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1.
Artigo em Inglês | MEDLINE | ID: mdl-32362456

RESUMO

BACKGROUND: We describe the molecular epidemiology and resistance patterns of blaOXA-48Klebsiella pneumoniae and Escherichia coli in Taiwan. METHODS: In this multicenter surveillance study from January 2012 to August 2015, the identified blaOXA-48Enterobacteriaceae isolates were subjected to antibiotics susceptibility testing. PCR method was used for detecting concomitant other beta-lactamases. Outer membrane porins were analyzed. Genetic relatedness and molecular epidemiology of the isolates were determined through pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Plasmid incompatibility was determined using PCR-based replicon typing. RESULTS: Forty-three blaOXA-48K. pneumoniae and two E. coli isolates were analyzed. The annual incidence of blaOXA-48K. pneumoniae isolates from 2012 to 2015 were 0%, 1.1%, 2.4%, and 7.6%, respectively. Forty-three (95.5%) of 45 isolates were non-susceptible to broad-spectrum beta-lactams (ceftriaxone, ceftazidime, cefepime, piperacillin/tazobactam), Forty-two (93.3%) of the 45 isolates showed resistance against all tested carbapenems (imipenem, meropenem, doripenem, and ertapenem). Molecular characterization revealed that they co-produced at least one extended-spectrum beta-lactamases or AmpC beta-lactamases, with at least one outer membrane porin loss. Thirty-eight (88.3%) of the 43 K. pneumoniae isolates belonged to ST11. PFGE analysis of 43 K. pneumoniae isolates revealed dissemination of multiple clones. Six of the 12 tested K. pneumoniae representatives of different pulso-types belonged to IncA/C. CONCLUSION: Concomitant loss of porins and production of other beta-lactamases renders the blaOXA-48-producing isolates in Taiwan a high-level carbapenem resistance and broad resistance against many beta-lactam antibiotics. Following dissemination of multiple clones of blaOXA-48 K pneumoniae ST 11, a trend of increased blaOXA-48 prevalence was noted.

2.
Nat Struct Mol Biol ; 27(5): 472-479, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32398826

RESUMO

Cryptochromes (CRYs) are blue-light receptors in plants that harbor FAD as a cofactor and regulate various physiological responses. Photoactivated CRYs undergo oligomerization, which increases the binding affinity to downstream signaling partners. Despite decades of research on the activation of CRYs, little is known about how they are inactivated. Binding of blue-light inhibitors of cryptochromes (BICs) to CRY2 suppresses its photoactivation, but the underlying mechanism remains unknown. Here, we report crystal structures of CRY2N (CRY2 PHR domain) and the BIC2-CRY2N complex with resolutions of 2.7 and 2.5 Å, respectively. In the BIC2-CRY2N complex, BIC2 exhibits an extremely extended structure that sinuously winds around CRY2N. In this way, BIC2 not only restrains the transfer of electrons and protons from CRY2 to FAD during photoreduction but also interacts with the CRY2 oligomer to return it to the monomer form. Uncovering the mechanism of CRY2 inactivation lays a solid foundation for the investigation of cryptochrome protein function.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32400043

RESUMO

A 5-year-old, clinically normal intact female Miniature Schnauzer was presented for demonstrative ultrasonography in a seminar. She had two pregnancies in the past and had a natural mating 2 months previously. Ultrasonography revealed a segmental and circumferential mural thickening of the right uterine horn. The endometrium was markedly thickened with multiple organized hyperechoic linear striations, perpendicular to the mucosal surface. Histology revealed focal endometrial hyperplasia resembling the maternal tissue of the normal canine placenta. A diagnosis of spontaneous pseudo-placentational endometrial hyperplasia (PEH) was made. This study described a unique ultrasonographic appearance of PEH, which may facilitate the diagnosis of PEH.

4.
Yi Chuan ; 42(5): 444-451, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32431296

RESUMO

Schlafen (SLFN) family genes were initially found in humans and rats to regulate cell growth and T cell differentiation, and exist widely in mice, horses, humans and other species and exhibit high homology. Lines of evidence suggest that SLFN proteins play important roles in inhibiting cell proliferation, promoting meiosis, regulating hematopoietic cells, reducing platelet numbers and the immune response, and also exert antiviral functions against several virus species including HIV-1, influenza virus and others. In addition, SLFN proteins have also been found to be closely related to cancer therapy, and act as a molecular marker to predict tumor development and the sensitivity to chemotherapy drugs. In this review, we discuss the classification, structures, characteristics, location and functions of SLFN family proteins, and focus on progress related to tumor and virus infection, aiming to provide new thoughts on exploration of SLFN protein functions and the underlying mechanisms.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32374907

RESUMO

The present study compared performances of the 3 major methods used for assessing platelet reactivity (PR)-VerifyNow, light-transmission aggregometry (LTA), and thromboelastography (TEG)-to predict ischaemic events in patients receiving clopidogrel. PubMed, EmBase and the Cochrane library were searched from their inception to April 2019 for prospective studies that examined PR using VerifyNow, LTA or TEG and the incidence of ischaemic events. The investigated diagnostic indices including sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio, and area under the receiver operating characteristic curves (AUC) of VerifyNow, LTA, and TEG, respectively. A total of 26 prospective studies involving 22,185 subjects were included in the analysis. The pooled AUC was 0.71 (95% CI: 0.67-0.75) for VerifyNow, 0.60 (95% CI: 0.55-0.64) for LTA, and 0.81 (95% CI: 0.77-0.84) for TEG. Results of indirect comparisons indicated the AUC of VerifyNow was higher than that of LTA (1.18, 95% CI: 1.08-1.30) and lower than that of TEG (0.88, 95% CI: 0.82-0.94). TEG outperformed the other 2 methods for assessing PR in all predictive measures, including sensitivity, specificity, PLR, and NLR. Despite a lack of studies that directly compared the 3 methods, our findings suggest that TEG should be recommended.

6.
Eur Respir J ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366488

RESUMO

BACKGROUND: The novel coronavirus (SARS-CoV-2) infected over 3300 health-care-workers (HCWs) in early 2020 in China. Little information is known about nosocomial infections of HCWs in the initial period. We analysed data from HCWs with nosocomial infections in Wuhan Union Hospital and their family members. METHODS: We collected and analysed data on exposure history, illness timelines, and epidemiologic characteristics of 25 laboratory-confirmed and two highly suspected HCWs as well as ten of their family members with COVID-19 from Jan 5 to Feb 12, 2020. Among them, demographics and clinical features of the 35 laboratory-confirmed cases were investigated and viral RNA of 12 cases was sequenced and analysed. RESULTS: Nine clusters were found among the patients. All patients showed mild to moderate clinical manifestation and recovered without deterioration. The average periods of incubation, clinical onset serial interval (COSI), and virus shedding were 4.5 days, 5.2±3.2 days, and 18.5 days, respectively. Complete genomic sequences of 12 different coronavirus strains demonstrated that the viral structure with small, irrelevant mutations was stable in the transmission chains and showed remarkable traits of infectious traceability. CONCLUSIONS: SARS-CoV-2 can be rapidly transmitted person-to-person regardless of whether they have symptoms in both hospital settings and social activities based on the short period of incubation and COSI. The public health service should take practical measures to curb the spread, including isolation of cases, tracing close-contacts, and containment of severe epidemic areas. Besides, the HCWs should be alert during the epidemic, and make self-quarantine if self-suspected.

7.
FEBS Open Bio ; 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32348629

RESUMO

Pinewood nematode (PWN; Bursaphelenchus xylophilus) is a devastating invasive species that is expanding into colder regions. Here, we investigated the molecular mechanisms underlying low-temperature resistance of PWN. We identified differentially expressed genes enriched under low temperature in previously published transcriptome data using the Kyoto Encyclopedia of Genes and Genomes. Quantitative real-time PCR was used to further validate the transcript level changes of three known cytochrome P450 genes under low temperature. RNA interference was used to validate the low-temperature resistance function of three cytochrome P450 genes from PWN. We report that differentially expressed genes were significantly enriched in two cytochrome P450-related pathways under low-temperature treatment. Heatmap visualization of transcript levels of cytochrome P450-related genes revealed widely different transcript patterns between PWNs treated under low and regular temperatures. Transcript levels of three cytochrome P450 genes from PWNs were elevated at low temperature, and knockdown of these genes decreased the survival rates of PWNs under low temperature. In summary, these findings suggest that cytochrome P450 metabolism plays a critical role in the low-temperature resistance mechanism of PWN.

8.
Food Res Int ; 131: 109006, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32247452

RESUMO

Interaction between α-lactalbumin (α-LA) and three similar chalconoids was compared using a combination of multi-spectral analysis and molecular docking, and their influence on structure and functional properties of α-LA was also investigated. Chalconoids strongly quenched α-LA fluorescence in a static mode and their binding constants to α-LA were declined in the order of hydroxy safflower yellow A (SYA), neohesperidin dihydrochalcone (NHDC) and naringin dihydrochalcone (NGDC). The main interaction forces involved in the binding of SYA, NHDC and NGDC to α-LA included hydrophobic forces and hydrogen bonds. There was non-radiative energy transfer between α-LA and three chalconoids, as indicated by the estimated by Förster's distance. The vicinity of SYA to tryptophan residues of α-LA showed the minimum value. Based on Fourier transform infrared spectroscopy (FTIR) spectra, SYA induced the conversion of more α-LA from α-helix into its ß-structures than NHDC and NGDC. Also, although the addition of three chalconoids had no significant effect on the emulsifying activity of α-LA, it slightly improved the emulsion stability of α-LA. In addition, SYA showed the maximum decrease on surface hydrophobicity of α-LA. Antioxidant capacity of SYA was also decreased more than that of NHDC and NGDC after the binding to α-LA. Additionally, docking studies indicated that SYA, NHDC and NGDC bound to the cleft between α-domains and ß-domains by three, two and two hydrogen bonds, respectively. Therefore, these findings suggest that there are significant differences among the effects of three similar chalconoids on structure and functionality of α-LA.

10.
Mol Neurodegener ; 15(1): 25, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32276587

RESUMO

BACKGROUND: Loss of function of triggering receptor expressed on myeloid cell 2 (TREM2), a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). Whether TREM2 levels are pathologically altered during the preclinical phase, and whether cerebrospinal fluid (CSF) soluble TREM2 protein (sTREM2) has a relationship with major pathological processes including Aß and tau deposition are still unclear. METHODS: According to the NIA-AA criteria, 659 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups, stage 0 (normal Aß1-42, T-tau and P-tau), stage 1 (low Aß1-42, normal T-tau and P-tau), stage 2 (low Aß1-42 and high T-tau or P-tau), and suspected non-AD pathology (SNAP) (normal Aß1-42 and high T-tau or P-tau), to examine changes of CSF sTREM2 in the preclinical AD. Biomarker cut-off was based on the assumption that one-third of adults with normal cognition have AD pathology. RESULTS: The level of CSF sTREM2 in the stage 1 decreased compared with the stage 0 (P < 0.001), and then increased in the stage 2 (P = 0.008). SNAP individuals also had significantly increased CSF sTREM2 (P < 0.001). Results of multiple linear regressions also showed positive correlations of CSF sTREM2 with Aß1-42 (ß = 0.192, P < 0.001), T-tau (ß = 0.215, P < 0.001) and P-tau (ß = 0.123, P < 0.001). CONCLUSION: CSF sTREM2 levels are dynamic in preclinical AD. Aß pathology is associated with a decrease in CSF sTREM2 in the absence of tau deposition and neurodegeneration. However, tau pathology and neurodegeneration are associated with an increase in CSF sTREM2.

11.
J Nat Med ; 74(3): 533-544, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32222939

RESUMO

Polydatin, a natural product, is detected in many daily diets, such as grape juices and peanut. Autophagy regulation is recognized as a new potential strategy for cancer therapy, and previous studies demonstrated that polydatin showed remarkable anti-cancer ability. Nevertheless, the capability of polydatin to induce autophagy and its role in anti-osteosarcoma remains obscure. In this study, we investigated the anticancer effect of polydatin on human osteosarcoma cell line MG-63 and its underlying mechanism. Our results indicated that polydatin significantly inhibited proliferation of MG-63 cells in a dose- and time-dependent manner, and increased their apoptosis and autophagic flux. Further experiments showed that polydatin reduced the expression and phosphorylation (Y705) level of STAT3 (Signal transducer and activator of transcription 3), increased the expression of autophagy-related genes (Atg12, Atg14, BECN1, PIC3K3), and therewith triggered autophagic cell death in MG-63 cells. Of note, the cytotoxicity effect of polydatin was rescued by co-treatment with Colivelin (STAT3 activator), suggesting the dependency of MG-63 cells on STAT3 for survival in this process. Moreover, polydatin-triggered autophagy and apoptosis were remarkably reduced following exposure to autophagy inhibitor 3-methyladenine, while cell viability was increased. In conclusion, these data demonstrated that polydatin induced MG-63 cell death through inducing apoptosis, and autophagy which was mediated via the STAT3 signaling. Therefore, polydatin might be a potential clinical drug in the remedy of osteosarcoma.

12.
Cell Death Dis ; 11(3): 169, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139670

RESUMO

The positive results of the apatinib phase III trial have cast new light on treatment for patients with advanced gastric cancer (GC). However, in terms of safety, apatinib toxicities may lead to a dose modification or treatment interruption. Therefore, proper intervention is urgently needed to help patients benefit from apatinib treatment. In this study, we found that apatinib promoted autophagy activation via upregulation of ATG7 expression and autophagy inhibition enhanced apatinib-induced apoptosis. With microRNA and circular RNA-sequencing analyses of GC xenograft models, we demonstrated that circRACGAP1 functioned as an endogenous sponge for miR-3657 to inhibit its activity and further upregulate ATG7 expression. Silencing of circRACGAP1 inhibited apatinib-induced autophagy, which was rescued by miR-3657. Moreover, knockdown of circRACGAP1 sensitized GC cells to apatinib via autophagy inhibition in vitro and in vivo. These findings provided the first evidence that the circRACGAP1-miR-3657-ATG7 axis mediates a novel regulatory pathway critical for the regulation of apatinib sensitivity in GC. Thus, specific blockage of circRACGAP1 may be a potential therapeutic strategy to reduce the toxicities of apatinib and enhance its therapeutic effect in human GC.

13.
Med Biol Eng Comput ; 58(5): 1015-1029, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32124223

RESUMO

The common CT imaging signs of lung diseases (CISLs) which frequently appear in lung CT images are widely used in the diagnosis of lung diseases. Computer-aided diagnosis (CAD) based on the CISLs can improve radiologists' performance in the diagnosis of lung diseases. Since similarity measure is important for CAD, we propose a multi-level method to measure the similarity between the CISLs. The CISLs are characterized in the low-level visual scale, mid-level attribute scale, and high-level semantic scale, for a rich representation. The similarity at multiple levels is calculated and combined in a weighted sum form as the final similarity. The proposed multi-level similarity method is capable of computing the level-specific similarity and optimal cross-level complementary similarity. The effectiveness of the proposed similarity measure method is evaluated on a dataset of 511 lung CT images from clinical patients for CISLs retrieval. It can achieve about 80% precision and take only 3.6 ms for the retrieval process. The extensive comparative evaluations on the same datasets are conducted to validate the advantages on retrieval performance of our multi-level similarity measure over the single-level measure and the two-level similarity methods. The proposed method can have wide applications in radiology and decision support. Graphical abstract.

14.
Medicine (Baltimore) ; 99(11): e19544, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176108

RESUMO

The relationship between coronary artery disease (CAD) and low serum 25-hydroxyvitamin D (25(OH)D) levels has emerged. Postmenopausal (PM) women are at increased risk of CAD and vitamin D (VitD) deficiency.To investigate the relationship between CAD and VitD levels in PM women.This case-control study included 93 consecutive female patients aged 50 to 79 years old undergoing coronary angiography for evaluation of CAD and 119 age-matched controls. Serum 25(OH)D concentrations were classed as adequate (serum 25(OH)D: ≥20 ng/mL); insufficient (serum 25(OH)D: 10 to <20 ng/mL); and deficient (serum 25(OH)D: <10 ng/mL). Major cardiovascular risk factors were also explored.CAD occurred in 67/127 (52.8%) patients with VitD deficiency; 21/66 (31.8%) patients that were VitD insufficient; and in 5/19 (26.3%) patients with adequate VitD levels. Multivariate regression analysis suggested that a deficiency of VitD increased CAD (odds ratio = 2.891; 95% confidence interval = 1.459-7.139, P < .001).VitD deficiency should be evaluated in PM women as a possible cause of CAD.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Pós-Menopausa , Deficiência de Vitamina D/complicações , Idoso , Estudos de Casos e Controles , China/epidemiologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/complicações , Feminino , Humanos , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue
15.
Future Med Chem ; 12(9): 775-794, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32125179

RESUMO

Aim: HIV-1 protease inhibitors regimens suffered from a number of drawbacks, among which, the most egregious issue was the growing emergence of drug-resistant strains. Materials & methods: The design strategy of maximizing the protease active site interactions with the inhibitor, especially promoting extensive hydrogen bonding with the protein backbone atoms, might be in favor of combating drug resistance. A series of HIV-1 protease inhibitors that incorporated enantiomeric isopropanols as the P1' ligands in combination with phenols as the P2 ligands were reported herein. Results: A number of inhibitors displayed potent protease enzyme inhibition activity. In particular, inhibitor 14c showed comparable potency as darunavir with IC50 value of 1.91 nM and activity against darunavir-resistant HIV-1 variants. Conclusion: The new kind of HIV-1 protease inhibitors deserves further study.

17.
J Affect Disord ; 264: 187-192, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32056749

RESUMO

BACKGROUND: Poor mental health status among both pregnant and postpartum women is commonly reported worldwide. The associations between mental health outcomes and giving birth to the second child since the implementation of China's universal two-child policy have not been identified. METHODS: A large-scale based mental health survey was conducted between March 2017 and December 2018 in Suzhou, China. The survey evaluated the symptoms of anxiety, hypomania, depression and poor sleep quality among both pregnant and postpartum women. RESULTS: A total of 3113 questionnaires were collected, the prevalence of anxiety, hypomanic and depressive symptoms and poor sleep quality in our sample were 3.2% (95%CI: 2.6%-3.9%), 51.7% (95%CI: 49.9%-53.4%), 12.4% (95%CI: 11.3%-13.6%) and 37.8% (95%CI: 36.0%-39.5%), respectively. Logistic regression showed that giving birth to the second child was positively associated with women's age, and was negatively correlated with higher educational level and living in rented housing. Women with the second pregnancy or child were positively associated with anxiety symptoms in the whole sample (OR = 1.75, 95%CI: 1.11-2.75) and among prenatal women (OR = 2.11, 95%CI: 1.16-3.83), while it was inversely correlated with depressive symptoms among postpartum women (OR = 0.63, 95%CI: 0.41-0.99). CONCLUSIONS: Women giving birth a second time were more prone to have anxiety symptoms among the prenatal women and the whole sample, and less likely to have depressive symptoms among the postpartum women. Efficacious measures and interventions are essential to improve maternal mental health.

18.
Life Sci ; 248: 117454, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088211

RESUMO

AIMS: Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. MAIN METHODS: Utilizing breast cancer cells MCF-7, MDA-MB-231 and BT549, cell proliferation, migration and invasion were detected. RT-qPCR was performed to detect CIZ1, TGF-ß1 and Snail expression, and the interactions of these related molecules were analyzed by GeneMANIA database. Western blot detected CIZ1, TGF-ß1/Smads signaling and Snail expression in DHA-treated cells, in TGFß1-induced cells with enhanced metastatic capacity, and in cells treated with DHA plus TGFß1/TGFß1 inhibitor SD-208. KEY FINDINGS: Results indicated DHA inhibited breast cancer cell proliferation and migration, with more potent effects compared with that of artemisinin. RT-qPCR and Western blot showed DHA inhibited CIZ1, TGF-ß1 and Snail expression, and these molecules were shown to have protein-protein interactions by bioinformatics. Furthermore, TGFß1-treatment enhanced MCF-7 migration and invasion, and CIZ1, TGF-ß1/Smads signaling and snail activities; DHA, SD-208, combination of DHA and SD-208 reversed these conditions, preliminarily proving the cascade regulation between TGF-ß1 signaling and CIZ1. MCF-7 xenografts model demonstrated the inhibition of DHA on tumor burden, and its mechanisms and well-tolerance in vivo; combination of DHA and SD-208 tried by us for the first time showed better treatment effects, but possible liver impairment made its use still keep cautious. SIGNIFICANCE: DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-ß1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-ß1 pathway inhibitor.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Artemisininas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Fator de Crescimento Transformador beta1/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal , Feminino , Humanos , Metástase Linfática , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Pteridinas/farmacologia , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Bioenerg Biomembr ; 52(2): 123-130, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32036542

RESUMO

Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid malignancies and resistant to chemotherapy. Novel therapeutic strategy is required for better management of ATC. In this work, we show that artesunate, an antimalarial drug, is active against chemoresistant ATC cells. Artesunate dose-dependently inhibits growth and induces apoptosis in chemo-sensitive (8505C and KAT-4) and -resistant (8505C-r and KAT-4-r) ATC cells, and acts synergistically with doxorubicin. Using multiple xenograft mouse models, artesunate is active against chemo-sensitive and -resistant ATC cells in vivo at doses that do not cause toxicity in mice. Our mechanism analysis reveals that artesunate acts on ATC cells through suppressing mitochondrial functions without affecting glycolysis, leading to oxidative stress and damage, regardless of whether they are sensitive or resistant to chemotherapy. Interestingly, KAT-4-r cells demonstrate decreased glycolysis, increased mitochondrial membrane potential and mitochondrial respiration compared to KAT-4 cells whereas such phenomenon is not observed between 8505C and 8505C-r cells. This suggests that some but not all ATC cells gain enhanced mitochondrial biogenesis after prolonged exposure to chemotherapy drug, which may explain the different sensitivities of 8505C-r and KAT-4-r to artesunate. Our work demonstrates that artesunate is a potential addition to the treatment armamentarium for ATC, particularly those with chemoresistance. Our findings also highlight the therapeutic value of targeting mitochondria in chemoresistant ATC.

20.
Reprod Sci ; 27(2): 731-742, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32046445

RESUMO

Dysregulation of microRNAs in endometrial cells plays a pivotal role in the pathogenesis of endometriosis (EM). This study aims to investigate the implication of aberrant miR-202-3p expression in EM and the underlying mechanisms. We demonstrated that miR-202-3p was significantly downregulated in eutopic endometrium of EM in comparison to normal endometrial samples (P < 0.05). Primary endometrial stromal cells (ESCs) isolated from eutopic or ectopic endometrium also showed a significant decrease in miR-202-3p level compared to ESCs from normal endometrium (P < 0.01). Functional studies using MTT, wound healing assay and transwell assay indicated that overexpression of miR-202-3p greatly impaired cell viability, migration, and invasion, whereas suppression of miR-202-3p exhibited the opposite effects (P < 0.05 or P < 0.01). miR-202-3p mimics or inhibitors transfection significantly decreased or increased expression of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1), respectively, in ESCs (P < 0.01). Using dual luciferase reporter assay, we validated ROCK1 as a direct target of miR-202-3p. Moreover, negative correlations between miR-202-3p and ROCK1 mRNA/protein levels were determined in both eutopic and normal control endometrium (P < 0.01). In conclusion, these findings suggest that suppression of miR-202-3p in ESCs results in enhanced cell viability, invasion, and migration at least partially via upregulation of its target ROCK1, which eventually contributes to the development of endometriosis.

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