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1.
Croat Med J ; 62(3): 215-226, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34212558

RESUMO

AIM: To determine the effects of metformin or liraglutide on oxidative stress level and antioxidative enzymes gene expression and activity in the blood and vessels of pre-diabetic obese elderly Sprague-Dawley (SD) rats of both sexes. METHODS: Male and female SD rats were assigned to the following groups: a) control group (fed with standard rodent chow); b) high-fat and high-carbohydrate diet (HSHFD) group fed with HSHFD from 20-65 weeks of age; c) HSHFD+metformin treatment (50 mg/kg/d s.c.); and d) HSHFD+liraglutide treatment (0.3 mg/kg/d s.c). Oxidative stress parameters (ferric reducing ability of plasma and thiobarbituric acid reactive substances) and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity and gene expression were determined from serum, aortas, and surface brain blood vessels (BBV). RESULTS: HSHFD increased body weight in both sexes compared with the control group, while liraglutide prevented this increase. Blood glucose level did not change. The liraglutide group had a significantly increased antioxidative capacity compared with the HSHFD group in both sexes. The changes in antioxidative enzymes' activities in plasma were more pronounced in male groups. The changes in antioxidative gene expression were more prominent in microvessels and may be attributed to weight gain prevention. CONCLUSIONS: Obesity and antidiabetic drugs caused sex-related differences in the level of antioxidative parameters. Liraglutide exhibited stronger antioxidative effects than metformin. These results indicate that weight gain due to HSHFD is crucial for developing oxidative stress and for inhibiting antioxidative protective mechanisms.


Assuntos
Metformina , Estado Pré-Diabético , Animais , Antioxidantes , Catalase/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Liraglutida/farmacologia , Masculino , Metformina/farmacologia , Obesidade/tratamento farmacológico , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Superóxido Dismutase/metabolismo
2.
Life Sci ; 277: 119492, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33864819

RESUMO

AIMS: Non-invasive and simultaneous recording of gastrointestinal (GI) activity during stress induction is still an unexplored field. In our previous investigation, the stress-induced alteration of the gastrointestinal tract was explored in rats. Our aims were to expand our previous rat experiment and to induce stress response in rats (Study 1) and humans (Study 2) to detect the GI tract activity, heart rate and body temperature. MATERIALS AND METHODS: In the preclinical sample, acute stress was induced by immobilization in Sprague-Dawley rats (N = 10). Acute stress response was generated by the Trier Social Stress Test among healthy volunteers (N = 16). Detection of acute stress was measured by using smooth muscle electromyography, which recorded the myoelectric waves of the gastrointestinal tract (stomach, ileum and colon) simultaneously with heart rate and body temperature in rats and humans. KEY FINDINGS: The myoelectric waves of the stomach, the cecum and the ileum increased during immobilization in rats, rising in parallel with heart rate and the dermal temperature of the abdominal surface. The same alterations were found during the stress period among humans, except in the case of the colon, where no change was detected. SIGNIFICANCE: The crucial role of the GI tract in stress response was revealed by translating the outcome of basic research into human results. The similar GI alterations during stress in rats and humans underpin the robustness of our findings. In summary, our preliminary translational-based study can serve as an appropriate basis for further human studies.


Assuntos
Trato Gastrointestinal/fisiologia , Miócitos de Músculo Liso/metabolismo , Estresse Fisiológico/fisiologia , Adulto , Animais , Ceco/fisiologia , Colo/fisiologia , Eletromiografia/métodos , Feminino , Motilidade Gastrointestinal/fisiologia , Voluntários Saudáveis , Humanos , Íleo/fisiologia , Masculino , Músculo Liso/fisiologia , Ratos , Ratos Sprague-Dawley , Estômago/fisiologia
3.
Eur J Pharmacol ; 896: 173924, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33548216

RESUMO

The objectives of this study were to investigate the effects of KISS1 94-121 fragment on the contractility of non-pregnant and pregnant rat uteri, and to determine the uterine and myometrial expressions of Kiss1r. Uterine muscle strips were obtained from non-pregnant Sprague-Dawley rats in oestrous phase and from pregnant rats on gestational days 5, 15, 18, 20 or 22. The in vitro contractility measurements were carried out in an isolated organ bath in the presence of KISS1 94-121. Experiments with 5-day pregnant tissues were also performed in the presence of kisspeptin-234 trifluoroacetate. The mRNA and protein expressions of Kiss1r were measured by RT-PCR and Western blot analysis, while localizations of receptors were defined by fluorescent immunohistochemistry. KISS1 94-121 induced a dose-dependent relaxation both in non-pregnant and pregnant intact and endometrium-denuded uteri. A gradual decrease was found in the uterine expressions of Kiss1r mRNA and protein towards the end of the gestational period, and it was further confirmed by the immunohistochemical results. The significant majority of Kiss1r is found in the myometrium, however the few endometrial Kiss1r also influences the uterine contractions. The relaxing effect of kisspeptin is continuously reduced towards the end of gestational period in parallel with the reduction of Kiss1r expression. Our results suggest a putative role of kisspeptin in the maintenance of uterine quiescence that may have significance in miscarriage or preterm contractions.


Assuntos
Kisspeptinas/farmacologia , Miométrio/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Kisspeptina-1/agonistas , Contração Uterina/efeitos dos fármacos , Animais , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Feminino , Técnicas In Vitro , Miométrio/metabolismo , Gravidez , Ratos Sprague-Dawley , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/metabolismo , Transdução de Sinais
4.
Brain Res ; 1748: 147074, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858029

RESUMO

In previous studies we have shown that a three-hit animal model of schizophrenia (Wisket rat) has several behavioral impairments related to the disorder along with altered mu-opioid (MOP) and cannabinoid (CB1) receptor signaling. As the dopamine hypothesis of schizophrenia is central to research in the field, the goal of the present study was to investigate dopaminergic D2 receptor (D2R) functions (binding capacity, G-protein activation and expression) in several brain regions (hippocampus, prefrontal cortex, striatum, olfactory bulb, cerebellum, brainstem, cortex and diencephalon) of control (Wistar) and Wisket rats. It was found that the D2R mediated maximal activation of G-proteins was substantially higher in hippocampus, striatum and olfactory bulb membranes prepared from the Wisket than in control animals, which was accompanied with lower potency of the D2R-mediated G-protein activation. In contrast, enhanced potency was detected in the prefrontal cortex without changes in the maximal activation. In saturation binding assays the maximal binding capacity of D2Rs was higher in the model animals in cerebral cortex, striatum and lower in the brainstem, while no changes in the dissociation constant values were detected. The D2R mRNA expression showed a trend for greater level in the investigated areas, while the D2R protein expression was significantly higher of Wisket rats compared to Wistar animals in the hippocampus and in the prefrontal cortex but not in the cerebellum. This study proved that the Wisket animals show altered D2 receptor expression and function which might be related to the schizophrenia-like symptoms.

5.
Eur J Pharm Biopharm ; 153: 177-186, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32531424

RESUMO

Nanocapsules (NCs) have become one of the most researched nanostructured drug delivery systems due to their advantageous properties and versatility. NCs can enhance the bioavailabiliy of hydrophobic drugs by impoving their solubility and permeability. Also, they can protect these active pharmaceutical agents (APIs) from the physiological environment with preventing e.g. the enzymatic degradation. NCs can be used for many administration routes: e.g. oral, dermal, nasal and ocular formulations are exisiting in liquid and solid forms. The nose is one of the most interesting alternative drug administration route, because local, systemic and direct central nervous system (CNS) delivery can be achived; this could be utilized in the therapy of CNS diseases. Therefore, the goal of this study was to design, prepare and investigate a novel, lamotrigin containing NC formulation for nasal administration. The determination of micrometric parameters (particle size, polydispersity index, surface charge), in vitro (drug loading capacity, release and permeability investigations) and in vivo characterization of the formulations were performed in the study. The results indicate that the formulation could be a promising alternative of lamotrigine (LAM) as the NCs were around 305 nm size with high encapsulation efficiency (58.44%). Moreover, the LAM showed rapid and high release from the NCs in vitro and considerable penetration to the brain tissues was observed during the in vivo study.


Assuntos
Lamotrigina/química , Nanocápsulas/química , Administração Intranasal/métodos , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Sistema Nervoso Central/efeitos dos fármacos , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Lamotrigina/administração & dosagem , Masculino , Nanocápsulas/administração & dosagem , Mucosa Nasal/metabolismo , Tamanho da Partícula , Permeabilidade , Ratos , Ratos Sprague-Dawley , Solubilidade
6.
Molecules ; 25(5)2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120992

RESUMO

Nasal drug delivery has become a popular research field in the last years. This is not surprising since the nose possesses unique anatomical and physical properties. Via the nasal mucosa local, systemic, and directly central nerve systemic (CNS) effect is achievable. Powders have favorable physicochemical properties over liquid formulations. Lamotrigine (LAM) is an antiepileptic agent with a relatively mild side effect spectrum, but only available in tablet form on market. Reducing the particle size to the nano range can affect the bioavailability of pharmaceutical products. The aim of this article was to continue the work started, compare the in vitro properties of a nanonized lamotrigine containing nasal powder (nanoLAMpowder) and its physical mixture (PM) that were prepared by dry milling. Moreover, to study their trans-epithelial absorption to reach the blood and target the brain by axonal transport. Due to the dry milling technique, the particle size of LAM, their surface and also their structure changed that led to higher in vitro dissolution and permeability rate. The results of the in vivo tests showed that the axonal transport of the drug was assumable by both intranasal formulations because the drug was present in the brain within a really short time, but the LAM from the nanoLAMpowder liberated even faster.


Assuntos
Anticonvulsivantes/administração & dosagem , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Lamotrigina/administração & dosagem , Nanopartículas/administração & dosagem , Pós/administração & dosagem , Administração Intranasal , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Transporte Axonal , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Cromatografia Líquida , Lamotrigina/sangue , Lamotrigina/farmacocinética , Masculino , Espectrometria de Massas , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanopartículas/ultraestrutura , Cavidade Nasal , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Tamanho da Partícula , Permeabilidade , Ratos , Ratos Sprague-Dawley , Solubilidade
7.
Int J Pharm ; 579: 119166, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32084574

RESUMO

The unique requirements of poorly water-soluble drug delivery have driven a great deal of research into new formulations and routes of administration. This study investigates the use of nanosuspensions for solubility enhancement and drug delivery. Simple methods were used to prepare nasal formulations of loratadine based on nanosuspension pre-dispersion with sodium hyaluronate as a mucoadhesive agent. The nanosuspension was prepared by antisolvent precipitation method followed by ultrasonication and characterized for particle size, polydispersity index, zeta potential, morphology, and structure. Moreover, the nasal formulations were characterized for drug loading, pH, particle size, viscosity, bioadhesive viscosity parameter, and were evaluated for in vitro dissolution and diffusion, in addition to in vivo studies in a rat model. Loratadine nanosuspension displayed a particle size of 311 nm, a polydispersity index of 0.16, and zeta potential of -22.05 mV. The nanosuspension preserved the crystalline status of the raw drug. The addition of sodium hyaluronate exhibited an increase in the mean particle size and zeta potential of the nanoparticles. The nasal formulations showed enhanced bioadhesive properties compared to the unprocessed loratadine in the reference samples. The nanosuspension based-formulation that contained 5 mg mL-1 sodium hyaluronate and 2.5 mg mL-1 loratadine (NF4) showed a significant enhancement of flux and permeability coefficient through a synthetic membrane. NF4 exhibited 24.73 µg cm-2 h-1 and 0.082 cm h-1, while the reference sample showed 1.49 µg cm-2 h-1 and 0.017 cm h-1, for the flux and the permeability coefficient, respectively. Nasal administration of NF4 showed a bioavailability of 5.54-fold relative to the oral administration. The results obtained in this study indicate the potential of the nasal route and the nanosuspension for loratadine delivery. The relative bioavailability of NF4 was 1.84-fold compared to unprocessed loratadine in the reference sample. Therefore, the nanosized loratadine could be suggested as a practical and simple nanosystem for the intranasal delivery with improved bioavailability.


Assuntos
Adesivos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/química , Loratadina/química , Loratadina/farmacocinética , Nanoestruturas/química , Suspensões/química , Adesivos/administração & dosagem , Administração Intranasal , Administração Oral , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos , Ácido Hialurônico/administração & dosagem , Masculino , Nanoestruturas/administração & dosagem , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Ratos , Propriedades de Superfície , Suspensões/administração & dosagem , Viscosidade
8.
Pharmaceutics ; 12(2)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991767

RESUMO

The aim of this study was to optimize the formulation of meloxicam (MEL)-containing human serum albumin (HSA) nanoparticles for nose-to-brain via a quality by design (QbD) approach. Liquid and dried formulations of nanoparticles containing Tween 80 and without the surfactant were investigated. Various properties, such as the Z-average, zeta potential, encapsulation efficacy (EE), conjugation of MEL and HSA, physical stability, in vitro dissolution, in vitro permeability, and in vivo plasma and brain distribution of MEL were characterized. From a stability point of view, a solid product (Mel-HSA-Tween) is recommended for further development since it met the desired critical parameters (176 ± 0.3 nm Z-average, 0.205 ± 0.01 PdI, -14.1 ± 0.7 mV zeta potential) after 6 months of storage. In vitro examination showed a significantly increased drug dissolution and permeability of MEL-containing nanoparticles, especially in the case of applying Tween 80. The in vivo studies confirmed both the trans-epithelial and axonal transport of nanoparticles, and a significantly higher cerebral concentration of MEL was detected with nose-to-brain delivery, in comparison with intravenous or per os administration. These results indicate intranasal the administration of optimized MEL-containing HSA formulations as a potentially applicable "value-added" product for the treatment of neuroinflammation.

9.
Drug Des Devel Ther ; 13: 4007-4020, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819372

RESUMO

Purpose: The aim of this work was to study the influence of solidification of meloxicam (Mel) containing nanosuspension (nanoMel) on the physical stability and drug bioavailability of the products. The nanoMel sample had poly(vinyl alcohol) (PVA) as a protective polymer, but no surfactant as a further stabilizing agent because the final aim was to produce surfactant-free solid phase products as well. Methods: The solidified samples produced by fluidization and lyophilization (fluidMel, lyoMel) were examined for particle size, crystallinity, and in vitro release of Mel compared to similar parameters of nanoMel. The products were subjected to an animal experiment using per oral administration to verify their bioavailability. Results: Mel containing (1%) nanoMel sample was produced by wet milling process using an optimized amount of PVA (0.5%) which resulted in 130 nm as mean particle size and a significant reduction in the degree of crystallinity (13.43%) of Mel. The fluidization technique using microcrystalline cellulose (MCC) as carrier resulted in a quick conversion and no significant change in the critical product parameters. The process of lyophilization required a longer operation time, which resulted in the amorphization of the crystalline carrier (trehalose) and the recrystallization of Mel increased its particle size and crystallinity. The fluidMel and lyoMel samples had nearly five-fold higher relative bioavailability than nanoMel application by oral administration. The correlation between in vitro and in vivo studies showed that the fixed Mel nanoparticles on the surface of solid carriers (MCC, trehalose) in both the artificial gastric juice and the stomach of the animals rapidly reached saturation concentration leading to faster dissolution and rapid absorption. Conclusion: The solidification of the nanosuspension not only increased the stability of the Mel nanoparticles but also allowed the preparation of surfactant-free compositions with excellent bioavailability which may be an important consideration for certain groups of patients to achieve rapid analgesia.


Assuntos
Analgesia , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Meloxicam/uso terapêutico , Nanopartículas/química , Dor/tratamento farmacológico , Administração Oral , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Humanos , Meloxicam/administração & dosagem , Meloxicam/química , Tamanho da Partícula , Álcool de Polivinil/química , Propriedades de Superfície , Suspensões/química
10.
Heliyon ; 5(10): e02697, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31687520

RESUMO

Aims: Aquaporins (AQPs) are channel proteins that facilitate the rapid passive movement of water. In our studies it was proved that the decreased AQP5 expression is followed by the increase of uterine contractility. The transient receptor potential vanilloid 4 (TRPV4) is a calcium channel, which is activated in response to osmotic changes. Our aim was to determine the possible role of AQP5 in this osmotic regulation of TRPV4, thus in pregnant uterine contraction. Main methods: We used RT-PCR and Western blot techniques for the detection of the TRPV4 expression during pregnancy in rat uterus. The localization of AQP5 and TRPV4 was determined by immunohistochemical studies. The role of TRPV4 in uterus contraction was investigated in an isolated organ bath system. In vitro uterus contractions were stimulated with KCl and its effect was investigated with the selective TRPV4 agonist (RN1747) and antagonist (RN1734). Key findings: The TRPV4 expression continuously increased from day 18 to the last day of pregnancy. The co-expression of TRPV4 and AQP5 in the myometrium and endometrium was determined in the late pregnant uterus. The TRPV4 antagonist and agonist significantly decreased and increased uterine contraction, respectively, especially on the last day of pregnancy. Significance: We presume the decreased AQP5 expression triggers hypertonic stress, which activates TRPV4 and increases uterus contraction on the day of labor. Based on these findings, we suppose the TRPV4 effect on uterus contraction is AQP5 control, which could be a new target in preterm birth therapy.

11.
Eur J Pharmacol ; 843: 27-33, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445018

RESUMO

Improper cervical function may lead premature or late-term birth. The RhoA/Rho-kinase (ROCK) signalling pathway takes part in cellular functions including smooth muscle contraction. No information is available about the cervical expression of the RhoA/ROCK system during pregnancy. Our aim was to detect the mRNA and protein expression of ROCK enzymes in rat cervices and to evaluate the effects of RhoA/ROCK inhibitors on cervical resistance. The mRNA and protein expressions of RhoA, ROCK I and II were measured in non-pregnant, pregnant and postpartum rat cervices and during parturition by Real-time qPCR and Western blot. The cervical resistance modifying effects of RhoA (simvastatin) and ROCK (fasudil, Y-27632) (10-6M) were investigated in tissue bath experiments. RhoA mRNA was increased on post-partum day 3, while the RhoA protein expression was decreased near and during parturition. ROCK I mRNA and protein expressions were fluctuating with a decrease in protein expression during parturition. ROCK II mRNA and protein expressions were sharply reduced during parturition. Simvastatin increased the cervical resistance on pregnancy days 20 and 22 while Y-27632 and fasudil reduced the resistance on pregnancy days 20. The decrease in RhoA/ROCK expression near parturition may take part in cervical ripening, especially in the final processes leading to delivery. ROCK inhibitors might be potential drug candidates to treat insufficient cervical ripening late-term pregnancies. The effect of simvastatin possibly due to its unique smooth muscle contracting activity in pregnant cervix. Compounds with simvastatin-like action might be new drug candidates for preterm cervical ripening.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Amidas/farmacologia , Maturidade Cervical/efeitos dos fármacos , Colo do Útero/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Piridinas/farmacologia , Sinvastatina/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Maturidade Cervical/fisiologia , Colo do Útero/fisiologia , Feminino , Técnicas In Vitro , Contração Muscular/fisiologia , Gravidez , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Proteínas rho de Ligação ao GTP/fisiologia , Quinases Associadas a rho/fisiologia
12.
Reprod Toxicol ; 81: 64-70, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30031112

RESUMO

Aquaporin (AQP) water channels are small hydrophobic integral membrane proteins. AQP5 expression, which is regulated by oxytocin, showed a dramatic down-regulation at the term and preterm uterus. Since antibiotics are among the drugs to treat intrauterine infections, our aim was to study the effects of antibiotics on AQP5 and uterine contractility on 22-day pregnant rats. The change in uterine AQP5 expression was investigated by PCR and Western blot techniques. Uterine contractility was tested in an organ bath system. 7 days of pre-treatment with amoxicillin or single dose of fosfomycin decreased the AQP5 protein level, while 7 days of treatment with doxycycline had no effect. Fosfomycin or amoxicillin pre-treatments enhanced, while doxycycline pre-treatment did not alter the oxytocin-induced contractions. Amoxicillin and fosfomycin may sensitize the uterus to oxytocin via the reduction of AQP5 expression. This synergism might have importance during the pharmacotherapy of infection-related preterm birth.


Assuntos
Amoxicilina/toxicidade , Antibacterianos/toxicidade , Aquaporina 5/fisiologia , Fosfomicina/toxicidade , Útero/efeitos dos fármacos , Animais , Doxiciclina , Feminino , Gravidez , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Contração Uterina/efeitos dos fármacos , Útero/fisiologia
13.
Int J Mol Sci ; 18(12)2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29194396

RESUMO

Water is the major component of cells and tissues, and the movement of water across the cell membrane is a fundamental property of life. Until the discovery of the first water channel, aquaporin, it was long assumed that the transport of water was due to simple diffusion through the lipid bilayer membrane that encloses cells. Aquaporin (AQP) molecules were first discovered in the human uterus in 1994, and since then several studies have investigated these channels in the female reproductive system. The expressions of AQPs have been proven in the reproductive system. Their levels are altered during the implantation process, both in the uterus and the fetal cells, and participate in the control of the flow of amniotic fluid. They seem to be very important for the normal placental functions. AQPs are present during parturition, participating in the control of pregnant myometrial contractions and cervical ripening. However, most of the physiological and regulatory roles of AQPs are not clarified in the reproductive tract. Furthermore, no satisfactory knowledge is available about their sensitivities to different drugs. AQP-selective ligands may contribute to the development of new drug candidates and the therapy of several reproductive disorders.


Assuntos
Líquido Amniótico/metabolismo , Aquaporinas/metabolismo , Genitália Feminina/metabolismo , Animais , Feminino , Regulação da Expressão Gênica , Humanos , Ligantes , Parto/metabolismo , Gravidez
14.
Reprod Toxicol ; 72: 153-158, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28610933

RESUMO

Constipation appears in the 2nd and 3rd trimester of pregnancy, while nausea is the strongest in the 1st trimester. This review summarizes the applicability of herbal laxatives and antiemetics in pregnancy. A human study has shown that flax oil as laxative is safe from 2nd trimester. Human data is not available about the rhubarb, but animal studies reveal that its emodin content induces fetal abnormalities. Fenugreek induces teratogenic malformation both in human and animals. Senna seed is proved as a safe laxative in pregnancy. The antiemetic ginger is safe during 1st trimester, but it reduces the gestational period when applied from the 2nd trimester. Cannabis induces fetal neurological disorders while fennel can shorten the gestational age. There is herbal alternative for laxative therapy (senna) for the whole length of pregnancy, but nausea and vomiting might be reduced by herbal medicine (ginger) safely in the 1st trimester, only.


Assuntos
Antieméticos/uso terapêutico , Laxantes/uso terapêutico , Preparações de Plantas/uso terapêutico , Gravidez , Animais , Feminino , Humanos
15.
Croat Med J ; 58(2): 96-104, 2017 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-28409493

RESUMO

Obesity is a global health problem even among pregnant women. Obesity alters quality of labor, such as preterm labor, prolonged labor, and higher oxytocin requirements in pregnant women. The most important factors to play a role in the altered gestational period and serve as drug targets to treat the consequences are female sexual hormones, calcium channels, adrenergic system, oxytocin, and prostaglandins. However, we have limited information about the impact of obesity on the pregnant uterine contractility and gestation time. Adipose tissue, which is the largest endocrine and paracrine organ, especially in obesity, is responsible for the production of adipokines and various cytokines and chemokines, and there are no reliable data available describing the relation between body mass index, glucose intolerance, and adipokines during pregnancy. Recent data suggest that the dysregulation of leptin, adiponectin, and kisspeptin during pregnancy contributes to gestational diabetes mellitus and pre-eclampsia. A preclinical method for obese pregnancy should be developed to clarify the action of adipokines and assess their impact in obesity. The deeper understanding of the adipokines-induced processes in obese pregnancy may be a step closer to the prevention and therapy of preterm delivery or prolonged pregnancy. Gestational weight gain is one of the factors that could influence the prenatal development, birth weight, and adiposity of newborn.


Assuntos
Adipocinas/metabolismo , Obesidade/fisiopatologia , Útero/fisiologia , Adiponectina/metabolismo , Peso ao Nascer , Índice de Massa Corporal , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Kisspeptinas/metabolismo , Leptina/metabolismo , Gravidez , Ganho de Peso
16.
Int J Mol Sci ; 17(8)2016 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-27556454

RESUMO

Thirteen mammalian aquaporin (AQP) water channels are known, and few of them play a role in the mammalian reproductive system. In our earlier study, the predominance of AQP5 in the late-pregnant rat uterus was proven. Our current aim was to investigate the effect of estrogen- and gestagen-related compounds on the expression of the AQP5 channel in the late-pregnant rat uterus. Furthermore, we examined the effect of hormonally-induced preterm delivery on the expression of AQP5 in the uterus. We treated pregnant Sprague-Dawley rats subcutaneously with 17ß-estradiol, clomiphene citrate, tamoxifen citrate, progesterone, levonorgestrel, and medroxyprogesterone acetate. Preterm delivery was induced by subcutaneous mifepristone and intravaginal prostaglandin E2. Reverse-transcriptase PCR and Western blot techniques were used for the detection of the changes in AQP5 mRNA and protein expressions. The amount of AQP5 significantly increased after progesterone and progesterone analogs treatment on 18 and 22 days of pregnancy. The 17ß-estradiol and estrogen receptor agonists did not influence the AQP5 mRNA level; however, estradiol induced a significant increase in the AQP5 protein level on the investigated days of gestation. Tamoxifen increased the AQP5 protein expression on day 18, while clomiphene citrate was ineffective. The hormonally-induced preterm birth significantly decreased the AQP5 level similarly to the day of delivery. We proved that AQP5 expression is influenced by both estrogen and progesterone in the late-pregnant rat uterus. The influence of progesterone on AQP5 expression is more predominant as compared with estrogen.


Assuntos
Aquaporina 5/genética , Aquaporina 5/metabolismo , Estradiol/farmacologia , Útero/metabolismo , Animais , Clomifeno/farmacologia , Estrogênios/farmacologia , Feminino , Levanogestrel/farmacologia , Acetato de Medroxiprogesterona/farmacologia , Gravidez , Progesterona/farmacologia , Progestinas/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Tamoxifeno/farmacologia , Útero/efeitos dos fármacos
17.
Reprod Biol Endocrinol ; 14(1): 33, 2016 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-27301276

RESUMO

BACKGROUND: The adrenergic system and progesterone play major roles in the control of the uterine function. Our aims were to clarify the changes in function and expression of the α2-adrenergic receptor (AR) subtypes after progesterone pretreatment in late pregnancy. METHODS: Sprague Dawley rats from pregnancy day 15 were treated with progesterone for 7 days. The myometrial expressions of the α2-AR subtypes were determined by RT-PCR and Western blot analysis. In vitro contractions were stimulated with (-)-noradrenaline, and its effect was modified with the selective antagonists BRL 44408 (α2A), ARC 239 (α2B/C) and spiroxatrine (α2A). The accumulation of myometrial cAMP was also measured. The activated G-protein level was investigated via GTPγS binding assays. RESULTS: Progesterone pretreatment decreased the contractile effect of (-)-noradrenaline through the α2-ARs. The most significant reduction was found through the α2B-ARs. The mRNA of all of the α2-AR subtypes was increased. Progesterone pretreatment increased the myometrial cAMP level in the presence of BRL 44408 (p < 0.001), spiroxatrine (p < 0.001) or the spiroxatrine + BRL 44408 combination (p < 0.05). Progesterone pretreatment increased the G-protein-activating effect of (-)-noradrenaline in the presence of the spiroxatrine + BRL 44408 combination. CONCLUSIONS: The expression of the α2-AR subtypes is progesterone-sensitive. It decreases the contractile response of (-)-noradrenaline through the α2B-AR subtype, blocks the function of α2A-AR subtype and alters the G protein coupling of these receptors, promoting a Gs-dependent pathway. A combination of α2C-AR agonists and α2B-AR antagonists with progesterone could be considered for the treatment or prevention of preterm birth.


Assuntos
Miométrio/efeitos dos fármacos , Progesterona/farmacologia , Receptores Adrenérgicos alfa 2/metabolismo , Contração Uterina/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Animais , AMP Cíclico/metabolismo , Feminino , Imidazóis/farmacologia , Isoindóis/farmacologia , Miométrio/metabolismo , Norepinefrina/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley
18.
Croat Med J ; 57(2): 100-9, 2016 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-27106352

RESUMO

AIM: To assess the effect of 17ß-estradiol pretreatment on the function and expression of α2- adrenergic receptors (ARs) subtypes in late pregnancy in rats. METHODS: Sprague-Dawley rats (n=37) were treated with 17ß-estradiol for 4 days starting from the 18th day of pregnancy. The myometrial expression of the α2-AR subtypes was determined by real time polymerase chain reaction and Western blot analysis. In vitro contractions were stimulated with (-)-noradrenaline, and its effect was modified with the selective antagonists BRL 44408 (α2A), ARC 239 (α2B/C), and spiroxatrine (α2A). The cyclic adenosine monophosphate (cAMP) accumulation was also measured. The activated G-protein level was investigated by guanosine 5'-O-[gamma-thio]triphosphate (GTPγS) binding assay. RESULTS: 17ß-estradiol pretreatment decreased the contractile effect of (-)-noradrenaline via the α2-ARs, and abolished the contractile effect via the α2B-ARs. All the α2-AR subtypes' mRNA was significantly decreased. 17ß-estradiol pretreatment significantly increased the myometrial cAMP level in the presence of BRL 44408 (P=0.001), ARC 239 (P=0.007), and spiroxatrine (P=0.045), but did not modify it in the presence of spiroxatrine + BRL 44408 combination (P=0.073). It also inhibited the G-protein-activating effect of (-)-noradrenaline by 25% in the presence of BRL 44408 + spiroxatrine combination. CONCLUSIONS: The expression of the α2-AR subtypes is sensitive to 17ß-estradiol, which decreases the contractile response of (-)-noradrenaline via the α2B-AR subtype, and might cause changes in G-protein signaling pathway. Estrogen dysregulation may be responsible for preterm labor or uterine inertia via the α2-ARs.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Estradiol/farmacologia , Trabalho de Parto Prematuro/fisiopatologia , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Animais , Feminino , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Contração Uterina/efeitos dos fármacos
19.
Eur J Pharmacol ; 769: 177-84, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26593425

RESUMO

The aim of the study was to investigate the roles of α1-adrenoceptor subtypes in the last-day pregnant rat uterus in vitro by the administration of subtype-specific antagonists (the α1A-adrenoceptor antagonist WB 4101 and the α1D-adrenoceptor antagonist BMY 7378) after 17ß-estradiol or progesterone pretreatment. In isolated organ bath studies, contractions were elicited with (-)-noradrenaline (10(-8)-10(-5)M) in the presence of propranolol (10(-5)M) and yohimbine (10(-6)M) in order to avoid ß-, and α2-adrenergic action. The myometrial expressions of the α1-adrenoceptor subtypes were determined by means of the real time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting techniques. The activated G protein levels were investigated through radiolabelled GTP binding assays. Both 17ß-estradiol and progesterone pretreatment changed the myometrial contracting effect of (-)-noradrenaline. In the presence of WB 4101, progesterone pretreatment decreased the (-)-noradrenaline-induced myometrial contraction. In the presence of BMY 7378, both the 17ß-estradiol and the progesterone pretreatment reduced the effect of (-)-noradrenaline. The mRNA and protein expressions of the α1A-adrenoceptors were decreased after 17ß-estradiol pretreatment. (-)-Noradrenaline increased the [(35)S]GTPγS binding of the α1-adrenoceptors, which was most markedly elevated by progesterone. Pertussis toxin inhibited the [(35)S]GTPγS binding-stimulating effect of (-)-noradrenaline, indicating the role of Gi proteins in the signal mechanisms. 17ß-estradiol pretreatment blocks the expression of the α1A-adrenoceptors, whereas it does not influence the expression of the α1D-adrenoceptors. Progesterone pretreatment does not have any effect on the myometrial mRNA and protein expressions of the α1-adrenoceptors, but it alters the G protein coupling of these receptors, promoting a Gi-dependent pathway.


Assuntos
Estradiol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Miométrio/efeitos dos fármacos , Miométrio/metabolismo , Progesterona/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Animais , Dioxanos/farmacologia , Feminino , Piperazinas/farmacologia , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos alfa 1/genética
20.
Vitam Horm ; 97: 223-40, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25677774

RESUMO

The presence and effects of nociceptin (N/OFQ) and nocistatin (NST) in the central nervous system have been reasonably well described, but less data are available on their peripheral functions. Besides their presence in several peripheral organs (white blood cells, airway, liver, skin, vascular and intestinal smooth muscles, ovary, and testis), they have been found in the pregnant myometrium in both rat and human. The level of their precursor prepronociceptin is elevated in the preterm human myometrium as compared with full-term samples, whereas it gradually increases toward term in the pregnant rat uterus. Both N/OFQ and NST inhibit myometrial contractions, an effect which can be enhanced by naloxone and blocked by Ca²âº-dependent K⁺ channel (BK(Ca)) inhibitors. Both compounds increase the myometrial cAMP level which may be responsible for the activation of this channel and subsequent intracellular hyperpolarization. NST releases calcitonin gene-related peptide from the sensory nerve ends, which explains its cAMP-elevating effect. In contrast with the nervous system, where they behave as antagonists, N/OFQ and NST are able to potentiate the uterine-relaxing effect of each other in both rat and human tissues. Further studies are required to clarify the roles of N/OFQ and NST in the regulation of the myometrial contractions and the perception of pain during delivery.


Assuntos
Modelos Biológicos , Peptídeos Opioides/metabolismo , Contração Uterina/metabolismo , Animais , Feminino , Humanos , Miométrio/metabolismo , Especificidade de Órgãos , Gravidez
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