RESUMO
AIM: Preeclampsia (PE) is a common medical complication of pregnancy characterized by high blood pressure and proteinuria after the 20th gestational week. This study aimed to investigate the potency of the combination of curcumin and aspirin in the treatment of PE and explore the underlying mechanisms. MATERIAL AND METHODS: The PE model was constructed in female rats by administering 0.5 mg/mL N-nitro-L-arginine methyl ester from gestational days (GDs) 6 to 16. The pregnant female rats were divided into five groups according to the drug treatment. The curcumin or aspirin was given to the rats by tail vein injection (0.36 mg/kg) or gavage treatment (1.5 mg/kg BW/day) from GD4 to GD18. RESULTS: Treatment with curcumin and aspirin combination significantly reduced the systolic blood pressure and proteinuria in the PE rats. Meanwhile, in comparison to the PE rats treated with single-dose curcumin or aspirin, the rats treated with combined curcumin and aspirin showed significantly decreased sFlt-1, increased placental growth factor, and alleviated oxidative stress in both blood and placental tissues, which are abnormal in no-treated PE rats. Furthermore, dramatically decreased inflammatory cytokines secretion and TLR4 and NF-κB p65 expression in placental tissues were also observed in the PE rats with combined treatment compared to those of no-treated, signal-dose curcumin or aspirin-treated PE rats. CONCLUSIONS: Our results suggested that the combined treatment of curcumin and aspirin significantly ameliorates the symptoms of PE in rats, which is most likely due to the inhibition of the placental TLR4/NF-κB p65 signaling pathway.
Assuntos
Curcumina , Pré-Eclâmpsia , Humanos , Ratos , Feminino , Gravidez , Animais , Aspirina/farmacologia , Aspirina/uso terapêutico , NF-kappa B/metabolismo , Placenta/metabolismo , Curcumina/farmacologia , Curcumina/metabolismo , Curcumina/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/uso terapêutico , Fator de Crescimento Placentário/metabolismo , Transdução de Sinais , Proteinúria/tratamento farmacológicoRESUMO
Inhibition of Toll-like receptor 4 (TLR4)-mediated inflammatory pathways exerts a critical effect on neuronal death; therefore, it is a possible new therapeutic approach for traumatic brain injury (TBI). Resatorvid (TAK-242) is a novel small-molecule compound widely used to inhibit TLR4-mediated pathways, but the protective mechanism of TAK-242 in TBI remains unclear. Herein, we analyzed the neuroprotective effects of TAK-242 in rats after TBI. The rat model of brain injury was established using a modified Free-fall device, and the rats were injected with TAK-242 (0.5 mg/kg) through the caudal vein before TBI. The rats were allocated into four groups: a sham group, a TBI group, a TBI + vehicle group, and a TBI + TAK-242 group. The brain tissue was extracted for histology and determination of the expression of autophagy-related proteins and inflammatory mediators. TAK-242 pretreatment significantly reduced the damage to hippocampal neurons. Neuronal autophagy increased after brain injury, whereas TAK-242 significantly reduced autophagy marker protein LC3-II in the hippocampus. In addition, TAK-242 pretreatment significantly downregulated NF-κB p65, TNF-α, and IL-1ß in the hippocampus. In conclusion, TAK-242 significantly reduced hippocampal neuronal damage by inhibiting autophagy and neuroinflammatory activity, possibly via the NF-κB signaling pathway.
RESUMO
We examined the relationships between exposure to polycyclic aromatic hydrocarbons (PAH) metabolites and sex hormones in pre- and postmenopausal women from the 2013-2016 National Health and Nutrition Examination Survey. The study comprised 648 premenopausal and 370 postmenopausal women (aged 20 years or older) with comprehensive data on PAH metabolites and sex steroid hormones. To evaluate the correlations between individual or mixture of the PAH metabolites and sex hormones stratified by menopausal status, we used linear regression and Bayesian kernel machine regression (BKMR). After controlling for confounders, 1-Hydroxynaphthalene (1-NAP) was inversely associated with total testosterone (TT), and 1-NAP, 3-Hydroxyfluorene (3-FLU), and 2-Hydroxyfluorene (2-FLU) were inversely associated with estradiol (E2). 3-FLU was positively associated with sex hormone-binding globulin (SHBG) and TT/E2, whereas 1-NAP and 2-FLU were inversely associated with free androgen index (FAI). In the BKMR analyses, chemical combination concentrations at or above the 55th percentile were inversely connected to E2, TT, and FAI values but positively correlated with SHBG when compared with the matching 50th percentile. In addition, we only found that mixed exposure to PAHs was positively associated with TT and SHBG in premenopausal women. Exposure to PAH metabolites, either alone or as a mixture, was negatively associated with E2, TT, FAI, and TT/E2 but positively associated with SHBG. These associations were stronger among postmenopausal women.
Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Humanos , Feminino , Inquéritos Nutricionais , Teorema de Bayes , Hormônios Esteroides Gonadais , Testosterona , MenopausaRESUMO
AIM OF THE STUDY: Accumulating studies have demonstrated that neuronal autophagy and inflammation are crucial for hippocampus development in rats subjected to traumatic brain injury (TBI). Therefore, we have investigated whether resveratrol is protective against brain damage through the attenuation of neuronal autophagy and inflammation, and explored underlying mechanisms. MATERIAL AND METHODS: Rats were injected with resveratrol (50 mg/kg, i.p.), following controlled cortical impact (CCI) injury. Brain water content, behavioral studies, and mNSS score were measured to assess the effects of resveratrol treatment. Autophagy-related proteins and inflammatory cytokines in the hippocampus were detected by Western blotting at 12, 24, and 48 hours after TBI. In addition, spatial distribution of LC3 was evaluated with immunofluorescence analysis 24 hours after injury. Finally, factors related to PI3K/Akt/mTOR signaling pathway were assessed at the same time in the hippocampus. RESULTS: Our results depicted that resveratrol could reduce the cerebral edema caused by TBI and improve the recovery of functional deficits in rats. Resveratrol was also able to remarkably reduce the expression of LC3 II and Beclin-1, while increased the expression levels of P62 in the hippocampus. Moreover, we found that interleukin b (IL-1b) and tumor necrosis factor a (TNF-a) were significantly decreased in resveratrol-treated rats. Indeed, we observed an activation of the PI3K/Akt/mTOR pathway after TBI, which may be related to the neuro-protective effect of resveratrol. CONCLUSIONS: Data presented herein support that resveratrol is a potential treatment against TBI through the inhibition of neuronal autophagy and inflammation by activation of PI3K/Akt/mTOR pathway.
Assuntos
Lesões Encefálicas Traumáticas , Fosfatidilinositol 3-Quinases , Animais , Autofagia , Lesões Encefálicas Traumáticas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Resveratrol/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/farmacologiaRESUMO
OBJECTIVE: Pre-eclampsia (PE) is a pregnancy-associated disease characterized by placental dysfunction and increased oxidative stress. Apocyanin is a potent antioxidant and anti-inflammatory which has shown beneficial effects on PE pathogenesis. Aspirin is recognized as the recommendable drug in PE prevention and therapy. Therefore, we aimed to investigate the effects of combining apocyanin and aspirin to treat PE on rat models induced by N-nitro-L-arginine methyl ester (L-NAME) from gestational day (GD) 6 to 16 and elucidate the potential mechanisms. METHODS: First, female pregnant rats were divided into five different groups: pregnant control, PE, PE + apocyanin, PE + aspirin, and PE + apocyanin + aspirin. Animals received apocyanin (16 mg/kg/day) orally or aspirin by gavage (1.5 mg/kg BM/day) from GD 4 to 16. Blood pressure and urine protein content were monitored every 4 days. RESULTS: In the PE rat model, elevated systolic blood pressure and proteinuria were ameliorated by the combination of apocyanin and aspirin. Meanwhile, compared with single-dose apocyanin or aspirin, the combined treatment significantly corrected abnormal pregnancy outcomes, decreased sFlt-1 and PlGF, and alleviated oxidative stress both in blood and placental tissues. Moreover, the combined treatment upregulated PI3K, Akt, Nrf2, and HO-1 protein levels in the placental tissues from PE rats. CONCLUSION: Overall, our results suggested that combined treatment of apocyanin and aspirin ameliorates the PE symptoms compared with single-dose apocyanin or aspirin in a PE rat model. Also, we demonstrated that activating the PI3K/Nrf2/HO-1 pathway can be a valuable therapeutic target to improve the pregnancy outcomes of PE.
Assuntos
Pré-Eclâmpsia , Animais , Aspirina/efeitos adversos , Feminino , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/farmacologia , Fator 2 Relacionado a NF-E2/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Fosfatidilinositol 3-Quinases/uso terapêutico , Placenta/metabolismo , Gravidez , Ratos , Transdução de SinaisRESUMO
Traumatic brain injury (TBI) is usually caused by accidental injuries and traffic accidents, with a very high mortality rate. Treatment and management following TBI are essential to reduce patient injury and help improve longterm prognosis. Wogonin is a flavonoid compound with an antioxidant effect extracted from Scutellaria baicalensis Georgi. However, the function and mechanism of wogonin in protecting brain injury remain to be elucidated. The present study established a TBI model of SpragueDawley rats and treated them with wogonin following trauma. The results showed that wogonin treatment significantly reduced neurobehavioral disorders, brain edema and hippocampal neuron damage caused by TBI. It was found that in TBI rats, administration of wogonin increased the levels of antioxidant factors glutathione, superoxide dismutase and catalase in the CA1 region of the hippocampus and significantly inhibited the production of malondialdehyde and reactive oxygen species. western blotting data showed that wogonin exerted antioxidant activity by downregulating the level of NOX2 protein. In inhibiting cell apoptosis, wogonin upregulated the expression of Bcl2 protein in the hippocampal CA1 region of TBI rats and inhibited caspase3 and Bax proteins. Additionally, wogonin inhibited the progression of injury following TBI through the PI3K/Akt/nuclear factorerythroid factor 2related factor 2 (Nrf2)/heme oxygenase1 (HO1) signaling pathway. Wogonin increased the expression of phosphorylated Akt, Nrf2 and HO1 in the hippocampus of TBI rats. Following the administration of PI3K inhibitor LY294002, the upregulation of these proteins by wogonin was partly reversed. In addition, LY294002 partially reversed the regulation of wogonin on NOX2, caspase3, Bax and Bcl2 proteins. Therefore, wogonin exerts antioxidant and antiapoptotic properties to prevent hippocampal damage following TBI, which is accomplished through the PI3K/Akt/Nrf2/HO1 pathway.
Assuntos
Lesões Encefálicas Traumáticas , Fator 2 Relacionado a NF-E2 , Animais , Apoptose , Lesões Encefálicas Traumáticas/tratamento farmacológico , Flavanonas , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
It has previously been demonstrated that bone marrow stromal cells (BMSCs) exhibit great therapeutic potential in neuronal injuries; however, there is limited understanding of the precise underlying mechanisms that contribute to functional improvement following brain injury. The aim of the present study was to assess the effect of BMSC treatment on traumatic brain injury (TBI) in rats, and investigate if they migrate to injured areas and promote neuromotor functional recovery via upregulation of neurotrophic factors and synaptic proteins. BMSCs were cultured in vitro from female Sprague Dawley (SD) rat bone marrow and were subsequently infused into male adult SD rats via the tail vein, following induction of TBI. The results demonstrated that treatment with BMSCs significantly reduced TBIinduced neuromotor impairment and neuronal loss, as assessed by rota rod testing, western blot analysis, modified neurological severity score and immunohistochemistry. The distribution of transplanted BMSCs was tracked by monitoring the expression of sex determining region Y (SRY) in rats. The number of cells doublepositive for SRY/neuronal nuclear antigen or SRY/glial fibrillary acidic protein was increased in the BMSC group, which demonstrated that BMSCs migrated to injured areas and differentiated into neurons and astrocytes, following TBI. Furthermore, administration of BMSCs increased expression of vascular endothelial growth factor and brain derived neurotrophic factor. Protein expression levels of synaptophysin were downregulated following TBI and this was reversed in part by treatment with BMSCs. These findings uncovered some underlying mechanisms of action of BMSCs, and may lead to their potential use as a future effective therapeutic agent for the treatment of TBI.