Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 167
Filtrar
1.
Eur J Med Chem ; 216: 113322, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33652353

RESUMO

In this paper, the 2,5-disubstituted furan derivatives containing 1,3,4-thiadiazole were synthesized and screened for their inhibitory activity against α-glucosidase and ß-glucuronidases to obtain potent α-glucosidase inhibitor 9 (IC50 = 0.186 µM) and E. coli ß-glucuronidase inhibitor 26 (IC50 = 0.082 µM), respectively. The mechanisms of the compounds were studied. The kinetic study revealed that compound 9 is a competitive inhibitor against α-glucosidase (Ki = 0.05 ± 0.003 µM) and molecular docking simulation showed several key interactions between 9 and the target including hydrogen bond and p-π stacking interaction. Derivative 26 (Ki = 0.06 ± 0.005 µM) displayed uncompetitive inhibition behavior against EcGUS. Furthermore, the result of docking revealed the furan ring of 26 may be a key moiety in obstructing the active domain of EcGUS. In addition, compound 15 exhibited significant inhibitory activity against these two enzymes, with potential therapeutic effects against diabetes and against CPT-11-induced diarrhea. At the same time, their low toxicity against normal liver tissue LO2 cells lays the foundation for in vivo studies and the development of bifunctional drug.

2.
Eat Weight Disord ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33587278

RESUMO

PURPOSE: Little is known about the association between dinner-to-bed time and obesity. Thus, this study was aimed to assess the relationships between dinner-to-bed and overweight/obesity in Chinese school-aged children in Ningbo, China. METHODS: Data of this study were based on 1667 schoolchildren (14-15 years) from 14 primary schools participated in this study in China. Anthropometric measurement of height, body weight and waist circumference (WC) was performed. Information about meal duration and other lifestyle behaviors was collected using a self-administered questionnaire. Multivariable logistic regression model was performed to assess the association between dinner-to-bed time and overweight/obesity. Restricted cubic spline regression was drawn to evaluate the shape of the relation between dinner-bed-time and the odds of overweight. RESULTS: Among the study participants, the prevalence of overweight was 17.6%, and the mean of dinner-to-bed time was 4.26 (0.93) h. In the logistic regression analysis, participants who had dinner-to-bed time less than 3 h or 3.01 ~ ≦ 4.00 h are more likely to be overweight (OR = 1.94, 95% CI 1.10-3.42; OR = 1.65, 95% CI 1.03-2.65, respectively) or characterised by abdominal obesity (OR = 3.03, 95% CI 1.86-4.95; OR = 2.61, 95% CI 1.73-3.92, respectively) compared with dinner-to-bed time more than 5 h. In addition, long dinner-to-bed time was associated with lower risks of overweight (OR = 0.83, 95% CI 0.70-0.97) and abdominal obesity (OR = 0.63, 95% CI 0.54-0.73). The cubic spline regression analysis showed that the association between dinner-to-bed time and overweight/abdominal obesity seems to be a linear. CONCLUSIONS: This study indicates that short dinner-to-bed time is associated with an increased likelihood of being overweight or characterised by abdominal obesity among Chinese school-aged children. LEVEL OF EVIDENCE: Level V; cross-section descriptive study.

3.
Biol Open ; 10(2)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33495209

RESUMO

Human pigmentation is a highly diverse and complex trait among populations and has drawn particular attention from both academic and non-academic investigators for thousands of years. Previous studies detected selection signals in several human pigmentation genes, but few studies have integrated contribution from multiple genes to the evolution of human pigmentation. Moreover, none has quantified selective pressures on human pigmentation over epochs and between populations. Here, we dissect dynamics and differences of selective pressures during different periods and between distinct populations with new approaches. We use genotype data of 19 genes associated with human pigmentation from 17 publicly available datasets and obtain data for 2346 individuals of six representative population groups from across the world. Our results quantify the strength of natural selection on light pigmentation not only in modern Europeans (0.0259/generation) but also in proto-Eurasians (0.00650/generation). Our results also suggest that several derived alleles associated with human dark pigmentation may be under positive directional selection in some African populations. Our study provides the first attempt to quantitatively investigate the dynamics of selective pressures during different time periods in the evolution of human pigmentation.This article has an associated First Person interview with the first author of the article.

4.
J Immunother Cancer ; 8(2)2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33298620

RESUMO

BACKGROUND: The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive. METHODS: The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism. RESULTS: We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden. CONCLUSIONS: Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.

5.
Cytokine ; 138: 155391, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33302223

RESUMO

Psoriasis is a common chronic inflammatory dermatitis in which various cytokines play a detrimental role. The cytokine tumor necrosis factor-related weak inducer of apoptosis (TWEAK) is involved in the pathogenesis of multiple inflammatory disorders. However, the potential role of TWEAK in various subtypes of psoriasis has not been studied in depth. To investigate whether the levels of TWEAK are associated with clinical traits and the levels of some known psoriasis-related cytokines, such as interleukin (IL)-17A, IL-22, interferon (IFN)-γ, and IL-36γ, 20 patients with psoriasis vulgaris (PV), 8 patients with pustular psoriasis (PP), 8 patients with erythrodermic psoriasis (EP), and 20 healthy controls (HCs) were recruited into this study. The levels of serum cytokines were detected by commercial enzyme-linked immunosorbent assay kits. The average levels of TWEAK, IL-17A, IL-22, IFN-γ, and IL-36γ were significantly higher in the psoriasis groups than in the HC group. Furthermore, there was a statistically significant correlation between TWEAK and IL-17A/IFN-γ in PV and IL-36γ in EP, but there was no correlation between TWEAK and IL-22 in any subtype of psoriasis. This study suggests that TWEAK may have a role in the pathogenesis of PV, PP, and EP via synergy with IL-17A, IFN-γ, or IL-36γ, but not with IL-22.

7.
Public Health Nutr ; : 1-23, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33168121

RESUMO

OBJECTIVE: To assess the prevalence of metabolic syndrome (MetS) in Chinese adults living in Ningbo and to examine the association between alcohol consumption, and MetS and its medical components. DESIGN: A representative survey in Ningbo was conducted in 2015 covering socio-demography. A food frequent questionnaire together with additional questionnaires was used to collect information on alcohol consumption, diet, demography, lifestyle, and medical information. Multivariable logistic regression and generalized linear models were used to examine the association between alcohol consumption, and both MetS and its medical components, respectively. SETTING: Ningbo, China. PARTICIPANTS: Total 2853 adults ≥20 years (44% men) in this final analysis. RESULTS: The prevalence of frequent alcohol drinkers and MetS were 29.9% and 28.0%, respectively. Significantly higher prevalence of MetS and mean values of medical components were found in the group of frequent alcohol drinkers with an exception for HDL-C, compared to less or non-alcohol drinkers. Frequent alcohol consumption was associated with higher odds of developing MetS and positively associated with medical components excepting waist circumference. CONCLUSIONS: Frequent alcohol consumption contributed to higher prevalence of MetS, and unfavorable influence on MetS and its medical components among Chinese adults. A public health intervention on alcohol restriction is necessary for the prevention and control the ongoing epidemic MetS.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33218140

RESUMO

Purpose: Poor vision is prevalent in school-aged students, especially in East Asia. This can not only cause irreversibly physical health impairments like glaucoma and cataracts, but also the loss of individual education and employment opportunities and deterioration of the quality of life. The present study aims to investigate the associations between poor vision, vision-related risk behaviors, and mathematics achievement in youth from China. Methods: The present study included a total of 106,192 Grade 4 students and 70,236 Grade 8 students from the China National Assessment of Educational Quality-Physical Education & Health 2015 (CNAEQ-PEH 2015). We conducted a standard logarithmic visual acuity scale for vision screening, a self-reported questionnaire for vision-related risk behavior and a standardized mathematics assessment for mathematics performance. Poor vision is defined as the visual acuity below 5.0 by using the standard logarithmic visual acuity chart. Linear regression was conducted. Results: The prevalence rate of poor vision in China was 37.1% in Grade 4 and 66.2% in Grade 8 in 2015. Students who had poor vision were more likely to have better mathematics achievement than those with normal vision. Reading in bed, insufficient sleep, and screen time during weekdays and weekends were associated with higher odds of poor vision. Conclusions: Poor vision was positively associated with mathematics academic achievements, while vision-related risk behaviors such as screen time, homework time and reading in bed were associated with a high prevalence of poor vision in compulsory education cycle students.

9.
J Nutr Biochem ; 88: 108533, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33250443

RESUMO

Resistance to high-fat diet-induced obesity (DIR) has been observed in mice fed a high-fat diet and may provide a potential approach for anti-obesity drug discovery. However, the metabolic status, gut microbiota composition, and its associations with DIR are still unclear. Here, ultraperformance liquid chromatography-tandem mass spectrometry-based urinary metabolomic and 16S rRNA gene sequencing-based fecal microbiome analyses were conducted to investigate the relationship between metabolic profile, gut microbiota composition, and body weight of C57BL/6J mice on chow or a high-fat diet for 8 weeks. PICRUSt analysis of 16S rRNA gene sequences predicted the functional metagenomes of gut bacteria. The results demonstrated that feeding a high-fat diet increased body weight and fasting blood glucose of high-fat diet-induced obesity (DIO) mice and altered the host-microbial co-metabolism and gut microbiota composition. In DIR mice, high-fat diet did not increase body weight while fasting blood glucose was increased significantly compared to chow fed mice. In DIR mice, the urinary metabolic pattern was shifted to a distinct direction compared to DIO mice, which was mainly contributed by xanthine. Moreover, high-fat diet caused gut microbiota dysbiosis in both DIO and DIR mice, but in DIR mice, the abundance of Bifidobacteriaceae, Roseburia, and Escherichia was not affected compared to mice fed a chow diet, which played an important role in the pathway coverage of FormylTHF biosynthesis I. Meanwhile, xanthine and pathway coverage of FormylTHF biosynthesis I showed significant positive correlations with mouse body weight. These findings suggest that gut microbiota-mediated xanthine metabolism correlates with resistance to high-fat DIO.

10.
Nat Commun ; 11(1): 5981, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239628

RESUMO

Targeting a specific chemokine/receptor axis in atherosclerosis remains challenging. Soluble receptor-based strategies are not established for chemokine receptors due to their discontinuous architecture. Macrophage migration-inhibitory factor (MIF) is an atypical chemokine that promotes atherosclerosis through CXC-motif chemokine receptor-4 (CXCR4). However, CXCR4/CXCL12 interactions also mediate atheroprotection. Here, we show that constrained 31-residue-peptides ('msR4Ms') designed to mimic the CXCR4-binding site to MIF, selectively bind MIF with nanomolar affinity and block MIF/CXCR4 without affecting CXCL12/CXCR4. We identify msR4M-L1, which blocks MIF- but not CXCL12-elicited CXCR4 vascular cell activities. Its potency compares well with established MIF inhibitors, whereas msR4M-L1 does not interfere with cardioprotective MIF/CD74 signaling. In vivo-administered msR4M-L1 enriches in atherosclerotic plaques, blocks arterial leukocyte adhesion, and inhibits atherosclerosis and inflammation in hyperlipidemic Apoe-/- mice in vivo. Finally, msR4M-L1 binds to MIF in plaques from human carotid-endarterectomy specimens. Together, we establish an engineered GPCR-ectodomain-based mimicry principle that differentiates between disease-exacerbating and -protective pathways and chemokine-selectively interferes with atherosclerosis.

11.
J Food Prot ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33038238

RESUMO

Larou is a traditional smoked meat product in China. In this experiment, larou was processed with different smoking materials and methods evaluating whether the control of processing methods could balance the quality of larou and the content of carcinogens. Pork bellies were marinated, dried and divided into four groups then directly smoked by four different smoking materials for 40 minutes. The best index smoking material would be brought into the indirect smoking device for larou single-factor variable indirect smoking with nano-activated carbon fiber. Results showed that the specific surface area of the nano-activated carbon fiber was 978.00 m 2 /g, and such fiber could effectively adsorb the smoking ash particles. In pomelo skins group (PS), the highest phenols content and variety were found as 4.48% and 11, which increased the smoking flavor most significantly. The moisture, SA, LAB, Y&M values were 32.64%, 0.98 log 10 CFU/g, 1.10 log 10 CFU/g, 0.59 log 10 CFU/g, which could best inhibit harmful bacteria and benefit microbial environment for larou fermentation maturity. The benzo[a]pyrene (B[a]P) content of indirect smoking device (IN) by PS was 1.82 µg/kg, whereas the B[a]P content of direct smoking by PS was 36.1 µg/kg, which indicated a significant difference ( p  < 0.01). These findings suggested that pomelo skins with indirect smoking device of larou could effectively maintain the inspection indexes and reduce the content of B[a]P. The control of this processing method can be used for the actual production of meat.

12.
Food Chem ; 341(Pt 1): 128148, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-33038776

RESUMO

The brown seaweed Undaria pinnatifida polysaccharides show various biological activities, but their hypoglycemic activity and the underlying mechanism remain unclear. Here, three fractions of sulfated polysaccharides Up-3, Up-4, and Up-5 were prepared by microwave-assisted extraction from U. pinnatifida. In vitro assays demonstrated that Up-3 and Up-4 had strong α-glucosidase inhibitory activity, and Up-3, Up-4, and Up-5 could improve the glucose uptake in insulin-resistant HepG2 cells without affecting their viability. In vivo studies indicated Up-3 and Up-4 markedly reduced postprandial blood glucose levels. Up-U (a mixture of Up-3, Up-4, and Up-5), reduced fasting blood glucose levels, increased glucose tolerance and alleviated insulin resistance in HFD/STZ-induced hyperglycemic mice. Histopathological observation and hepatic glycogen measurement showed that Up-U alleviated the damage of the pancreas islet cell, reduced hepatic steatosis, and promoted hepatic glycogen synthesis. These findings suggest that Up-U could alleviate postprandial and HFD/STZ-induced hyperglycemia and was a potential agent for diabetes treatment.

13.
Sci Rep ; 10(1): 18536, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116168

RESUMO

On 3 July 2015, the Mw 6.5 Pishan earthquake occurred at the junction of the southwestern margin of the Tarim Basin and the northwestern margin of the Tibetan Plateau. To understand the seismogenic mechanism and the post-seismic deformation behavior, we investigated the characteristics of the post-seismic deformation fields in the seismic area, using 9 Sentinel-1A TOPS synthetic aperture radar (SAR) images acquired from 18 July 2015 to 22 September 2016 with the Small Baseline Subset Interferometric SAR (SBAS-InSAR) technique. Postseismic LOS deformation displayed logarithmic behavior, and the temporal evolution of the post-seismic deformation is consistent with the aftershock sequence. The main driving mechanism of near-field post-seismic displacement was most likely to be afterslip on the fault and the entire creep process consists of three creeping stages. Afterward, we used the steepest descent method to invert the afterslip evolution process and analyzed the relationship between post-seismic afterslip and co-seismic slip. The results witness that 447 days after the mainshock (22 September 2016), the afterslip was concentrated within one principal slip center. It was located 5-25 km along the fault strike, 0-10 km along with the fault dip, with a cumulative peak slip of 0.18 m. The 447 days afterslip seismic moment was approximately 2.65 × 1017 N m, accounting for approximately 4.1% of the co-seismic geodetic moment. The deep afterslip revealed that a creeping process from steady-state "secondary" creeping to accelerating "tertiary" creep in the deep of fault. The future seismic hazard deserves further attention and research.

14.
Mar Drugs ; 18(9)2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867177

RESUMO

A low fasting blood glucose level is a common symptom in diabetes patients and can be induced by high-fat diet (HFD) feeding at an early stage, which may play important roles in the development of diabetes, but has received little attention. In this study, five polysaccharides were prepared from Sargassumfusiforme and their effects on HFD-induced fasting hypoglycemia and gut microbiota dysbiosis were investigated. The results indicated that C57BL/6J male mice fed an HFD for 4 weeks developed severe hypoglycemia and four Sargassumfusiforme polysaccharides (SFPs), consisting of Sf-2, Sf-3, Sf-3-1, and Sf-A, significantly prevented early fasting hypoglycemia without inducing hyperglycemia. Sf-1 and Sf-A could also significantly prevent HFD-induced weight gain. Sf-2, Sf-3, Sf-3-1, and Sf-A mainly attenuated the HFD-induced decrease in Bacteroidetes, and all five SFPs had a considerable influence on the relative abundance of Oscillospira, Mucispirillum, and Clostridiales. Correlation analysis revealed that the fasting blood glucose level was associated with the relative abundance of Mucispinllum and Oscillospira. Receiver operating characteristic analysis indicated that Mucispinllum and Oscillospira exhibited good discriminatory power (AUC = 0.745-0.833) in the prediction of fasting hypoglycemia. Our findings highlight the novel application of SFPs (especially Sf-A) in glucose homeostasis and the potential roles of Mucispinllum and Oscillospira in the biological activity of SFPs.

15.
Nat Commun ; 11(1): 4779, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963246

RESUMO

Highly reproducible smoking-associated DNA methylation changes in whole blood have been reported by many Epigenome-Wide-Association Studies (EWAS). These epigenetic alterations could have important implications for understanding and predicting the risk of smoking-related diseases. To this end, it is important to establish if these DNA methylation changes happen in all blood cell subtypes or if they are cell-type specific. Here, we apply a cell-type deconvolution algorithm to identify cell-type specific DNA methylation signals in seven large EWAS. We find that most of the highly reproducible smoking-associated hypomethylation signatures are more prominent in the myeloid lineage. A meta-analysis further identifies a myeloid-specific smoking-associated hypermethylation signature enriched for DNase Hypersensitive Sites in acute myeloid leukemia. These results may guide the design of future smoking EWAS and have important implications for our understanding of how smoking affects immune-cell subtypes and how this may influence the risk of smoking related diseases.


Assuntos
Metilação de DNA/efeitos dos fármacos , Epigenoma , Fumar/efeitos adversos , Algoritmos , Grupo com Ancestrais do Continente Asiático , Sangue , Ilhas de CpG , Epigenômica/métodos , Grupos Étnicos , Feminino , Humanos , Linfócitos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Células Mieloides
16.
J Enzyme Inhib Med Chem ; 35(1): 1736-1742, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32928007

RESUMO

Gut microbial ß-glucuronidases have the ability to deconjugate glucuronides of some drugs, thus have been considered as an important drug target to alleviate the drug metabolites-induced gastrointestinal toxicity. In this study, thiazolidin-2-cyanamide derivatives containing 5-phenyl-2-furan moiety (1-13) were evaluated for inhibitory activity against Escherichia coli ß-glucuronidase (EcGUS). All of them showed more potent inhibition than a commonly used positive control, d-saccharic acid 1,4-lactone, with the IC50 values ranging from 1.2 µM to 23.1 µM. Inhibition kinetics studies indicated that compound 1-3 were competitive type inhibitors for EcGUS. Molecular docking studies were performed and predicted the potential molecular determinants for their potent inhibitory effects towards EcGUS. Structure-inhibitory activity relationship study revealed that chloro substitution on the phenyl moiety was essential for EcGUS inhibition, which would help researchers to design and develop more effective thiazolidin-2-cyanamide type inhibitors against EcGUS.

17.
Polymers (Basel) ; 12(9)2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32937738

RESUMO

In this study, we visualised CO2-brine, density-driven convection in a Hele-Shaw cell. Several experiments were conducted to analyse the effects of the salinity and temperature. The salinity and temperature of fluids were selected according to the storage site. By using charge coupled device (CCD) technology, convection finger formation and development were obtained through direct imaging and processing. The process can be divided into three stages: diffusion-dominated, convection-dominated and shutdown stages. Fingers were formed along the boundary at the onset time, reflecting the startup of convection mixing. Fingers formed, moved and aggregated with adjacent fingers during the convection-dominated stage. The relative migration of brine-saturated CO2 and brine enhanced the mass transfer. The effects of salinity and temperature on finger formation, number, and migration were analysed. Increasing the salinity accelerated finger formation but suppressed finger movement, and the onset time was inversely related to the salinity. However, the effect of temperature on convection is complex. The dissolved CO2 mass was investigated by calculating the CO2 mass fraction in brine during convection mixing. The results show that convection mixing greatly enhanced mass transfer. The study has implications for predicting the CO2 dissolution trapping time and accumulation for the geological storage of CO2.

18.
Front Neurosci ; 14: 545, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32742251

RESUMO

With the rapid development of machine learning techniques, multivariate pattern analysis (MVPA) is becoming increasingly popular in the field of neuroimaging data analysis. Several software packages have been developed to facilitate its application in neuroimaging studies. As most of these software packages are based on command lines, researchers are required to learn how to program, which has greatly limited the use of MVPA for researchers without programming skills. Moreover, lacking a graphical user interface (GUI) also hinders the standardization of the application of MVPA in neuroimaging studies and, consequently, the replication of previous studies or comparisons of results between different studies. Therefore, we developed a GUI-based toolkit for MVPA of neuroimaging data: MVPANI (MVPA for Neuroimaging). Compared with other existing software packages, MVPANI has several advantages. First, MVPANI has a GUI and is, thus, more friendly for non-programmers. Second, MVPANI offers a variety of machine learning algorithms with the flexibility of parameter modification so that researchers can test different algorithms and tune parameters to identify the most suitable algorithms and parameters for their own data. Third, MVPANI also offers the function of data fusion at two levels (feature level or decision level) to utilize complementary information contained in different measures obtained from multimodal neuroimaging techniques. In this paper, we introduce this toolkit and provide four examples to demonstrate its usage, including (1) classification between patients and controls, (2) identification of brain areas containing discriminating information, (3) prediction of clinical scores, and (4) multimodal data fusion.

19.
Exp Mol Med ; 52(8): 1341-1350, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32855437

RESUMO

Ovarian hyperstimulation syndrome (OHSS) is one of the most life-threatening and potentially fatal complications associated with controlled ovarian hyperstimulation (COH) during in vitro fertilization (IVF) treatment. Although the pathogenesis of OHSS remains unclear, elevated serum estradiol (E2) levels before human chorionic gonadotropin (hCG) administration are associated with the risk of OHSS. The pineal hormone melatonin and its receptors are expressed in human granulosa cells and have been shown to stimulate E2 production. However, the effect of melatonin on the expression of aromatase, an enzyme responsible for a key step in the biosynthesis of E2, in human granulosa cells remains to be determined. Here, we demonstrate that melatonin upregulates aromatase expression in primary cultured human granulosa-lutein (hGL) cells through the melatonin receptor-mediated PKA-CREB pathway. Using a mouse model of OHSS, we demonstrate that administration of the melatonin receptor inhibitor luzindole inhibits the development of OHSS. In addition, the expression of ovarian aromatase and serum E2 levels are upregulated in OHSS mice compared to control mice, but this upregulation is attenuated by inhibition of the function of melatonin. Moreover, clinical results reveal that aromatase expression levels are upregulated in hGL cells from OHSS patients. Melatonin and E2 levels in the follicular fluid are significantly higher in OHSS patients than in non-OHSS patients. Furthermore, melatonin levels are positively correlated with E2 levels in follicular fluid. This study helps to elucidate the mechanisms mediating the expression of aromatase in hGL cells and provides a potential mechanism explaining the high E2 levels in patients with OHSS.

20.
Mol Cell Endocrinol ; 518: 110981, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791190

RESUMO

Melatonin can be synthesized and secreted not only by the pineal gland but also by many extra-pineal tissues. It has been shown that many ovarian functions are regulated by melatonin locally. Ovarian hyperstimulation syndrome (OHSS) is a serious complication during ovulation induction of the in vitro fertilization treatment. To date, the etiology of OHSS is not fully understood. However, vascular endothelial growth factor (VEGF) is recognized as a critical mediator for the pathogenesis of OHSS. High expression of melatonin has been detected in the follicular fluid of OHSS patients. However, whether VEGF expression can be regulated by melatonin in human granulosa cells and further contributes to the pathogenesis of OHSS remain unknown. In this study, we show that melatonin stimulates VEGF expression in human granulosa-lutein (hGL) cells. Our results reveal that the MT2 receptor and activation of AKT are involved in melatonin-induced VEGF expression. Using a rat OHSS model, we report that the VEGF levels are up-regulated in the ovaries of OHSS rats. Blocking the melatonin system by administrating MT2 receptor antagonist, 4-P-PDOT, alleviates OHSS symptoms by decreasing the expression of VEGF. In addition, the expression levels of melatonin and VEGF in the follicular fluid of OHSS patients are up-regulated and positively correlated. This study demonstrates an important role for melatonin in regulating the pathogenesis of OHSS.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...