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Introduction: The reproductive system is tightly regulated by environmental and physiological signals. Melatonin, known as the hormone of darkness, plays a crucial role in regulating both the circadian and reproductive systems in mammals. Hypothyroidism is a key endocrine disorder that harms the reproductive system. Despite many studies on melatonin's effects on the reproductive system, there is conflicting information regarding melatonin synthesis modulation in hypothyroidism. The objective of this study was to investigate the modulation of plasma melatonin levels and gene expression of Aanat and Asmt in the pineal gland and gonads of rats with hypothyroidism at different times of the day. Methods: Female and male Wistar rats were divided into control and hypothyroid groups. Hypothyroidism was induced using propylthiouracil (PTU) for 15 days, rats were euthanized six hours after lights on (ZT6), before lights off (ZT11.5), and six hours after lights off (ZT18). Free thyroxine (FT4) and melatonin were quantified in plasma, and gene expressions of melatonin synthesizing enzymes (Aanat and Asmt) were measured in pineal and sexual organs (testis and ovary). Also, morphological analysis was performed in sexual organs. Results: The results reveal some disparities between the sexes. Hypothyroidism reduced antral and primary follicles in the ovary, and reduced the weight of testis, epididymis, and prostate. In relation to gene expression, we observed a reduction in Aanat expression in the pineal gland during the light phase (ZT6), and in males, this reduction occurred during the dark phase (ZT18). Regarding Asmt expression, there was a decrease in females also during the dark phase (ZT18). In the gonads, there was an increase in expression in both sexes at ZT11.5. Additionally, it was interesting to observe the association between FT4 levels and Asmt expression in the gonads. Conclusions: This study showed that acute hypothyroidism can affect components of the melatonergic system in gonads, particularly gene expression of melatonin synthesis enzymes (Aanat and Asmt) contributing to changes in reproduction organs during disease progression. These findings enhance our understanding of melatonin synthesis in the reproductive system during hypothyroidism, showing distinct responses in male and female rats, and suggest that hypothyroidism affects the circadian rhythmicity of melatonin synthesis in a sex-dependent manner.
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Acetilserotonina O-Metiltransferasa , Hipotiroidismo , Melatonina , Glándula Pineal , Ratas Wistar , Testículo , Animales , Melatonina/sangre , Femenino , Masculino , Hipotiroidismo/metabolismo , Ratas , Glándula Pineal/metabolismo , Acetilserotonina O-Metiltransferasa/metabolismo , Acetilserotonina O-Metiltransferasa/genética , Testículo/metabolismo , Testículo/patología , N-Acetiltransferasa de Arilalquilamina/metabolismo , N-Acetiltransferasa de Arilalquilamina/genética , Gónadas/metabolismo , Ovario/metabolismo , Ovario/patología , PropiltiouraciloRESUMEN
Oxidative stress (OS) and endoplasmic reticulum stress (ERS) are at the genesis of placental disorders observed in preeclampsia, intrauterine growth restriction, and maternal hypothyroidism. In this regard, cationic manganese porphyrins (MnPs) comprise potent redox-active therapeutics of high antioxidant and anti-inflammatory potential, which have not been evaluated in metabolic gestational diseases yet. This study evaluated the therapeutic potential of two MnPs, [MnTE-2-PyP]5+ (MnP I) and [MnT(5-Br-3-E-Py)P]5+ (MnP II), in the fetal-placental dysfunction of hypothyroid rats. Hypothyroidism was induced by administration of 6-Propyl-2-thiouracil (PTU) and treatment with MnPs I and II 0.1 mg/kg/day started on the 8th day of gestation (DG). The fetal and placental development, and protein and/or mRNA expression of antioxidant mediators (SOD1, CAT, GPx1), hypoxia (HIF1α), oxidative damage (8-OHdG, MDA), ERS (GRP78 and CHOP), immunological (TNFα, IL-6, IL-10, IL-1ß, IL-18, NLRP3, Caspase1, Gasdermin D) and angiogenic (VEGF) were evaluated in the placenta and decidua on the 18th DG using immunohistochemistry and qPCR. ROS and peroxynitrite (PRX) were quantified by fluorometric assay, while enzyme activities of SOD, GST, and catalase were evaluated by colorimetric assay. MnPs I and II increased fetal body mass in hypothyroid rats, and MnP I increased fetal organ mass. MnPs restored the junctional zone morphology in hypothyroid rats and increased placental vascularization. MnPs blocked the increase of OS and ERS mediators caused by hypothyroidism, showing similar levels of expression of HIFα, 8-OHdG, MDA, Gpx1, GRP78, and Chop to the control. Moreover, MnPs I and/or II increased the protein expression of SOD1, Cat, and GPx1 and restored the expression of IL10, Nlrp3, and Caspase1 in the decidua and/or placenta. However, MnPs did not restore the low placental enzyme activity of SOD, CAT, and GST caused by hypothyroidism, while increased the decidual and placental protein expression of TNFα. The results show that treatment with MnPs improves the fetal-placental development and the placental inflammatory state of hypothyroid rats and protects against oxidative stress and reticular stress caused by hypothyroidism at the maternal-fetal interface.
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Hipotiroidismo , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Animales , Embarazo , Femenino , Ratas , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Inflamasomas/metabolismo , Modelos Animales de Enfermedad , Placenta/metabolismo , Placenta/efectos de los fármacos , Placentación/efectos de los fármacos , Antioxidantes/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Desarrollo Fetal/efectos de los fármacos , Manganeso , Metaloporfirinas/farmacología , Chaperón BiP del Retículo EndoplásmicoRESUMEN
This study evaluated whether the treatment of pseudopregnancy in bitches with vitamin B6 modulates uterine expression of receptors for progesterone (PR), oestrogen (ERα), androgen (AR), thyroid hormone (TRα) and the kisspeptin/Kiss1r system. Eighteen pseudopregnant bitches were treated for 20 days in groups receiving placebo (n = 6); cabergoline (5 µg/kg/day; n = 6); or vitamin B6 (50 mg/kg/day; n = 6). Blood was collected on the 1st day of drug administration and 120 h later to measure serum prolactin (PRL). After treatment, they were ovariohysterectomized and uterine fragments were collected for histomorphometry and immunohistochemical evaluation of PR, ERα, AR, TRα, Kiss1 and Kiss1r. After 120 h of cabergoline or vitamin B6 treatment, PRL levels were reduced in the bitches, confirming the antiprolactinemic effect of these drugs. Furthermore, regardless of treatment, the animals exhibited uterine histomorphometry consistent with dioestrus. The PR showed strong immunostaining in all regions and an increase in scores was observed for this receptor in animals treated with vitamin B6 in deep glands. In contrast, ERα and Kiss1R receptors showed weak to no immunostaining in all uterine regions and no changes between groups. Regarding AR, most animals treated with vitamin B6 showed increased trends in the deep gland and myometrium marking scores. In contrast, in both vitamin B6 and cabergoline treatments, a reduction in TRα marking scores was observed compared to the control group. In addition, on the endometrial surface, a reduction was observed in the marked area of Kiss1 after administration of cabergoline when compared to the pseudopregnant control group. These findings shed valuable insight into the use of vitamin B6 as a drug with actions similar to cabergoline in reducing PRL and uterine modulation in bitches.
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Cabergolina , Kisspeptinas , Prolactina , Seudoembarazo , Útero , Animales , Femenino , Perros , Kisspeptinas/farmacología , Kisspeptinas/metabolismo , Útero/efectos de los fármacos , Útero/metabolismo , Cabergolina/farmacología , Prolactina/metabolismo , Seudoembarazo/veterinaria , Seudoembarazo/metabolismo , Receptores de Progesterona/metabolismo , Receptores Androgénicos/metabolismo , Ergolinas/farmacologíaRESUMEN
OBJECTIVE: To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: 98 male Wistar rats. METHODS: Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR. RESULTS: Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1). CONCLUSION AND CLINICAL RELEVANCE: These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.
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Neuralgia , Traumatismos de los Nervios Periféricos , Quinuclidinas , Ratas , Masculino , Animales , Antioxidantes/metabolismo , Ratas Wistar , Enfermedades Neuroinflamatorias , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-10/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estudios Prospectivos , Estrés Oxidativo , Hiperalgesia/tratamiento farmacológico , Estrés del Retículo Endoplásmico , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Superóxido Dismutasa/metabolismo , Hipoxia/tratamiento farmacológicoRESUMEN
Hypothyroidism compromises the testicular redox status and is associated with reduced sperm quality and infertility in men. In this regard, studies have demonstrated the antioxidant potential of kisspeptin in reproductive and metabolic diseases. In this study, we evaluate the effects of kisspeptin-10 (Kp10) on the testicular redox, as well as mediators of the unfolded protein response (UPR) in adult rats with hypothyroidism. Adult male Wistar rats were randomly separated into the Control (n = 15), Hypo (n = 13) and Hypo + Kp10 (n = 14) groups, and hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals received Kp10. Testis samples were collected for enzymatic, immunohistochemical and/or gene evaluation of mediators of oxidative stress (TBARs, lipid hydroperoxides (LOOH), ROS, peroxynitrite, SOD, CAT and GPX), endoplasmic reticulum stress (GRP78, ATF6, PERK, CHOP, HO-1 and sXBP1) and antiapoptocytes (BCL-2). Hypothyroidism increased apoptosis index, TBARS and LOOH concentrations, and reduced testicular gene expression of Sod1, Sod2 and Gpx1, as well as the expression of Grp78, Atf6, Ho1 and Chop. Treatment with Kp10, in turn, reduced testicular apoptosis and the production of peroxynitrite, while increased SOD1 and GPX ½ expression, and enzymatic activity of CAT, but did not affect the lower expression of UPR mediators caused by hypothyroidism. This study demonstrated that hypothyroidism causes oxidative stress and dysregulated the UPR pathway in rat testes and that, although Kp10 does not influence the low expression of UPR mediators, it improves the testicular redox status, configuring it as an important antioxidant factor in situations of thyroid dysfunction.
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Antioxidantes , Hipotiroidismo , Humanos , Ratas , Masculino , Animales , Antioxidantes/metabolismo , Testículo/metabolismo , Kisspeptinas/metabolismo , Ratas Wistar , Superóxido Dismutasa-1/genética , Chaperón BiP del Retículo Endoplásmico , Ácido Peroxinitroso/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Semen/metabolismo , Oxidación-Reducción , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/metabolismo , Estrés Oxidativo , Respuesta de Proteína DesplegadaRESUMEN
OBJECTIVES: The aim of this study was to evaluate the expression profile of sex steroid receptors and redox mediators in the uterus of domestic cats with pyometra. METHODS: Twelve cats were used and divided into groups: (1) non-gestational healthy diestrus (n = 7) and (2) pyometra (n = 5). The plasma profiles of estradiol and progesterone (P4) as well as uterine expression levels of estradiol alpha (ERα), progesterone (PR) and androgen (AR) receptors, of the antioxidant enzymes superoxide dismutase 1 (SOD1), catalase and glutathione peroxidase 1 (GPX1), and of the oxidative damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) were evaluated. RESULTS: Cats with pyometra showed higher plasma P4 levels and increased uterine messenger RNA (mRNA) and protein expression of ERα and PR, mainly in the glandular epithelium for ERα and in stromal and myometrial cells for PR. In addition, there was an increase in 8-OHdG immunostaining and GPX1 mRNA and protein expression in cats with pyometra compared with those in non-gestational diestrus, while catalase showed a reduction in endometrial immunostaining in cats with pyometra. There were no differences in uterine AR and SOD1 expression between the groups. CONCLUSION AND RELEVANCE: The findings of this study showed that pyometra is associated with oxidative stress in the uterus of domestic cats and alterations of the profile of sex steroid receptors, especially ERα and PR, and of antioxidant enzymes, suggesting that changes in these mediators may play a role with the etiopathogenesis of this disease.
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Enfermedades de los Gatos , Piómetra , Femenino , Gatos , Animales , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Piómetra/veterinaria , Progesterona , Catalasa/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Antioxidantes/metabolismo , Superóxido Dismutasa-1/metabolismo , Útero/metabolismo , Estrógenos/metabolismo , Estradiol/metabolismo , Oxidación-Reducción , ARN Mensajero/metabolismo , Enfermedades de los Gatos/metabolismoRESUMEN
The domestic cat (Felis catus) is considered an important model for the study of feline reproductive morphophysiology. However, although the morphological changes and clinical signs that occur during the estrous cycle and pregnancy are well known, little is known about the molecular mechanisms involved in the reproductive physiology of this animal species. Thus, this paper reviews the current knowledge about the modulation and expression profile of hormonal, immunological, redox, and growth mediators involved in the uterine, ovarian, and placental morphophysiology of domestic cats.
RESUMEN
We evaluated whether the administration of kisspeptin-10 (Kp10) is capable of restoring gonadal function in hypothyroid male rats. Hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals were treated with Kp10. Hypothyroidism reduced testicular and sex gland mass, decreased the proliferation of the seminiferous epithelium, and compromised sperm morphology, motility, and vigor. A decrease in plasma LH and testosterone levels and an increase in prolactin secretion were observed in the hypothyroid rats. Hypothyroidism reduced Kiss1 and Kiss1r protein and gene expression and Star and Cyp11a1 mRNA levels in the testis. Furthermore, it reduced Lhb, Prl, and Drd2 and increased Tshb and Gnrhr expression in the pituitary. In the hypothalamus, hypothyroidism increased Pdyn and Kiss1r while reducing Gnrh1. Kp10 treatment in hypothyroid rats restored testicular and seminal vesicle morphology, improved sperm morphology and motility, reversed high prolactin levels, and increased LH and testosterone levels. In addition, Kp10 increased testicular expression of Kiss1, Kiss1r, Fshr, and Nr5a1 and pituitary Kiss1 expression. Our findings describe the inhibitory effects of hypothyroidism on the male gonadal axis and sperm quality and demonstrate that Kp10 treatment reverses high prolactin levels and improves gonadal function and sperm quality in hypothyroid rats.
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Hipotiroidismo , Kisspeptinas , Ratas , Animales , Masculino , Kisspeptinas/farmacología , Kisspeptinas/metabolismo , Prolactina/metabolismo , Hormona Luteinizante , Receptores de Kisspeptina-1/metabolismo , Semen/metabolismo , Hipotiroidismo/metabolismo , Testículo/metabolismo , TestosteronaRESUMEN
Sex steroids and antioxidant enzymes modulate uterine and placental physiology. Failures in the expression, signaling, and/or secretion of these mediators are associated with female infertility and gestational problems. However, there is no data on the expression profile of receptors for sex steroids and antioxidant enzymes in the maternal-fetal interface of domestic cats. Uterus and placenta samples from non-pregnant diestrus cats and cats in mid- and late pregnancy were used to analyze the protein and gene expression of the receptors for estrogen alpha (ERα), progesterone (PR), and androgen (AR) and the antioxidant enzymes superoxide dismutase 1 (SOD1), catalase, and glutathione peroxidase 1 (GPX1) by immunohistochemistry and qPCR. Higher uterine expression of ERα, Pr, and Sod1 was observed in the pregnant cats, especially in mid-pregnancy, compared to non-pregnant diestrus cats, as well as reduced endometrial catalase immunostaining. In the placenta, the mRNA expression of Erα, Pr, Ar, and Gpx1 was higher in late pregnancy in relation to mid-pregnancy. Moreover, weak or no placental expression was observed for catalase in mid- and late pregnancy, while strong immunostaining was observed for AR in trophoblasts and decidual cells in mid-pregnancy. The findings of this study demonstrated that pregnancy in female cats increases the uterine expression of sex steroid receptors and antioxidant enzymes, and that the placental expression of these mediators varies according to gestational age.
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Antioxidantes , Receptor alfa de Estrógeno , Embarazo , Gatos , Femenino , Animales , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Antioxidantes/metabolismo , Catalasa/genética , Catalasa/metabolismo , Superóxido Dismutasa-1/metabolismo , Placenta/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Progesterona/metabolismo , Estrógenos/metabolismo , Andrógenos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismoRESUMEN
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), challenged public health systems worldwide. Individuals in low-income countries/regions are still at individual and community risk concerning inequality, sanitation, and economic conditions. Besides, during the pandemic, the transmission in municipalities and communities in the countryside and less developed regions kept viral spread and required structured and strengthened clinical and laboratory surveillance. Here, we present an observational, analytic, cross-sectional study conducted using secondary data from the Laboratório de Farmacogenômica e Epidemiologia Molecular (LAFEM)-Universidade Estadual de Santa Cruz (UESC), to evaluate individual and community factors associated to SARS-CoV-2 infection in outpatients from different cities from Southern Region of Bahia State, in Brazil. The data were collected between June 2021 and May 2022. The SARS-CoV-2 positivity by RT-qPCR was correlated with low socio-economic indicators, including the Human development index (HDIc) and Average worker salary (AWSc). Besides, in general, females were less likely to test positive for SARS-CoV-2 (OR = 0.752; CI 95% 0.663-0.853; p < 0.0001), while brown individuals had more positivity for infection (p < 0.0001). In addition, those who had clinical symptoms were more likely to test positive for SARS-CoV-2 (OR = 6.000; CI 95% 4.932-7.299; p < 0.0001). Although dry cough, headache, and fever were the most frequent, loss of taste (OR = 5.574; CI 95% 4.334-7.186) and loss of smell (OR = 6.327; CI 95% 4.899-8.144) presented higher odds ratio to be positive to SARS-CoV-2 by RT-qPCR. Nonetheless, the distribution of these characteristics was not homogenous among the different cities, especially for age and gender. The dynamic of SARS-CoV-2 positivity differed between cities and the total population and reinforces the hypothesis that control strategies for prevention needed to be developed based on both individual and community risk levels to mitigate harm to individuals and the health system.
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COVID-19 , Femenino , Humanos , Brasil/epidemiología , Ciudades/epidemiología , COVID-19/epidemiología , Estudios Transversales , Pandemias , SARS-CoV-2/genéticaRESUMEN
CONTEXT: Proliferation, differentiation, migration and apoptosis of trophoblastic cells are influenced by hypoxia, as well as adequate modulation of oxidative stress and the unfolded protein response (UPR) pathway. AIMS: We aimed to evaluate the expression profile of redox and UPR mediators in the placenta of rats throughout pregnancy. METHODS: Placental expression of hypoxia-inducible factor 1α (HIF1α), 8-Hydroxy-2'-deoxyguanosine (8-OHdG), superoxide dismutase 1 (SOD1), glutathione peroxidase (GPX), catalase (Cat), activating transcription factor 6 (ATF6), protein kinase RNA-like endoplasmic reticulum kinase (PERK), 78 kD glucose-regulated protein (GRP78) and C/EBP-homologous protein (CHOP), as well as reactive oxygen species (ROS) and peroxynitrite production, were evaluated in Wistar rats on the 10th, 12th, 14th, 16th and 18th day of pregnancy (DP). KEY RESULTS: Increased immunostaining of HIF1α was observed on the 16th and 18th DP, while 8-OHdG and ROS production were greater on the 14th DP. SOD1 and Cat had increased immunostaining on the 14th and 18th DP, while staining of GPX1/2, GRP78 and CHOP was greater on the 18th DP. With regard to gene expression, Hif1α and Sod1 showed increased mRNA expression on the 12th and 16th DP, while Gpx1 had increased expression on the 10th and 16th DP. Cat , Perk and Grp78 gene expression was greater on the 14th DP, unlike Atf6 , which showed greater expression on the 12th DP. In contrast, Chop maintained increased expression from the 12th to the 18th DP. CONCLUSIONS: The placental expression of redox and UPR mediators in rats is influenced by gestational age, with greater expression in periods of greater HIF1α and 8-OHdG expression and at the end of the pregnancy. IMPLICATIONS: This study provides data on the physiological modulation of redox and UPR mediators during placental development in rats.
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Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Ratas , Femenino , Embarazo , Animales , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Placenta/metabolismo , Proteínas de Choque Térmico/metabolismo , Ratas Wistar , Respuesta de Proteína Desplegada , Apoptosis , Oxidación-Reducción , Hipoxia/metabolismoRESUMEN
Decidual immunological mediators modulate placental formation, decidualization and fetal development. However, the effect of maternal hyperthyroidism on decidual immunology needs further research. The aim of this study was to evaluate the population of uterine natural killer cells (uNKs) and the expression of immunological mediators in the decidua of female rats throughout pregnancy. Wistar rats were used and hyperthyroidism was induced by daily administration of L-thyroxine (T4) throughout pregnancy. The population of uNK cells in decidua was evaluated by immunostaining Lectin DBA, as well as the expression of interferon γ (INFγ), macrophage migration inhibitory factor (MIF), interleukin 15 (IL-15) and inducible nitric oxide synthase (iNOS) at 7, 10, 12, 14 and 19 days of gestation (DG). Maternal hyperthyroidism reduced the DBA+ uNK cell population in the decidua at 7 (P < 0.05) and 10 (P < 0.01) DGs compared to that in the control group, while it increased in the basal decidua (P < 0.05) and metrial gland (P < 0.0001) at the 12th DG. Hyperthyroidism also increased immunostaining of IL-15 (P < 0.0001), INFγ (P < 0.05), and MIF (P < 0.05) in the 7th DG, and increased immunostaining of IL-15 (P < 0.0001) and MIF (P < 0.01) in the 10th DG. However, excess thyroxine reduced IL-15 expression in the metrial gland and/or basal decidua in the 12th (P < 0.05), 14th (P < 0.01), and 19th (P < 0.001) DGs, as was also observed for INFγ in the basal decidua (P<0.001) and metrial gland (P < 0.0001) in the 12th DG. Regarding iNOS, an antiinflammatory cytokine, lower expression was observed in the basal decidua of hyperthyroid animals at 7 and 12 DGs (P < 0.05), whereas an increase occurred in the 10th DG (P < 0.05). These data demonstrate that maternal hyperthyroidism in female rats, particularly between 7 and 10 DGs, reduces the population of DBA+ uNKs in the decidua and increases the expression of inflammatory cytokines, suggesting a more proinflammatory environment in early pregnancy caused by this gestational disease.
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Hipertiroidismo , Placenta , Ratas , Embarazo , Femenino , Animales , Placenta/metabolismo , Decidua/metabolismo , Interleucina-15/metabolismo , Interleucina-15/farmacología , Ratas Wistar , Células Asesinas Naturales/metabolismo , Hipertiroidismo/metabolismoRESUMEN
Gestational diseases such as preeclampsia and gestational diabetes cause inflammasome activation and pyroptosis in the placenta and changes in placental kisspeptin levels. Although maternal hypothyroidism also reduces the kisspeptin/Kiss1R system at the maternal-fetal interface, there is still no information on whether this dysfunction causes inflammasome activation and pyroptosis in the placenta or influences the modulatory role of kisspeptin in these processes. This study aimed to evaluate whether hypothyroidism activates the inflammasome-NLRP3 pathway and pyroptosis at the maternal-fetal interface of rats and whether kisspeptin can modulate these processes. Hypothyroidism was induced in Wistar rats by the administration of propylthiouracil. Kisspeptin-10 (Kp10) treatment began on the 8th day of gestation (DG). Gene and/or protein expressions of NLRP3, Caspase 1, IL-1ß, IL-18, and Gasdermin D (Gsmd) were evaluated in the deciduae and placentae at the 18th DG. Hypothyroidism increased the decidual and placental stainings of NLRP3, IL-1ß, and Gasdermin D, and increased the gene expressions of Nlrp3, Ilß, and Il18 in the placenta and of Gsmd in the decidua. Treatment with Kp10 suppressed the increase in NLRP3/Nlrp3, IL-1ß, Il18, and Gasdermin D/Gsmd caused by hypothyroidism at the maternal-fetal interface. However, Kp10 increased the placental gene expressions of Casp1 and Il1ß. The findings demonstrated that maternal hypothyroidism activated the inflammasome-NLRP3 pathway and pyroptosis at the maternal-fetal interface of rats and that treatment with Kp10 was able to block these processes, thus suggesting that kisspeptin analogues may be promising in the treatment of gestational diseases that involve inflammasome activation and pyroptosis.
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Hipotiroidismo , Inflamasomas , Ratas , Femenino , Embarazo , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piroptosis/fisiología , Interleucina-18/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Gasderminas , Placenta/metabolismo , Ratas Wistar , Caspasa 1/metabolismo , Interleucina-1beta/metabolismoRESUMEN
Sex steroids and antioxidant enzymes are important in female sexual development and adequate modulation of the estrous cycle, pregnancy, and fetal development. Therefore, modifications in its signaling or expression in the genital system are associated with reproductive dysfunctions. However, the spatial-temporal expression profile of receptors for sex steroids and antioxidant enzymes in the uterus of domestic cats throughout the estrous cycle needs to be studied. Cats in proestrus/estrus (N = 6), diestrus, (N = 7), and anestrus (N = 6) were used to evaluate the uterine expression of estrogen alpha (ERα), progesterone (PR), and androgen (AR) receptors and of the antioxidant enzymes superoxide dismutase 1 (SOD1), catalase and glutathione peroxidase 1 (GPX1) by immunohistochemistry and qPCR. The uterus of cats in diestrus showed lower protein and mRNA expression of ERα and PR compared to proestrus/estrus and anestrus, mainly in the luminal and glandular epithelium and myometrium, different from catalase and SOD1, which showed higher expression in diestrus in relation to other phases of the cycle. GPX1, on the other hand, showed lower uterine gene expression in diestrus compared to proestrus/estrus and anestrus. No significant differences in AR expression were observed. In conclusion, ERα and PR sex steroid receptors and antioxidant enzymes are expressed differently in the uterus of domestic cats during the estrous cycle.
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Antioxidantes , Receptores de Progesterona , Embarazo , Gatos , Femenino , Animales , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Catalasa/genética , Catalasa/metabolismo , Antioxidantes/metabolismo , Receptor alfa de Estrógeno/metabolismo , Superóxido Dismutasa-1/metabolismo , Ciclo Estral/metabolismo , Útero/metabolismo , Estrógenos/metabolismo , Progesterona/metabolismo , Hormonas Esteroides Gonadales/metabolismo , Glutatión Peroxidasa GPX1RESUMEN
Maternal hypothyroidism is associated with fetal growth restriction, placental dysfunction, and reduced kisspeptin/Kiss1R at the maternal-fetal interface. Kisspeptin affects trophoblastic migration and has antioxidant and immunomodulatory activities. This study aimed to evaluate the therapeutic potential of kisspeptin in the fetal-placental dysfunction of hypothyroid Wistar rats. Hypothyroidism was induced by daily administration of propylthiouracil. Kisspeptin-10 (Kp-10) treatment was performed every other day or daily beginning on day 8 of gestation. Feto-placental development, placental histomorphometry, and expression levels of growth factors (VEGF, PLGF, IGF1, IGF2, and GLUT1), hormonal (Dio2) and inflammatory mediators (TNFα, IL10, and IL6), markers of hypoxia (HIF1α) and oxidative damage (8-OHdG), antioxidant enzymes (SOD1, Cat, and GPx1), and endoplasmic reticulum stress mediators (ATF4, GRP78, and CHOP) were evaluated on day 18 of gestation. Daily treatment with Kp-10 increased free T3 and T4 levels and improved fetal weight. Both treatments reestablished the glycogen cell population in the junctional zone. Daily treatment with Kp-10 increased the gene expression levels of Plgf, Igf1, and Glut1 in the placenta of hypothyroid animals, in addition to blocking the increase in 8-OHdG and increasing protein and/or mRNA expression levels of SOD1, Cat, and GPx1. Daily treatment with Kp-10 did not alter the higher protein expression levels of VEGF, HIF1α, IL10, GRP78, and CHOP caused by hypothyroidism in the junctional zone compared to control, nor the lower expression of Dio2 caused by hypothyroidism. However, in the labyrinth zone, this treatment restored the expression of VEGF and IL10 and reduced the GRP78 and CHOP immunostaining. These findings demonstrate that daily treatment with Kp-10 improves fetal development and placental morphology in hypothyroid rats, blocks placental oxidative damage, and increases the expression of growth factors and antioxidant enzymes in the placenta.
Asunto(s)
Hipotiroidismo , Placentación , Animales , Antioxidantes/metabolismo , Femenino , Desarrollo Fetal , Transportador de Glucosa de Tipo 1/metabolismo , Hipotiroidismo/tratamiento farmacológico , Interleucina-10/metabolismo , Kisspeptinas/metabolismo , Estrés Oxidativo , Placenta/metabolismo , Embarazo , Ratas , Ratas Wistar , Superóxido Dismutasa-1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Maternal hypothyroidism is associated with pre-eclampsia and intrauterine growth restriction, gestational diseases involving oxidative stress (OS) and endoplasmic reticulum stress (ERS) in the placenta. However, it is not known whether hypothyroidism also causes OS and ERS at the maternal-fetal interface. The aim was to evaluate the fetal-placental development and the expression of mediators of OS and of the unfolded protein response (UPR) in the maternal-fetal interface of hypothyroid rats. Hypothyroidism was induced in Wistar rats with propylthiouracil and the fetal-placental development and placental and decidual expression of antioxidant, hypoxia, and UPR mediators were analyzed at 14 and 18 days of gestation (DG), as well the expression of 8-OHdG and MDA, and reactive oxygen species (ROS) and peroxynitrite levels. Hypothyroidism reduced fetal weight at 14 and 18 DG, in addition to increasing the percentage of fetal death and reducing the weight of the uteroplacental unit at 18 DG. At 14 DG, there was greater decidual and/or placental immunostaining of Hif1α, 8-OHdG, MDA, SOD1, GPx1/2, Grp78 and CHOP in hypothyroid rats, while there was a reduction in placental and/or decidual gene expression of Sod1, Gpx1, Atf6, Perk, Ho1, Xbp1, Grp78 and Chop in the same gestational period. At 18 DG, hypothyroidism increased the placental ROS levels and the decidual and/or placental immunostaining of HIF1α, 8-OHdG, MDA, ATF4, GRP78 and CHOP, while it reduced the immunostaining and enzymatic activity of SOD1, CAT, GST. Hypothyroidism increased the placental mRNA expression of Hifα, Nrf2, Sod2, Gpx1, Cat, Perk, Atf6 and Chop at 18 DG, while decreasing the decidual expression of Sod2, Cat and Atf6. These findings demonstrated that fetal-placental restriction in female rats with hypothyroidism is associated with hypoxia and dysregulation in placental and decidual expression of UPR mediators and antioxidant enzymes, and activation of oxidative stress and endoplasmic reticulum stress at the maternal-fetal interface.
Asunto(s)
Estrés del Retículo Endoplásmico , Hipotiroidismo , Animales , Antioxidantes/metabolismo , Estrés del Retículo Endoplásmico/genética , Femenino , Humanos , Hipotiroidismo/genética , Hipotiroidismo/metabolismo , Hipoxia/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Ácido Peroxinitroso/metabolismo , Placenta/metabolismo , Embarazo , Propiltiouracilo/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismoRESUMEN
Background: Hypothyroidism causes ovarian dysfunction and infertility in women, in addition to being associated with hyperprolactinemia and reduced hypothalamic expression of kisspeptin (Kp). However, it remains unknown whether and how Kp is able to reverse the ovarian dysfunction caused by hypothyroidism. Methods: Hypothyroidism was induced in adult female Wistar rats using 6-propyl-2-thiouracil for 3 months. In the last month, half of the animals received Kp10. Blood samples were collected for dosage of free thyroxine, thyrotropin (TSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2), and uteruses and ovaries were collected for histomorphometry. Body and ovarian weight and the number of corpora lutea were also evaluated. Half of the brains were evaluated by immunohistochemistry to Kp, and the other half had the arcuate nucleus of hypothalamus (ARC) and preoptic area microdissected for gene evaluation of Kiss1, Nkb, Pdyn, and Gnrh1. The pituitary gland and corpora lutea were also dissected for gene evaluation. Results: Hypothyroidism kept the animals predominantly acyclic and promoted a reduction in ovarian weight, number of corpora lutea, endometrial thickness, number of endometrial glands, and plasma LH, in addition to increasing the luteal messenger RNA (mRNA) expression of Star and Cyp11a1 and reducing 20αHsd. An increase in plasma PRL and P4 levels was also caused by hypothyroidism. Kp immunoreactivity and Kiss1 and Nkb mRNA levels in the ARC and Kiss1 in the anteroventral periventricular nucleus of hypothalamus were reduced in hypothyroid rats. Hypothyroid animals had lower pituitary gene expression of Gnrhr, Lhb, Prl, and Drd2, and an increase in Tshb. The treatment with Kp10 restored estrous cyclicality, plasma LH, ovarian and uterine morphology, and Cyp11a1, 3ßHsd, and 20αHsd mRNA levels in the corpora lutea. Kp10 treatment did not alter gene expression for Kiss1 or Nkb in the ARC of hypothyroid rats. Nevertheless, Kp10 increased Lhb mRNA levels and reduced Tshb in the pituitary compared with the hypothyroid group. Conclusions: The present findings characterize the inhibitory effects of hypothyroidism on the hypothalamic-pituitary-gonadal axis in female rats and demonstrate that Kp10 is able to reverse the ovarian dysfunction caused by hypothyroidism, regardless of hyperprolactinemia.
Asunto(s)
Hiperprolactinemia , Hipotiroidismo , Femenino , Animales , Ratas , Kisspeptinas/genética , Kisspeptinas/metabolismo , Kisspeptinas/farmacología , Hiperprolactinemia/metabolismo , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Ratas Wistar , Hormona Luteinizante , Núcleo Arqueado del Hipotálamo/metabolismo , Prolactina/metabolismo , Prolactina/farmacología , ARN Mensajero/metabolismoRESUMEN
Alterations of circulating and placental levels of kisspeptin have been associated with gestational diseases. However, there are still no studies on the placental and decidual expression of Kiss1 and its receptor Kiss1r in maternal hypothyroidism, which is the aim of this work. We demonstrate that the fetoplacental restriction caused by hypothyroidism in rats is associated with a reduction in the Kiss1r expression and reduced Kiss1 and Kiss1r mRNA levels in the decidua and/or placenta. This demonstrate that fetoplacental restriction in hypothyroid rats is linked with a suppression of the kisspeptin/Kiss1r system at the maternal-fetal interface.
Asunto(s)
Hipotiroidismo , Kisspeptinas , Animales , Femenino , Kisspeptinas/genética , Kisspeptinas/metabolismo , Placenta/metabolismo , Embarazo , Ratas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismoRESUMEN
The Kisspeptin/Kiss1r system has been studied in mammalian ovaries. However, there are still no studies on the modulation of this system and its relationship with angiogenic and immunological mediators in the ovary of domestic cats, especially during pregnancy. We evaluated the expression of Kisspeptin/Kiss1r and angiogenic and immunological mediators during folliculogenesis, luteogenesis and luteal regression of cyclic and pregnant cats. The ovary exhibited moderate to intense expression for Kiss1, VEGF, Flk-1, INFγ and MIF in oocytes and the follicular wall, while Kiss1r expression was low in granulosa cells. In these cells, there was also a greater expression of Kiss1, INFγ and MIF, mainly in secondary follicles, while tertiary and preovulatory follicles exhibited greater expression of VEGF and Flk-1 in this layer. In luteogenesis, Kiss1 immunostaining was higher in mature corpora lutea (MCL) of pregnant cats compared to vacuolated CL (VCL) and corpus albicans (CA). Pregnancy also increased the luteal gene expression of Kiss1 as well as Kiss1, Kiss1r, Flk-1, and MIF immunostaining in MCL, while reduced the area of VEGF expression in VCL and luteal mRNA expression of Mif when compared to non-pregnant animals. In addition, positive gene correlation between Kiss1r and Mif was observed in the CL. Kiss1, Kiss1r, Vegf and Mif expression were lower in the CA of cats in anestrus. These findings reveal that the expression of Kisspeptin/Kiss1r and angiogenic and immunological mediators, in the ovary of domestic cats, depend on the follicular and luteal stage, and the luteal expression of these mediators is influenced by pregnancy.
Asunto(s)
Kisspeptinas , Ovario , Animales , Gatos , Cuerpo Lúteo/metabolismo , Femenino , Células de la Granulosa/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Mamíferos/metabolismo , Ovario/metabolismo , Embarazo , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismoRESUMEN
In December 2019, a novel coronavirus was detected in Wuhan, China, and rapidly spread worldwide. In Brazil, to date, there have been more than 20,000,000 confirmed cases of COVID-19 and more than 550,000 deaths. The purpose of the current study was to determine the clinical and epidemiological profile of the population affected by COVID-19 that have attended referral hospitals in Southern region of Bahia State, to better understand the disease and its risk factors in order to enable more appropriate conduct for patients. An observational, descriptive, cross-sectional, exploratory study was conducted using secondary data collected from the Laboratório de Farmacogenômica e Epidemiologia Molecular, Universidade Estadual de Santa Cruz (LAFEM/UESC). Chi-squared and Fisher's exact tests were applied to determine the association between clinical symptoms and laboratory results, and to identify risk factors associated with SARS-CoV-2 infection. A total of 3135 individuals with suspected severe respiratory illness were analyzed and 41.4% of them tested positive for SARS-CoV-2 infection. Male individuals and having comorbidities were risk factors significantly associated with SARS-CoV-2 infection (OR = 1.17 and OR = 1.37, respectively). Interestingly, being a healthcare professional was a significantly protective factor (OR = 0.81, p < 0.001). Our findings highlight the importance of routinely testing the population for early identification of infected individuals, and also provide important information to health authorities and police makers to improve control measures, management, and screening protocols.