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1.
Front Endocrinol (Lausanne) ; 15: 1374825, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38742194

RESUMO

Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E2). However, clinical data are conflicting on whether E2 lowers AD risk. One potential contributing factor is APOE. The greatest genetic risk factor for AD is APOE4, a factor that is pronounced in female individuals post-menopause. Clinical data suggests that APOE impacts the response of AD patients to E2 replacement therapy. However, whether APOE4 prevents, is neutral, or promotes any positive effects of E2 is unclear. Therefore, our goal was to determine whether APOE modulates the impact of E2 on behavior and AD pathology in vivo. To that end, mice that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce Aß42 were ovariectomized at either 4 months (early) or 8 months (late) and treated with vehicle or E2 for 4 months. In E3FAD mice, we found that E2 mitigated the detrimental effect of ovariectomy on memory, with no effect on Aß in the early paradigm and only improved learning in the late paradigm. Although E2 lowered Aß in E4FAD mice in the early paradigm, there was no impact on learning or memory, possibly due to higher Aß pathology compared to E3FAD mice. In the late paradigm, there was no effect on learning/memory and Aß pathology in E4FAD mice. Collectively, these data support the idea that, in the presence of Aß pathology, APOE impacts the response to E2 supplementation post-menopause.


Assuntos
Doença de Alzheimer , Apolipoproteína E3 , Apolipoproteína E4 , Estradiol , Camundongos Transgênicos , Ovariectomia , Animais , Estradiol/farmacologia , Feminino , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Camundongos , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Humanos , Comportamento Animal/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de Doenças
2.
Biochem Biophys Res Commun ; 716: 150026, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38701557

RESUMO

BACKGROUND: Previous in vivo and in vitro studies have demonstrated that estrogen receptor agonist G-1 regulates glucose and lipid metabolism. This study focused on the effects of G-1 on cardiometabolic syndrome and anti-obesity under a high fat diet (HFD). METHODS: Bilateral ovariectomized female mice were fed an HFD for 6 weeks, and treated them with G-1. A cardiomyocyte insulin resistance model was used to simulate the in vivo environment. The main outcome measures were blood glucose, body weight, and serum insulin levels to assess insulin resistance, while cardiac function and degree of fibrosis were assessed by cardiac ultrasound and pathological observations. We also examined the expression of p-AMPK, p-AKT, and GLUT4 in mice hearts and in vitro models to explore the mechanism by which G-1 regulates insulin signaling. RESULTS: G-1 reduced body weight in mice on an HFD, but simultaneously increased blood glucose and promoted insulin resistance, resulting in myocardial damage. This damage included disordered cardiomyocytes, massive accumulation of glycogen, extensive fibrosis of the heart, and thickening of the front and rear walls of the left ventricle. At the molecular level, G-1 enhances gluconeogenesis and promotes glucose production by increasing the activity of pyruvate carboxylase (PC) while inhibiting GLUT4 translocation via the AMPK/TBC1D1 pathway, thereby limiting glucose uptake. CONCLUSION: Despite G-1's the potential efficacy in weight reduction, the concomitant induction of insulin resistance and cardiac impairment in conjunction with an HFD raises significant concerns. Therefore, comprehensive studies of its safety profile and effects under specific conditions are essential prior to clinical use.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina , Camundongos Endogâmicos C57BL , Ovariectomia , Receptores Acoplados a Proteínas G , Animais , Feminino , Dieta Hiperlipídica/efeitos adversos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Camundongos , Transportador de Glucose Tipo 4/metabolismo , Receptores de Estrogênio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Insulina/metabolismo , Insulina/sangue
3.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732143

RESUMO

This study explores low-intensity extracorporeal shock wave therapy (LiESWT)'s efficacy in alleviating detrusor hyperactivity with impaired contractility (DHIC) induced by ovarian hormone deficiency (OHD) in ovariectomized rats. The rats were categorized into the following four groups: sham group; OVX group, subjected to bilateral ovariectomy (OVX) for 12 months to induce OHD; OVX + SW4 group, underwent OHD for 12 months followed by 4 weeks of weekly LiESWT; and OVX + SW8 group, underwent OHD for 12 months followed by 8 weeks of weekly LiESWT. Cystometrogram studies and voiding behavior tracing were used to identify the symptoms of DHIC. Muscle strip contractility was evaluated through electrical-field, carbachol, ATP, and KCl stimulations. Western blot and immunofluorescence analyses were performed to assess the expressions of various markers related to bladder dysfunction. The OVX rats exhibited significant bladder deterioration and overactivity, alleviated by LiESWT. LiESWT modified transient receptor potential vanilloid (TRPV) channel expression, regulating calcium concentration and enhancing bladder capacity. It also elevated endoplasmic reticulum (ER) stress proteins, influencing ER-related Ca2+ channels and receptors to modulate detrusor muscle contractility. OHD after 12 months led to neuronal degeneration and reduced TRPV1 and TRPV4 channel activation. LiESWT demonstrated potential in enhancing angiogenic remodeling, neurogenesis, and receptor response, ameliorating DHIC via TRPV channels and cellular signaling in the OHD-induced DHIC rat model.


Assuntos
Modelos Animais de Doenças , Tratamento por Ondas de Choque Extracorpóreas , Contração Muscular , Canais de Cátion TRPV , Bexiga Urinária , Animais , Feminino , Ratos , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética , Tratamento por Ondas de Choque Extracorpóreas/métodos , Bexiga Urinária/fisiopatologia , Bexiga Urinária/metabolismo , Bexiga Urinária Hiperativa/terapia , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Urinária Hiperativa/etiologia , Ovariectomia , Ratos Sprague-Dawley , Ovário/metabolismo
4.
Int J Pharm Compd ; 28(3): 260-263, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38768506

RESUMO

Pyometra is a common disease in intact female canines characterized by an infection of the uterus. If it is not treated immediately, it could result in various complications such as fistulous tract development, sepsis, hemorrhage, uveitis, conjunctivitis, pyelonephritis, urinary tract infection, and myocarditis. In this case report, we highlight the benefits of the application of a topical ointment on wound healing after ovariohysterectomy in canine Pyometra. Following surgical intervention, the dog developed necrosis in her nipples and lost a portion of her mammary tissues. A large cyst formed and later ruptured, leaving the animal with a large wound. The vet applied a topical ointment, AlpaWash, to the affected area and prescribed antibiotic, analgesic, and antiinflammatory drugs to help manage the condition. The vet reported complete healing of the wounds within one month from the commencement of the treatment regimen.


Assuntos
Piometra , Cicatrização , Animais , Feminino , Cães , Piometra/veterinária , Piometra/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Histerectomia/veterinária , Doenças do Cão/tratamento farmacológico , Ovariectomia/veterinária , Pomadas , Ferida Cirúrgica/tratamento farmacológico , Ferida Cirúrgica/veterinária
5.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167227, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38733774

RESUMO

Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS). Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17ß-estradiol (E2) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E2 prevented OLA-induced phospho-JNK in hypothalamic neurons. These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.


Assuntos
Tecido Adiposo Marrom , Estrogênios , Hipotálamo , Fígado , Camundongos Knockout , Olanzapina , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Desacopladora 1 , Animais , Feminino , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Camundongos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Estrogênios/metabolismo , Estrogênios/farmacologia , Olanzapina/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Masculino , Metabolismo Energético/efeitos dos fármacos , Injeções Intraperitoneais , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Estradiol/farmacologia , Ovariectomia
6.
Aging (Albany NY) ; 16(9): 7870-7888, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38709288

RESUMO

BMP9 has demonstrated significant osteogenic potential. In this study, we investigated the effect of Leptin on BMP9-induced osteogenic differentiation. Firstly, we found Leptin was decreased during BMP9-induced osteogenic differentiation and serum Leptin concentrations were increased in the ovariectomized (OVX) rats. Both in vitro and in vivo, exogenous expression of Leptin inhibited the process of osteogenic differentiation, whereas silencing Leptin enhanced. Exogenous Leptin could increase the malonylation of ß-catenin. However, BMP9 could increase the level of Sirt5 and subsequently decrease the malonylation of ß-catenin; the BMP9-induced osteogenic differentiation was inhibited by silencing Sirt5. These data suggested that Leptin can inhibit the BMP9-induced osteogenic differentiation, which may be mediated through reducing the activity of Wnt/ß-catenin signalling via down-regulating Sirt5 to increase the malonylation level of ß-catenin partly.


Assuntos
Regulação para Baixo , Fator 2 de Diferenciação de Crescimento , Leptina , Osteogênese , Sirtuínas , Via de Sinalização Wnt , beta Catenina , Animais , beta Catenina/metabolismo , beta Catenina/genética , Sirtuínas/metabolismo , Sirtuínas/genética , Feminino , Ratos , Osteogênese/efeitos dos fármacos , Leptina/metabolismo , Leptina/farmacologia , Fator 2 de Diferenciação de Crescimento/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Ovariectomia , Diferenciação Celular/efeitos dos fármacos , Ratos Sprague-Dawley
7.
Aging (Albany NY) ; 16(9): 7553-7577, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38742935

RESUMO

After menopause, the incidence of cardiovascular disease rapidly rises in women. The disappearing protection provided by sex steroids is a consequence of the development of many risk factors. Preclinical studies are necessary to understand better the effects of ovarian hormones loss cardiac aging. To mimic menopause in mice and study its consequences, we delayed ovariectomy at 12 months and followed animals for 12 months. Using RNA sequencing, we investigated changes in the myocardial exome with aging. In addition, with four-core genotypes (FCG) transgenic mice, we studied sex chromosome effects on cardiac aging. Heart weight increased from 3 to 24 months (males + 35%, females + 29%). In males, 75% of this increase had occurred at 12 months; in females, only 30%. Gonadectomy of mice at 12 months blocked cardiac hypertrophy in both sexes during the second year of life. The dosage of the X chromosomes did not influence cardiac growth in young and older mice. We performed an RNA sequencing study in young and old mice. We identified new highly expressed genes modulated during aging (Bdh, Myot, Cpxm2, and Slc38a1). The myocardial exome in older animals displayed few differences related to the animal's sex or the presence or absence of sex steroids for a year. We show that the morphological evolution of the heart depends on the biological sex via gonadal sex hormone actions. The myocardial exome of old male and female mice is relatively similar. Our study emphasizes the need to consider sex steroid effects in studying cardiac aging.


Assuntos
Envelhecimento , Hormônios Esteroides Gonadais , Cromossomos Sexuais , Animais , Feminino , Masculino , Envelhecimento/genética , Camundongos , Hormônios Esteroides Gonadais/metabolismo , Cromossomos Sexuais/genética , Camundongos Transgênicos , Ovariectomia , Coração , Miocárdio/metabolismo , Miocárdio/patologia , Fatores Sexuais , Cardiomegalia/genética
8.
Hepatol Commun ; 8(5)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38704651

RESUMO

BACKGROUND: Alcohol-associated liver disease is a complex disease regulated by genetic and environmental factors such as diet and sex. The combination of high-fat diet and alcohol consumption has synergistic effects on liver disease progression. Female sex hormones are known to protect females from liver disease induced by high-fat diet. In contrast, they promote alcohol-mediated liver injury. We aimed to define the role of female sex hormones on liver disease induced by a combination of high-fat diet and alcohol. METHODS: Wild-type and protein arginine methyltransferase (Prmt)6 knockout female mice were subjected to gonadectomy (ovariectomy, OVX) or sham surgeries and then fed western diet and alcohol in the drinking water. RESULTS: We found that female sex hormones protected mice from western diet/alcohol-induced weight gain, liver steatosis, injury, and fibrosis. Our data suggest that these changes are, in part, mediated by estrogen-mediated induction of arginine methyltransferase PRMT6. Liver proteome changes induced by OVX strongly correlated with changes induced by Prmt6 knockout. Using Prmt6 knockout mice, we confirmed that OVX-mediated weight gain, steatosis, and injury are PRMT6 dependent, while OVX-induced liver fibrosis is PRMT6 independent. Proteomic and gene expression analyses revealed that estrogen signaling suppressed the expression of several components of the integrin pathway, thus reducing integrin-mediated proinflammatory (Tnf, Il6) and profibrotic (Tgfb1, Col1a1) gene expression independent of PRMT6 levels. Integrin signaling inhibition using Arg-Gly-Asp peptides reduced proinflammatory and profibrotic gene expression in mice, suggesting that integrin suppression by estrogen is protective against fibrosis development. CONCLUSIONS: Taken together, estrogen signaling protects mice from liver disease induced by a combination of alcohol and high-fat diet through upregulation of Prmt6 and suppression of integrin signaling.


Assuntos
Estradiol , Integrinas , Camundongos Knockout , Proteína-Arginina N-Metiltransferases , Transdução de Sinais , Animais , Camundongos , Feminino , Transdução de Sinais/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Integrinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ovariectomia , Etanol/efeitos adversos , Cirrose Hepática Alcoólica/metabolismo , Cirrose Hepática Alcoólica/prevenção & controle , Cirrose Hepática Alcoólica/patologia , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
9.
Drug Des Devel Ther ; 18: 1515-1528, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38716369

RESUMO

Purpose: Estrogen deficiency is the main reason of postmenopausal osteoporosis. Eldecalcitol (ED-71) is a new active vitamin D analogue clinically used in the treatment of postmenopausal osteoporosis. We aimed to investigate whether EphrinB2-EphB4 and RANKL/RANK/OPG signaling cooperate in mediating the process of osteoporosis by ED-71. Methods: In vivo, the ovariectomized (OVX) rats were administered orally with 30 ng/kg ED-71 once a day for 8 weeks. HE staining, Masson staining and Immunofluorescence staining were used to evaluate bone mass, bone formation, osteoclastogenesis associated factors and the expression of EphrinB2, EphB4, RANKL and OPG. In vitro, H2O2 stimulation was used to simulate the cell environment in osteoporosis. Immunofluorescence, quantitative real time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and Western Blot were applied to detect the expression of EphrinB2, EphB4, RANKL and OPG. In osteoblasts, EphB4 was knocked down by EphB4 small-interfering RNA (siRNA) transfection. LY294002 (PI3K inhibitor) or ARQ092 (AKT inhibitor) was used to block PI3K/AKT pathway. An indirect co-culture system of osteoblasts and osteoclasts was established. The mRNA and protein expression of osteoclastogenes is associated factors were tested by qRT-PCR and Western Blot. Results: ED-71 increased bone mass and decreased the number of osteoclasts in OVX rats. Moreover, ED-71 promoted the expression of EphrinB2, EphB4, and decreased the RANKL/OPG ratio in osteoblasts. Osteoclastogenesis was restrained when osteoclasts were indirectly co-cultured with ED-71-treated osteoblasts. After silencing of EphB4 expression in osteoblasts, ED-71 inhibited the expression of P-PI3K and P-AKT and increased the ratio of RANKL/OPG. This reversed the inhibitory effect of ED-71 on osteoclastogenes. Therefore, in ED-71-inhibited osteoclastogenes, EphB4 is a key factor affecting the secretion of RANKL and OPG by osteoblasts. EphB4 suppressed the RANKL/OPG ratio through activating PI3K/AKT signaling in osteoblasts. Conclusion: ED-71 inhibits osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis, improving bone mass in ovariectomized rats. PI3K/AKT pathway is involved this process.


Assuntos
Efrina-B2 , Osteoprotegerina , Ovariectomia , Ligante RANK , Ratos Sprague-Dawley , Receptor EphB4 , Animais , Ratos , Ligante RANK/metabolismo , Ligante RANK/antagonistas & inibidores , Feminino , Receptor EphB4/metabolismo , Receptor EphB4/antagonistas & inibidores , Efrina-B2/metabolismo , Efrina-B2/antagonistas & inibidores , Osteoprotegerina/metabolismo , Vitamina D/farmacologia , Vitamina D/análogos & derivados , Osteogênese/efeitos dos fármacos , Células Cultivadas , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos
10.
Sci Rep ; 14(1): 10227, 2024 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702443

RESUMO

Hydrolyzed egg yolk peptide (YPEP) was shown to increase bone mineral density in ovariectomized rats. However, the underlying mechanism of YPEP on osteoporosis has not been explored. Recent studies have shown that Wnt/ß-catenin signaling pathway and gut microbiota may be involved in the regulation of bone metabolism and the progression of osteoporosis. The present study aimed to explore the preventive effect of the YPEP supplementation on osteoporosis in ovariectomized (OVX) rats and to verify whether YPEP can improve osteoporosis by regulating Wnt/ß-catenin signaling pathway and gut microbiota. The experiment included five groups: sham surgery group (SHAM), ovariectomy group (OVX), 17-ß estradiol group (E2: 25 µg /kg/d 17ß-estradiol), OVX with low-dose YPEP group (LYPEP: 10 mg /kg/d YPEP) and OVX with high-dose YPEP group (HYPEP: 40 mg /kg/d YPEP). In this study, all the bone samples used were femurs. Micro-CT analysis revealed improvements in both bone mineral density (BMD) and microstructure by YPEP treatment. The three-point mechanical bending test indicated an enhancement in the biomechanical properties of the YPEP groups. The serum levels of bone alkaline phosphatase (BALP), bone gla protein (BGP), calcium (Ca), and phosphorus (P) were markedly higher in the YPEP groups than in the OVX group. The LYPEP group had markedly lower levels of alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) and C-terminal telopeptide of type I collagen (CTX-I) than the OVX group. The YPEP groups had significantly higher protein levels of the Wnt3a, ß-catenin, LRP5, RUNX2 and OPG of the Wnt/ß-catenin signaling pathway compared with the OVX group. Compared to the OVX group, the ratio of OPG/RANKL was markedly higher in the LYPEP group. At the genus level, there was a significantly increase in relative abundance of Lachnospiraceae_NK4A136_group and a decrease in Escherichia_Shigella in YPEP groups, compared with the OVX group. However, in the correlation analysis, there was no correlation between these two bacteria and bone metabolism and microstructure indexes. These findings demonstrate that YPEP has the potential to improve osteoporosis, and the mechanism may be associated with its modulating effect on Wnt/ß-catenin signaling pathway.


Assuntos
Densidade Óssea , Osteoporose , Ovariectomia , Via de Sinalização Wnt , Animais , Ovariectomia/efeitos adversos , Via de Sinalização Wnt/efeitos dos fármacos , Feminino , Osteoporose/prevenção & controle , Osteoporose/metabolismo , Densidade Óssea/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Gema de Ovo/química , Gema de Ovo/metabolismo , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas do Ovo/farmacologia , Proteínas do Ovo/metabolismo , Peptídeos/farmacologia , beta Catenina/metabolismo , Fosfatase Alcalina/metabolismo , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Microtomografia por Raio-X
12.
J Neuroimmune Pharmacol ; 19(1): 16, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38652402

RESUMO

Our previous research demonstrated that allergic rhinitis could impact behavior and seizure threshold in male mice. However, due to the complex hormonal cycles and hormonal influences on behavior in female mice, male mice are more commonly used for behavioral tests. In this study, we aimed to determine whether these findings were replicable in female mice and to explore the potential involvement of sexual hormones in regulating neuroinflammation in an allergic model. Our results indicate that pain threshold was decreased in female mice with allergic rhinitis and the levels of IL-23/IL-17A/IL-17R were increased in their Dorsal root ganglia. However, unlike males, female mice with AR did not display neuropsychological symptoms such as learning and memory deficits, depression, and anxiety-like behavior. This was along with decreased levels of DNA methyl transferase 1 (DNMT1) and inflammatory cytokines in their hippocampus. Ovariectomized mice were used to mitigate hormonal effects, and the results showed that they had behavioral changes and neuroinflammation in their hippocampus similar to male mice, as well as increased levels of DNMT1. These findings demonstrate sex differences in how allergic rhinitis affects behavior, pain sensitivity, and seizure thresholds. Furthermore, our data suggest that DNMT1 may be influenced by sexual hormones, which could play a role in modulating inflammation in allergic conditions.


Assuntos
Modelos Animais de Doenças , Doenças Neuroinflamatórias , Limiar da Dor , Rinite Alérgica , Convulsões , Caracteres Sexuais , Animais , Feminino , Camundongos , Masculino , Rinite Alérgica/metabolismo , Rinite Alérgica/psicologia , Limiar da Dor/fisiologia , Doenças Neuroinflamatórias/metabolismo , Convulsões/metabolismo , Comportamento Animal/fisiologia , Ovariectomia , DNA (Citosina-5-)-Metiltransferase 1/metabolismo
13.
J Ethnopharmacol ; 330: 118191, 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-38621468

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Mijiao (MJ) formula, a traditional herbal remedy, incorporates antlers as its primary constituent. It can effectively treat osteoporosis (OP), anti-aging, enhance immune activity, and change depression-like behavior. In this study, we investigated that MJ formula is a comprehensive treatment strategy, and may provide a potential approach for the clinical treatment of postmenopausal osteoporosis. AIM OF THE STUDY: The purpose of this study was to determine whether MJ formula promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and improved osteoporosis in ovariectomized rats by regulating the NAT10-mediated Runx2 mRNA ac4C modification. MATERIALS AND METHODS: Female Sprague-Dawley (SD) rats were used to investigate the potential therapeutic effect of MJ formula on OP by creating an ovariectomized (OVX) rat model. The expression of osteogenic differentiation related proteins in BMSCs was detected in vivo, indicating their role in promoting bone formation. In addition, the potential mechanism of its bone protective effect was explored via in vitro experiments. RESULTS: Our study showed that MJ formula significantly mitigated bone mass loss in the OVX rat model, highlighting its potential as an OP therapeutic agent. We found that the possible mechanism of action was the ability of this formulation to stabilize Runx2 mRNA through NAT10-mediated ac4C acetylation, which promoted osteogenic differentiation of BMSCs and contributed to the enhancement of bone formation. CONCLUSIONS: MJ formula can treat estrogen deficiency OP by stabilizing Runx2 mRNA, promoting osteogenic differentiation and protecting bone mass. Conceivably, MJ formulation could be a safe and promising strategy for the treatment of osteoporosis.


Assuntos
Diferenciação Celular , Subunidade alfa 1 de Fator de Ligação ao Core , Medicamentos de Ervas Chinesas , Células-Tronco Mesenquimais , Osteogênese , Osteoporose , Ovariectomia , RNA Mensageiro , Ratos Sprague-Dawley , Animais , Feminino , Osteogênese/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Células-Tronco Mesenquimais/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , RNA Mensageiro/metabolismo , Osteoporose/tratamento farmacológico , Ratos , Modelos Animais de Doenças , Células Cultivadas
14.
Int J Mol Sci ; 25(8)2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38673844

RESUMO

This study aimed to examine minimodeling-based bone formation between the epiphyses and metaphyses of the long bones of eldecalcitol (ELD)-administered ovariectomized rats. Sixteen-week-old female rats were divided into four groups: sham-operated rats receiving vehicle (Sham group), ovariectomized (OVX) rats receiving vehicle (Vehicle group), or ELDs (30 or 90 ng/kg BW, respectively; ELD30 and ELD90 groups). ELD administration increased bone volume and trabecular thickness, reducing the number of osteoclasts in both the epiphyses and metaphyses of OVX rats. The Sham and Vehicle groups exhibited mainly remodeling-based bone formation in both regions. The epiphyses of the ELD groups showed a significantly higher frequency of minimodeling-based bone formation than remodeling-based bone formation. In contrast, the metaphyses exhibited significantly more minimodeling-based bone formation in the ELD90 group compared with the ELD30 group. However, there was no significant difference between minimodeling-based bone formation and remodeling-based bone formation in the ELD90 group. While the minimodeling-induced new bone contained few sclerostin-immunoreactive osteocytes, the underlying pre-existing bone harbored many. The percentage of sclerostin-positive osteocytes was significantly reduced in the minimodeling-induced bone in the epiphyses but not in the metaphyses of the ELD groups. Thus, it seems likely that ELD could induce minimodeling-based bone formation in the epiphyses rather than in the metaphyses, and that ELD-driven minimodeling may be associated with the inhibition of sclerostin synthesis.


Assuntos
Marcadores Genéticos , Osteogênese , Vitamina D , Vitamina D/análogos & derivados , Animais , Feminino , Ratos , Osteogênese/efeitos dos fármacos , Vitamina D/farmacologia , Ovariectomia , Epífises/efeitos dos fármacos , Epífises/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Remodelação Óssea/efeitos dos fármacos , Ratos Sprague-Dawley , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Osso e Ossos/metabolismo , Osso e Ossos/efeitos dos fármacos
15.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167165, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38653355

RESUMO

The mechanisms that underly reproductive hormone effects on cognition, neuronal plasticity, and AD risk, particularly in relation to gonadotropin LH receptor (LHCGR) signaling, remain poorly understood. To address this gap in knowledge and clarify the impact of circulating steroid hormones on the therapeutic effects of CNS LHCGR activation, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV) and evaluated functional, structural, plasticity-related signaling cascades, Aß pathology, and transcriptome differences in reproductively intact and ovariectomized (OVX) APP/PS1 AD female mice. Here we demonstrate that CNS hCG delivery restored function to wild-type levels only in OVX APP/PS1 mice. Spine density was increased in all hCG treated groups independently of reproductive status. Notably, increases in BDNF signaling and cognition, were selectively upregulated only in the OVX hCG-treated group. RNA sequencing analyses identified a significant increase in peripheral myeloid and pro-inflammatory genes within the hippocampi of the OVX group that were completely reversed by hCG treatment, identifying a potential mechanism underlying the selective therapeutic effect of LHCGR activation. Interestingly, in intact mice, hCG administration mimicked the effects of gonadectomy. Together, our findings indicate that CNS LHCGR agonism in the post-menopausal context is beneficial through trophic and immune mechanisms. Our findings also underscore the presence of a steroid-LHCGR mechanistic interaction that is unexplored yet potentially meaningful to fully understand "post-menopausal" brain function and CNS hormone treatment response.


Assuntos
Doença de Alzheimer , Gonadotropina Coriônica , Modelos Animais de Doenças , Receptores do LH , Animais , Feminino , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Camundongos , Gonadotropina Coriônica/farmacologia , Receptores do LH/metabolismo , Receptores do LH/genética , Receptores do LH/agonistas , Camundongos Transgênicos , Ovariectomia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Reprodução/efeitos dos fármacos , Presenilina-1/genética , Presenilina-1/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Cognição/efeitos dos fármacos
16.
J Pharm Biomed Anal ; 245: 116166, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38669816

RESUMO

The study aimed to investigate the relieving effect of QingYan Formula (QYF) in treating perimenopausal syndrome. A combination of metabonomic analysis and in vitro pharmacodynamic experiments was employed to achieve this objective.Over a period of 12 weeks, ovariectomized (OVX) rats were orally administered QYF's 70 % ethanol extract or estradiol valerate (EV). The results demonstrate that QYF restored the estrous cycle of ovariectomized rats and exhibited significant estrogenic activity, as indicated by reversal of uterine and vagina atrophy, improvement of serum estradiol level and decrease of serum luteinizing hormone(LH) level. Additionally, QYF administration effectively reduced high bone turnover and repaired trabecular microstructure damage. Metabonomic analysis of the OVX rats treated with QYF revealed the identification of 55 different metabolites in the serum, out of which 35 may be potential biomarkers. QYF could regulate the disturbed metabolic pathways including the Biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, bile secretion, and steroid hormone biosynthesis. PI3KCA, SRC, and MAPK3 are potential therapeutic targets for QYF therapeutic effects. These findings support the efficacy of QYF in alleviating perimenopausal syndrome and regulating lipid metabolic disorders in OVX rats.


Assuntos
Medicamentos de Ervas Chinesas , Metabolômica , Ovariectomia , Perimenopausa , Ratos Sprague-Dawley , Animais , Feminino , Metabolômica/métodos , Medicamentos de Ervas Chinesas/farmacologia , Ratos , Perimenopausa/efeitos dos fármacos , Estradiol/sangue , Estradiol/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Biomarcadores/sangue , Hormônio Luteinizante/sangue , Ciclo Estral/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/metabolismo , Modelos Animais de Doenças
17.
Nutrients ; 16(8)2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38674937

RESUMO

Osteoporosis, a disease defined by the primary bone strength due to a low bone mineral density, is a bone disorder associated with increased mortality in the older adult population. Osteoporosis is mainly treated via hormone replacement therapy, bisphosphates, and anti-bone resorption agents. However, these agents exert severe side effects, necessitating the development of novel therapeutic agents. Many studies are focusing on osteogenic agents as they increase the bone density, which is essential for osteoporosis treatment. Here, we aimed to investigate the effects of Diospyros lotus L. leaf extract (DLE) and its components on osteoporosis in MC3T3-E1 pre-osteoblasts and ovariectomized mice and to elucidate the underlying related pathways. DLE enhanced the differentiation of MC3T3-E1 pre-osteoblasts, with a 1.5-fold elevation in ALP activity, and increased the levels of osteogenic molecules, RUNX family transcription factor 2, and osterix. This alteration resulted from the activation of bone morphogenic protein 2/4 (BMP2/4) and transformation of growth factor ß (TGF ß) pathways. In ovariectomized mice, DLE suppressed the decrease in bone mineral density by 50% and improved the expression of other bone markers, which was confirmed by the 3~40-fold increase in osteogenic proteins and mRNA expression levels in bone marrow cells. The three major compounds identified in DLE exhibited osteogenic and estrogenic activities with their aglycones, as previously reported. Among the major compounds, myricitrin alone was not as strong as whole DLE with all its constituents. The osteogenic activity of DLE was partially suppressed by the inhibitor of estrogen signaling, indicating that the estrogenic activity of DLE participated in its osteogenic activity. Overall, DLE suppresses osteoporosis by inducing osteoblast differentiation.


Assuntos
Densidade Óssea , Diospyros , Osteoblastos , Osteogênese , Extratos Vegetais , Animais , Feminino , Camundongos , Densidade Óssea/efeitos dos fármacos , Proteína Morfogenética Óssea 2/efeitos dos fármacos , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/efeitos dos fármacos , Proteína Morfogenética Óssea 4/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diospyros/química , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Ovariectomia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
18.
J Appl Physiol (1985) ; 136(5): 1195-1208, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38572539

RESUMO

Hypertensive postmenopausal women are more likely to develop adverse cardiac remodeling and respond less effectively to drug treatment than men. High-intensity interval exercise (HIIE) is a nonpharmacological strategy for the treatment of hypertension; however, the effectiveness in women remains uncertain. This study was designed to evaluate 1) the effects of HIIE training upon morphological and functional markers of cardiovascular health in female SHR and 2) to determine whether the hormonal shift induced by ovariectomy could influence cardiovascular responses to HIIE. Thirty-six SHR were randomly assigned to four groups: ovariectomized sedentary, ovariectomized trained, sham-operated sedentary, and sham-operated trained. The trained rats performed HIIE 5 days/wk for 8 wk. Blood pressure and echocardiographic measurements were performed before and after training in animals. Cardiac response to ß-adrenergic stimulation and the expression of calcium regulatory proteins and estrogen receptors in heart samples were assessed. Endothelium-dependent vasorelaxation in response to acetylcholine was evaluated in aortic rings as well as the expression of nitric oxide synthase isoforms (eNOS and P-eNOS) by Western blotting. In both groups of trained SHR, HIIE induced eccentric cardiac remodeling with greater inotropic and chronotropic effects, as well as an increase in SERCA and ß1AR expression. However, although the trained rats showed improved endothelial function and expression of eNOS and P-eNOS in the aorta, there was no demonstrated effect on blood pressure. In addition, the responses to HIIE training were not affected by ovariectomy. This work highlights the importance of assessing the cardiovascular efficacy and safety of different exercise modalities in women.NEW & NOTEWORTHY This study reports the effects of high-intensity interval exercise (HIIE) training on cardiac and endothelial function in female hypertensive rats. Despite a lack of effect on blood pressure (BP), HIIE training induces eccentric cardiac remodeling with greater functionals effects. Furthermore, training has beneficial effects on endothelial function. However, ovarian hormones do not seem to modulate cardiac and aortic adaptations to this training modality. All this underlines the need to consider training modalities on the cardiovascular system in women.


Assuntos
Pressão Sanguínea , Treinamento Intervalado de Alta Intensidade , Hipertensão , Ovariectomia , Condicionamento Físico Animal , Ratos Endogâmicos SHR , Animais , Feminino , Treinamento Intervalado de Alta Intensidade/métodos , Ratos , Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Hipertensão/metabolismo , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/métodos , Óxido Nítrico Sintase Tipo III/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Remodelação Ventricular/fisiologia
19.
Bioorg Chem ; 147: 107364, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38636434

RESUMO

Osteoporosis is particularly prevalent among postmenopausal women and the elderly. In the present study, we investigated the effect of the novel small molecule E0924G (N-(4-methoxy-pyridine-2-yl)-5-methylfuran-2-formamide) on osteoporosis. E0924G significantly increased the protein expression levels of osteoprotegerin (OPG) and runt-related transcription factor 2 (RUNX2), and thus significantly promoted osteogenesis in MC3T3-E1 cells. E0924G also significantly decreased osteoclast differentiation and inhibited bone resorption and F-actin ring formation in receptor activator of NF-κB ligand (RANKL)-induced osteoclasts from RAW264.7 macrophages. Importantly, oral administration of E0924G in both ovariectomized (OVX) rats and SAMP6 senile mice significantly increased bone mineral density and decreased bone loss compared to OVX controls or SAMR1 mice. Further mechanistic studies showed that E0924G could bind to and then activate peroxisome proliferator-activated receptor delta (PPARδ), and the pro-osteoblast effect and the inhibition of osteoclast differentiation induced by E0924G were significantly abolished when PPARδ was knocked down or inhibited. In conclusion, these data strongly suggest that E0924G has the potential to prevent OVX-induced and age-related osteoporosis by dual regulation of bone formation and bone resorption through activation of the PPARδ signaling pathway.


Assuntos
Reabsorção Óssea , Osteogênese , Ovariectomia , PPAR delta , Transdução de Sinais , Animais , Camundongos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/metabolismo , Ratos , PPAR delta/metabolismo , Feminino , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Células RAW 264.7 , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Osteoporose/metabolismo , Relação Dose-Resposta a Droga , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Ratos Sprague-Dawley , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Diferenciação Celular/efeitos dos fármacos
20.
Acta Cir Bras ; 39: e391024, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38656061

RESUMO

PURPOSE: Osteoporosis is a bone disease which commonly occurred in postmenopausal women. Almost 10 percent of world population and approximately 30% of women (postmenopausal) suffer from this disease. Alternative medicine has great success in the treatment of osteoporosis disease. Bryodulcosigenin, a potent phytoconstituent, already displayed the anti-inflammatory and antioxidant effect. In this study, we made effort to analyze the antiosteoporosis effect of bryodulcosigenin against ovariectomy (OVX) induced osteoporosis in rats. METHODS: Swiss albino Wistar rats were grouped into fIve groups and given an oral dose of bryodulcosigenin (10, 20 and 30 mg/kg) for eight weeks. Body weight, uterus, bone mineral density, cytokines, hormones parameters, transforming growth factor (TGF)-ß, insulin-like growth factor (IGF), osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand (RANKL), and its ratio were estimated. RESULTS: Bryodulcosigenin significantly (p < 0.001) suppressed the body weight and enhanced the uterine weight and significantly (p < 0.001) increased the bone mineral density in whole femur, caput femoris, distal femur and proximal femur. Bryodulcosigenin significantly (P < 0.001) altered the level of biochemical parameters at dose dependent manner, significantly (P < 0.001) improved the level of estrogen and suppressed the level of follicle stimulating hormone and luteinizing hormone. Bryodulcosigenin significantly (P < 0.001) improved the level of OPG and suppressed the level of RANKL. CONCLUSIONS: Bryodulcosigenin reduced the cytokines level and suppressed the TGF-ß and IGF. We concluded that bryodulcosigenin is an antiosteoporosis medication based on the findings.


Assuntos
Densidade Óssea , Osteoporose , Ovariectomia , Ratos Wistar , Animais , Feminino , Densidade Óssea/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Osteoporose/etiologia , Ratos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Útero/efeitos dos fármacos , Citocinas/sangue , Citocinas/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Resultado do Tratamento
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