of more effective preventative strategies is emphasized.


Assuntos
Estrogênios/metabolismo , Resistência à Insulina/fisiologia , Caracteres Sexuais , Animais , Feminino , Humanos , Fatores de Risco
13.
Nat Commun ; 12(1): 3386, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099644

RESUMO

During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Implantação do Embrião , Infertilidade Feminina/genética , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Animais , Biópsia , Modelos Animais de Doenças , Endométrio/metabolismo , Endométrio/patologia , Estrogênios/metabolismo , Feminino , Humanos , Camundongos , Camundongos Knockout , Gravidez , Transdução de Sinais/fisiologia , Proteína Smad1/análise , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad5/análise , Proteína Smad5/genética , Proteína Smad5/metabolismo
14.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071671

RESUMO

Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far. Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a significant role in explaining these differences. Additionally, the impact of sex chromosomes as well as the influence of gene-sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. This narrative review explored current evidence on sex/gender differences in DKD, taking into account hormonal, genetic and clinical factors.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Estrogênios/metabolismo , Feminino , Humanos , Masculino , Fatores de Risco , Fatores Sexuais
15.
Womens Health (Lond) ; 17: 17455065211022262, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34096383

RESUMO

In COVID-19 disease, are reported gender differences in relation to severity and death. The aim of this review is to highlight gender differences in the immune response to COVID-19. The included studies were identified using PubMed, until 30 October 2020. The search included the following keywords: SARS-CoV-2, COVID-19, gender, age, sex, and immune system. Literature described that females compared to males have greater inflammatory, antiviral, and humoral immune responses. In female, estrogen is a potential ally to alleviate SARS-COV-2 disease. In male, testosterone reduces vaccination response and depresses the cytokine response. In the older patients, and in particular, in female older patients, it has been reported a progressive functional decline in the immune systems. Differences by gender were reported in infection diseases, including SARS-CoV-2. These data should be confirmed by the other epidemiological studies.


Assuntos
Envelhecimento/imunologia , COVID-19/imunologia , Sistema Imunitário/fisiologia , Imunidade/fisiologia , Fatores Sexuais , Estrogênios/metabolismo , Feminino , Humanos , Masculino , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Testosterona/metabolismo , Vacinação
16.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074015

RESUMO

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.


Assuntos
Adenocarcinoma/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Antineoplásicos/farmacologia , Apoptose/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Esofágicas/metabolismo , MicroRNAs/metabolismo , Estresse Oxidativo/genética , Proteína Supressora de Tumor p53/metabolismo , Adenocarcinoma/genética , Sistema y+ de Transporte de Aminoácidos/genética , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Neoplasias Esofágicas/genética , Estrogênios/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Técnicas de Inativação de Genes , Ontologia Genética , Glutationa/metabolismo , Humanos , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética
17.
Nat Metab ; 3(5): 618-635, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34031590

RESUMO

Macrophages generate mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically driven and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state wherein stimulus-induced pro-inflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyoestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and pro-inflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mitochondrial reactive oxygen species and mitochondrial reactive electrophilic species are TLR-dependent signalling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signalling and pharmacologically triggering mitohormesis represents a new anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of pro-inflammatory gene transcription by mitochondria.


Assuntos
Reprogramação Celular , Metabolismo Energético , Tolerância Imunológica , Macrófagos/imunologia , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Acetilcoenzima A/metabolismo , Anti-Inflamatórios/farmacologia , Estrogênios/metabolismo , Regulação da Expressão Gênica , Lipopolissacarídeos/imunologia , Ativação de Macrófagos , Modelos Biológicos , Espécies Reativas de Oxigênio/metabolismo , Estresse Fisiológico
18.
Mol Biol Rep ; 48(4): 3845-3851, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33993404

RESUMO

Polycystic ovary syndrome (PCOS) is an endocrine disorder and affects 5-10% of reproductive-age women. Chronic anovulation, polycystic ovaries, and hyperandrogenism are the important features of this syndrome. Furthermore, hyperinsulinemia and central obesity are frequent in PCOS women. In recent years, noncoding RNAs detection provided new ideas to explain the etiology of female reproductive disorders. Long noncoding RNAs (lncRNAs) as a subset of noncoding RNAs are associated with the pathogenesis of manifold reproductive-related disorders. Various investigations emphasized the potential involvement of lncRNAs in PCOS development. Therefore, in this paper, we will summarize the function of numerous lncRNAs in the apoptosis and proliferation of granulosa cells (GCs), insulin resistance (IR), and steroidogenesis in PCOS.


Assuntos
Síndrome do Ovário Policístico/metabolismo , RNA Longo não Codificante/genética , Androgênios/metabolismo , Animais , Apoptose , Proliferação de Células , Estrogênios/metabolismo , Feminino , Humanos , Insulina/metabolismo , Síndrome do Ovário Policístico/genética , RNA Longo não Codificante/metabolismo
19.
J Ovarian Res ; 14(1): 70, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020688

RESUMO

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mainly attacks the respiratory system and is characterized by pneumonia, cytokine storm, coagulation disorders and severe immune downregulation. Although public health experts predicted worst outcomes in Africa, the incidence, hospitalization and mortality rates have been lower in Africa compared to other continents. Interestingly, lower incidence and mortality rates have been observed in women from Africa compared to their cohorts from other continents. Also, in the US non-Hispanic Black females have lower COVID-19 and death rates compared to their white counterparts. It's unclear why this significant difference exists; however, the ovarian function, genetics and immunological statuses could play a major role. Women of African descent have elevated levels of estrogen compared with Caucasians hence we anticipate that estrogen might offer some protection against the SARS-CoV-2 infections. The racial differences in lifestyle, age and inaccessibility to contraceptive usage might also play a role. Here, we provide insight on how the high levels of estrogen in African women might contribute to the lower cases and fatalities in Africa. Specifically, estrogen might offer protection against COVID-19 by suppressing hyper-production of cytokines, promoting anti-inflammatory cytokines, stimulating antibody production and suppressing endoplasmic reticulum (ER) stress. This will as well provide useful information on how future pandemics could be managed using Africa as a case study.


Assuntos
Teste para COVID-19/tendências , COVID-19/epidemiologia , COVID-19/etiologia , África/epidemiologia , Afro-Americanos , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/tratamento farmacológico , COVID-19/mortalidade , Teste para COVID-19/métodos , Síndrome da Liberação de Citocina/etiologia , Estresse do Retículo Endoplasmático , Estrogênios/metabolismo , Estrogênios/farmacologia , Feminino , Humanos , Incidência , Masculino , Mortalidade , Fatores Raciais , Fatores Sexuais
20.
Aquat Toxicol ; 236: 105843, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34010734

RESUMO

Octocrylene (OC) is a broad-spectrum ultraviolet-absorbing chemical used in sunscreen and other personal care products. Its health effects are a concern because it has been detected in water, fish, humans, and food chains. In vivo and in vitro investigations were performed in zebrafish (Danio rerio) larvae and a zebrafish liver cell line (ZFL), respectively, to understand the potential risks and molecular mechanisms of OC toxicity. The 96-h median lethal concentration (LC50) of OC was determined to be 251.8 µM in larvae and 5.5 µM in ZFL cells. Quantitative real-time PCR (qRT-PCR) showed that OC induced the expression of genes for CYPs (CYP1A, CYP3A65), estrogen receptors (ERα, ERß1, GPER), vitellogenin (VTG1), and sex determination (BRCA2, CYP19A, DMRT1, SOX9A), both in vitro and in vivo. A whole-transcriptome sequencing method was used to evaluate the gene expression profile of larvae exposed to OC. OC was found to mediate the biosynthesis of estrogens (such as estriol) and affect the antioxidant pathway (glutathione transferases and peroxisome). These findings clarify the toxic effects and molecular mechanisms of OC and support banning its use in cosmetics.


Assuntos
Acrilatos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Linhagem Celular , Estrogênios/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Larva/efeitos dos fármacos , Dose Letal Mediana , Fígado/efeitos dos fármacos , Protetores Solares/toxicidade , Transcriptoma , Vitelogeninas/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
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