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2.
Hum Reprod ; 35(1): 187-194, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31943006

RESUMO

STUDY QUESTION: Are fructose levels altered in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Elevated serum fructose levels are associated with PCOS in Chinese Han women with overweight/obesity and hyperinsulinemia, and fructose levels are higher in follicular fluids from PCOS patients than from control subjects. WHAT IS KNOWN ALREADY: Both fructose levels and PCOS are closely linked to obesity and insulin resistance. However, the relationship between fructose and PCOS remains largely unknown. STUDY DESIGN, SIZE, DURATION: A total of 157 Chinese Han women (67 controls and 90 PCOS patients) were recruited at Shengjing Hospital of China Medical University. To systematically study the relationship between serum fructose levels and PCOS, the study population of control subjects and PCOS patients was divided into overweight/obese and lean subgroups, and hyper-fasting serum insulin (FSI) and normal-FSI subgroups, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fructose levels were measured in serum samples collected from 80 patients with PCOS (32 lean, 48 overweight/obese) and 59 control subjects (27 lean, 32 overweight/obese) and in follicular fluid samples collected from mature follicles (17-22 mm) and matched immature follicles (8-13 mm) from 10 patients with PCOS and 8 control subjects. MAIN RESULTS AND THE ROLE OF CHANCE: Serum fructose levels were increased in overweight/obese and hyper-FSI PCOS patients compared with the control subjects. Fructose had an area under the curve (AUC) of 79.7% at a cutoff value of 10.13 pmol/µl, with a sensitivity of 91.7% and a specificity of 59.3% for the prediction of PCOS in overweight/obese patients. In the hyper-FSI group, fructose had an AUC of 72% at a cutoff value of 10.49 pmol/µl, with a sensitivity of 71.1% and a specificity of 64.4% for the prediction of PCOS. There were no differences between fructose, total testosterone, free testosterone or dehydroepiandrosterone sulfate levels with respect to the reliability of predicting PCOS in the overweight/obese or hyper-FSI groups using the method outlined by Hanley and McNeil. Notably, the combination of fructose and total testosterone levels resulted in the highest AUC of 86.0% and high sensitivity (85.4%) and specificity (83.1%) for the prediction of PCOS in overweight/obese patients. The positive predictive value (PPV) and negative predictive value (NPV) were 80.4 and 87.5%, respectively. Similarly, the combination of fructose and total testosterone levels also resulted in a high AUC of 80.2% and moderate sensitivity (73.3%) and high specificity (84.7%) for the prediction of PCOS in hyper-FSI patients. The PPV and NPV were 78.6 and 80.6%, respectively. Furthermore, fructose levels were significantly higher in follicular fluids from PCOS patients than from control subjects, regardless of whether the follicles were mature or immature. LIMITATIONS, REASONS FOR CAUTION: It remains unclear whether fructose levels contribute directly to follicular development and the pathogenesis of PCOS or are merely a biomarker of these processes. WIDER IMPLICATIONS OF THE FINDINGS: The results of the present study, together with our previous study, show that monosaccharide status may be a novel marker for PCOS, highlighting the importance of further investigation into the role of monosaccharides, especially fructose, in the pathogenesis of PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (No. 81671423 and No. 81402130), the National Key Research and Development Program of China (No. 2018YFC1003100), Liaoning Provincial Key Research and Development Program (No. 2018225090), the Fok Ying Tung Education Foundation (No. 151039), Distinguished Talent Program of Shengjing Hospital (No. ME76) and Distinguished Teacher Program of China Medical University (No. QGZ2018079). No competing interests were declared.

3.
Ophthalmic Res ; 63(2): 165-173, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31846979

RESUMO

PURPOSE: To evaluate which ocular axis, the corneal topographic axis (CTA), pupillary axis (PA) or line of sight (LOS), for measuring the tilt and decentration of intraocular lens (IOL) is most relevant to correct distance visual acuity (CDVA). METHODS: A Scheimpflug device (Pentacam HR) was prospectively used to determine the tilt and decentration of IOLs in vivo 3 months after cataract surgery. A new method was developed to reliably measure PA and LOS. We further evaluated CTA and then used Spearman correlation coefficient and linear regression to assess the correlation between CDVA and IOL displacement based on the data of three different ocular axes. RESULTS: Forty-six eyes from 46 patients were evaluated. The majority of decentration and tilt of IOL with reference to CTA, PA and LOS were towards the subtemporal direction. We found that the horizontal meridian data measured using CTA and PA were statistically significantly different (p = 0.011 for tilt; p = 0.005 for decentration). The correlation between CDVA and the distance of decentration temporally (r = -0.344, p = 0.035) and inferiorly (r = -0.336, p = 0.042) of the IOL with regard to CTA was significant. PA and LOS measurements had no correlation with any indices. CONCLUSION: Assessment of tilt and decentration of the IOL with reference to different ocular axes was markedly different. IOL tilt and decentration measured by CTA were significantly correlated with CDVA.

4.
Shock ; 53(1): 103-113, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31841452

RESUMO

As tissue-resident cells in the lung, alveolar macrophages display remarkable heterogeneity and play a crucial role in the development and control of septic acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Recent evidence suggests that α-ketoglutarate (α-KG) plays an important role in alternative activation of macrophage (M2) through metabolic and epigenetic reprogramming, and thus possesses anti-inflammatory properties. However, the underlying mechanisms of α-KG's effect on alveolar macrophage polarization and the potential effects of α-KG in ALI/ARDS remain unclear. Here, we examined the effects and mechanisms of α-KG on alveolar macrophage polarization, and investigated the possible effects of α-KG on lipopolysaccharide (LPS)-induced ALI/ARDS in a mouse model. We found that α-KG inhibited M1 macrophage polarization and promoted IL-4-induced M2 macrophage polarization in MH-S cells (a murine alveolar macrophage cell line). Further experiments showed that α-KG down-regulated the expression of M1-polarized marker genes and inhibited the activities of mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal protein S6 kinase (p70S6K) signaling pathway in M1-polarized MH-S cells. Moreover, our results showed that α-KG promoted IL-4-induced M2 polarization of MH-S cells by augmenting nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ) and increasing expression of relevant fatty acid metabolic genes. Finally, using an LPS-induced ALI/ARDS mouse model, we found that α-KG ameliorated the LPS-induced inflammation and lung pathological damage, as well as α-KG pretreated mice had better clinical scores compared with the LPS group. These findings reveal new mechanisms of α-KG in regulating macrophage polarization which may provide novel strategies for the prevention and treatment of inflammatory diseases, including sepsis and septic ALI/ARDS.

5.
Int J Med Robot ; : e2063, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830358

RESUMO

BACKGROUND: Breast cancer is one of the most common cancer diagnosed among US women. Early and accurate diagnosis using breast biopsy techniques is essential in detecting cancer. METHODS: In this paper, we present a new cable-driven robot for MRI-guided breast biopsy. A compact three degree-of-freedom (DOF) semi-automated robot driven by ultrasonic motors is designed with non-magnetic materials. Next, a novel insertion trajectory planning algorithm based on the breast holder that we created is proposed and designed, which can help radiologists locate the lesion and calculate the insertion trajectory. To improve the accuracy of insertion, kinematic analysis and accuracy compensation methods are introduced. RESULTS: An experimental study based on image recognition and positioning is performed to validate the performance of the new robot. The results show that the mean position accuracy is 0.7 ± 0.04 mm. CONCLUSIONS: Application of the new robot can improve breast biopsy accuracy and reduce surgery time.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31681178

RESUMO

Background: Recent reports have highlighted the role of monosaccharide biosynthesis in the pathogenesis of polycystic ovary syndrome (PCOS), suggesting that these processes may serve as a biomarker in PCOS. Mannose is the main monosaccharide for protein glycosylation in mammals; however, the correlation between mannose and PCOS remains largely unknown. Materials and Methods: A total of 132 Chinese Han women were recruited at Shengjing Hospital of China Medical University. Mannose levels were measured in serum samples collected from 71 patients with PCOS (29 lean, 42 obese) and 61 control subjects (28 lean, 33 obese). Receiver operating characteristics (ROC) curves were prepared to compare the diagnostic performance of mannose and hormonal parameters, individually or in combination. Multivariate logistic regression analysis was used to assess whether serum mannose levels were associated with PCOS after adjusting for other co-variables. Results: We showed that serum mannose levels were significantly increased in PCOS patients compared with control subjects regardless of obese status, and hyperandrogenic PCOS patients had higher serum mannose levels than normo-androgenic PCOS and control subjects. In addition, serum mannose levels were significantly correlated with serum androgen levels. Mannose had an area under the curve (AUC) of 73% at a cutoff value of 225.79 ng/mL with a sensitivity of 66.2% and specificity of 73.8% for predicting PCOS. There were no differences between mannose, total testosterone, free testosterone, or dehydroepiandrosterone sulfate in the reliability of predicting PCOS using the method outlined by Hanley and McNeil. Combining mannose and total testosterone resulted in a higher AUC of 83.3%, and had moderate sensitivity (78.9%) and specificity (77%) for predicting PCOS. The positive and negative predictive values were 80% and 75.8%, respectively. Multivariate logistic regression revealed that higher serum mannose levels were strongly associated with an increased risk of PCOS (P = 0.016; odds ratio, 5.623; 95% confidence interval, 1.371-23.070). Conclusion: Taken together, substantially elevated serum mannose levels are significantly associated with PCOS, highlighting the importance of further research into the role of mannose in the pathogenesis of PCOS.

7.
Onco Targets Ther ; 12: 6927-6936, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695408

RESUMO

Background: Activation of NLPR3 inflammasome is associated with the development and progression of some types of malignant tumors, but its role in endometrial cancer is unclear. This study aimed to investigate the expression and function of NLRP3 inflammasome in endometrial cancer. Materials and methods:  The expression levels of NLRP3, its inflammasome components and estrogen receptor ß in endometrial cancer and paired non-tumor tissues were detected. The effects of NLPR3 silencing or overexpression on the proliferation, migration, and invasion of Ishikawa and HEC-1A cells were determined. The impact of NLPR3 silencing on the growth of implanted tumors was determined in vivo. The effects of estrogen on NLPR3 inflammasome activation and Ishikawa cell proliferation were determined. Results: The upregulation of NLRP3, ASC, caspase-1, and IL-1ß was associated with the progression of endometrial cancer and poor survival. NLPR3 silencing inhibited the proliferation, migration, and invasion of endometrial cancer cells while NLPR3 overexpression had opposite effects. NLPR3 silencing reduced IL-1ß and caspase-1 expression and the growth of implanted endometrial tumors, accompanied by decreased pro-IL-1ß maturation. Estrogen enhanced NLPR3, ERß, pro-IL-1ß, IL-1ß expression, and endometrial cancer cell proliferation, which were mitigated by treatment with ERß inhibitor but not ERα inhibitor. Conclusion: Our results suggest that estrogen acts through ERß to enhance the activation of NLPR3 inflammasome and promote the progression of endometrial cancer. NLPR3 inflammasome may be a new therapeutic target for endometrial cancer.

8.
Int J Oncol ; 55(6): 1249-1260, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638165

RESUMO

The purpose of the present study was to compare metabolites from formalin­fixed and paraffin­embedded (FFPE) pancreatic tissue blocks with those identified in optimal cutting temperature (OCT)­embedded pancreatic tissue blocks. Thus, ultra­performance liquid chromatograph­mass spectrometry/mass spectrometry­based metabolic profiling was performed in paired frozen (n=13) and FFPE (n=13) human pancreatic adenocarcinoma tissue samples, in addition to their benign counterparts. A total of 206 metabolites were identified in both OCT­embedded and FFPE tissue samples. The method feasibility was confirmed through reproducibility and a consistency assessment. Partial least­squares discriminant analysis and heatmap analysis reliably distinguished tumor and normal tissue phenotypes. The expression of 10 compounds, including N­acetylaspartate and creatinine, was significantly different in both OCT­embedded and FFPE tumor samples. These ten compounds may be viable candidate biomarkers of malignant pancreatic tissues. The super­categories to which they belonged exhibited no significant differences between FFPE and OCT­embedded samples. Furthermore, purine, arginine and proline, and pyrimidine metabolism used a shared pathway found in both OCT­embedded and FFPE tissue samples. These results supported the notion that metabolomic data acquired from FFPE pancreatic cancer specimens are reliable for use in retrospective and clinical studies.

9.
Cancer Gene Ther ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31664166

RESUMO

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to kill a wide variety of tumor cells with minimal effects on normal cell. However, renal cell carcinoma (RCC) cells 786-0 and OS-RC-2 were resistant to TRAIL. The present study examines the potential of combining polyphenolic compound resveratrol (RES) with TRAIL. We found that RES can sensitize RCC cells to TRAIL-induced death. Electron microscopy analyses showed that RES plus TRAIL can induce both autophagy and apoptosis in RCC cells. It was proved that the apoptosis is caspase-dependent and the activation of caspase-8, caspase-9, and caspase-3 was involved in this process. Besides, we also found that XIAP expression was significantly inhibited after RES plus TRAIL treatment in RCC cells. Furthermore, a fiber-modified replication-deficient adenovirus Ad5/35-TRAIL was generated to test the synergistic effect of RES and TRAIL in vivo. Our data demonstrated that RES plus Ad5/35-TRAIL significantly inhibited RCC xenograft growth in nude mice. These results suggest the possibility of a new combination therapeutic leading to the improvement of RCC treatment.

10.
Cancer Manag Res ; 11: 8911-8921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632151

RESUMO

Purpose: Metadherin (MTDH), as an oncogene, is associated with metastasis and poor prognosis. This study investigated MTDH expressions and development of gastric cancer (GC) cell phenotypes and the contribution of MTDH to epithelial-mesenchymal transition (EMT). Patients and methods: MTDH expression was assayed in human GC cell lines and tumor tissue from 92 GC patients. Functional experiments were performed to characterize MTDH activity. Expressions of EMT-related proteins (vimentin and E-cadherin), phosphorylated ß-catenin and ß-catenin were assayed by immunohistochemistry, Western blotting, immunofluorescence, and co-immunoprecipitation, respectively. Results: MTDH expressions were higher in GC tissue than that in gastric mucosa from the same patient. MTDH overexpression was correlated with metastasis and enhanced malignant GC phenotypes, i.e., proliferation, migration, invasiveness, and chemoresistance. MTDH overexpression was associated with expressions of vimentin, E-cadherin and cancer stem-cell biomarkers including CD44, CD133, and Oct4. MTDH complexed with ß-catenin and decreased phosphorylated ß-catenin levels to facilitate ß-catenin translocation into the nucleus and expressions of downstream genes. Conclusion: MTDH overexpression in GC cells is associated with EMT and development of cancer stem cell malignant phenotypes and affects the subcellular translocation of ß-catenin. The results warrant investigation of the prognostic value of MTDH in GC and as a therapeutic target.

11.
Int J Mol Sci ; 20(21)2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31652737

RESUMO

A deep insight into the function and kinetics of ATP-binding cassette (ABC) transporters may aid in the development of pharmaceutics that can minimize the particular facet of chemo-resistance. We utilized bioluminescence imaging to monitor the ABC transporter mediated intracellular drug efflux function. We also investigated the potential association between the intracellular bioluminescent pharmacokinetic profiles and the anti-tumor efficacy of the coix seed extract and gemcitabine against pancreatic cancer cells in vitro and in vivo. The bioluminescent pharmacokinetic parameters and pharmacodynamic index (IC50 and TGI) were determined. The expression levels ABCB1 and ABCG2 were assessed. Results showed that coix seed extract could synergistically enhance the anti-cancer efficacy of gemcitabine (p < 0.05). Meanwhile coix seed extract alone or in combination with gemcitabine could significantly increase the AUCluc while decreasing the Kluc (p < 0.01). Western blot and immunohistochemistry assay demonstrated that coix seed extract could significantly mitigate gemcitabine-induced upregulation of ABCB1 and ABCG2 protein. The Pearson correlation analysis demonstrated that the bioluminescent pharmacokinetic parameters and pharmacodynamic index have strong association in vitro and in vivo. In conclusion coix seed extract could augment the efficacy of gemcitabine therapy in pancreatic cancer cells may at least partly due to the alteration of ABC transporter-mediated drug efflux function.

12.
BMJ Open ; 9(8): e027201, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471431

RESUMO

OBJECTIVES: This study aimed to elucidate the status of hypertension and to analyse the hypertension changes in prevalence, awareness, treatment and control rate among the portion of Chinese nursing staff based on the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) High Blood Pressure Guideline and the 2010 Chinese Guideline for the Management of Hypertension. DESIGN: Cross-sectional study. SETTING: 512 medical institutions in 13 cities in Hebei Province. PARTICIPANTS: The candidates of registered nurses from 512 medical institutions in 13 cities in Hebei Province (N=143 772) were invited to participate in the survey, and few of them who refused to participate were excluded from the research group based on the reasons that 93 603 incumbent nurses at the age of 18-65 accepted to the survey and submitted questionnaires online. Undoubtedly, a response rate of 65.11% was achieved. After excluding 788 individuals with incomplete information in the questionnaires, 92 815 participants were included in the final analysis. MAIN OUTCOME MEASURES: The prevalence, awareness, treatment and control rates of hypertension. RESULTS: 92 815 participants were included in the final analysis, among which consisted of 3677 men (3.96%) and 89 138 women (96.04%). The mean age of the participants was 31.65 (SD=7.47) years.We demonstrated that 26 875 nursing staff were diagnosed as having hypertension according to the new standard by the 2017 ACC/AHA guideline, more than 20 551 cases compared with the previous threshold on the 2010 Chinese guideline. The prevalence of hypertension among nursing staff was 28.96% in the context of the 2017 ACC/AHA guideline, 3.25 times higher than that (6.81%) evaluated by the criteria of the 2010 Chinese guideline. However, the awareness, treatment and control rate (13.50%, 10.73% and 0.81%) were 3.25, 3.22 and 17.48 times lower than those (57.37%, 45.30% and 14.97%) based on the 2010 Chinese guideline, respectively. CONCLUSIONS: This research illustrated that it was crucial to improve the awareness rate, drug treatment rate and control rate of hypertension for nurses. Meanwhile, according to the 2017 ACC/AHA guideline, the prevalence of hypertension in China will increase significantly, which poses a more severe challenge to the management of hypertension in China.

13.
BMC Genomics ; 20(1): 676, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455220

RESUMO

BACKGROUND: Single cell transcriptome sequencing has become an increasingly valuable technology for dissecting complex biology at a resolution impossible with bulk sequencing. However, the gap between the technical expertise required to effectively work with the resultant high dimensional data and the biological expertise required to interpret the results in their biological context remains incompletely addressed by the currently available tools. RESULTS: Single Cell Explorer is a Python-based web server application we developed to enable computational and experimental scientists to iteratively and collaboratively annotate cell expression phenotypes within a user-friendly and visually appealing platform. These annotations can be modified and shared by multiple users to allow easy collaboration between computational scientists and experimental biologists. Data processing and analytic workflows can be integrated into the system using Jupyter notebooks. The application enables powerful yet accessible features such as the identification of differential gene expression patterns for user-defined cell populations and convenient annotation of cell types using marker genes or differential gene expression patterns. Users are able to produce plots without needing Python or R coding skills. As such, by making single cell RNA-seq data sharing and querying more user-friendly, the software promotes deeper understanding and innovation by research teams applying single cell transcriptomic approaches. CONCLUSIONS: Single cell explorer is a freely-available single cell transcriptomic analysis tool that enables computational and experimental biologists to collaboratively explore, annotate, and share results in a flexible software environment and a centralized database server that supports data portal functionality.


Assuntos
/métodos , Análise de Célula Única/métodos , Software , Biologia Computacional/métodos , Bases de Dados Factuais , Transcriptoma , Interface Usuário-Computador , Fluxo de Trabalho
14.
J Med Virol ; 91(11): 1918-1929, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31317548

RESUMO

Influenza A (H1N1) is a rapidly spreading acute respiratory illness that remains a worldwide burden on public health. To simulate natural infection routes, BALB/C mice were challenged with the H1N1 virus by aerosol and intranasal instillation routes. We compared the weight change and survival of the mice for 14 consecutive days after infection. The infected mice were euthanized at days 3, 5, 7, and 9 to perform necropsies, lung pathological analyses, viral titers measurement, and lung cytokines examination. The aerosol-treated mice showed clinical symptoms on day 4, obvious lung lesions on day 5, rapid weight loss on day 7, peak virus replication in the lungs on days 7 to 9, and bronchial epithelial hyperplasia on day 9. However, after intranasal instillation, the mice exhibited clinical signs on day 2, rapid weight loss and obvious lung lesions on day 3, and peak virus replication in the lungs on days 3 to 5; no bronchial epithelial hyperplasia was detected. High levels of proinflammatory cytokines and chemokines were detected in the lungs of infected mice by both two routes. Disease and lung lesion progressions were slower in the mice that inhaled H1N1-containing aerosols than in those treated by intranasal instillation, and lung lesions were homogeneous in the aerosol group and heterogeneous in the intranasal group. In this study, BALB/C mouse models of H1N1 virus aerosol inhalation were successfully established and compared with mouse models of intranasal inoculation, aerosol mouse models had an infection route and lung pathology characteristics that more closely resembled those observed in humans.

15.
Chem Biol Drug Des ; 94(2): 1537-1544, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31059203

RESUMO

The extensive use of antibiotics in medicine results in the multidrug resistance of bacteria, making the development of new antimicrobial agents an urgent need. Antimicrobial peptides (AMPs) are considered as a new class of antibiotic with characteristics including an ability to kill target cells rapidly and a broad spectrum of activity. We have developed a potent antimicrobial peptide MAP-0403 (MIC = 5 µM), but it exhibited a high hemolytic side-effect (70.7%). To reduce its hemolytic effect and increase antimicrobial activity, three peptides derivatives of MAP-0403 (J-1, J-2, and J-3) were designed, synthesized by solid phase synthesis, purified by RP-HPLC, and characterized by MALDI-TOF MS. Structure-activity relationships of these peptides were studied by using circular dichroism and antimicrobial assays. The percentage of helical structure in J-1, J-2, and J-3 was lower than that of MAP-0403. The antimicrobial activity of J-1 was the same as that of MAP-0403 (MIC = 5 µM), J-2 exhibited the highest activity (MIC = 2.5 µM), while J-3 showed decreased activity (MIC = 10 µM). Compared to MAP-0403, J-2 showed significantly reduced hemolytic effect (3.4%), while J-1 and J-3 showed slightly decreased hemolytic effect (46.2%, 55.6%, respectively). Peptide J-2 was discovered as a novel and potent antimicrobial agents.

16.
Cell Mol Neurobiol ; 39(6): 823-831, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31065924

RESUMO

Severe haemorrhagic transformation (HT), a common complication of recombinant tissue plasminogen activator (rtPA) treatment, predicts poor clinical outcomes in acute ischaemic stroke. The search for agents to mitigate this effect includes investigating biomolecules involved in neovascularization. This study examines the role of Cathepsin K (Ctsk) in rtPA-induced HT after focal cerebral ischaemia in mice. After knockout of Ctsk, the gene encoding Ctsk, the outcomes of Ctsk+/+ and Ctsk-/- mice were compared 24 h after rtPA-treated cerebral ischaemia with respect to HT severity, neurological deficits, brain oedema, infarct volume, number of apoptotic neurons and activated microglia/macrophage, blood-brain barrier integrity, vascular endothelial growth factor (VEGF) expression and Akt-mTOR pathway activation. We observed that haemoglobin levels, brain oedema and infarct volume were significantly greater and resulted in more severe neurological deficits in Ctsk-/- than in Ctsk+/+ mice. Consistent with our hypothesis, the number of NeuN-positive neurons was lower and the number of TUNEL-positive apoptotic neurons and activated microglia/macrophage was higher in Ctsk-/- than in Ctsk+/+ mice. Ctsk knockout mice exhibited more severe blood-brain barrier (BBB) disruption, with microvascular endothelial cells exhibiting greater VEGF expression and lower ratios of phospo-Akt/Akt and phospo-mTOR/mTOR than in Ctsk+/+ mice. This study is the first to provide molecular insights into Ctsk-regulated HT after cerebral ischaemia, suggesting that Ctsk deficiency may disrupt the BBB via Akt/mTOR/VEGF signalling, resulting in neurological deficits and neuron apoptosis. Ctsk administration has the potential as a novel modality for improving the safety of rtPA treatment following stroke.


Assuntos
Isquemia Encefálica/complicações , Catepsina K/deficiência , Hemorragia Cerebral/etiologia , Animais , Apoptose , Barreira Hematoencefálica/patologia , Catepsina K/metabolismo , Infarto da Artéria Cerebral Média/patologia , Macrófagos/patologia , Masculino , Camundongos Knockout , Microglia/patologia , Neurônios/patologia , Permeabilidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ativador de Plasminogênio Tecidual , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Front Microbiol ; 10: 268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30873131

RESUMO

Objectives: To investigate the specific role of Toll-like receptor 4 (TLR4) in the regulation of the intestinal mucosa-associated microbiota by vitamin A (VA). Methods: Both TLR4-/- (knockout, KO) and wild-type (WT) female mice were randomly fed a VA normal (VAN) or VA deficient (VAD) diet for 4 weeks to establish the following four mouse model groups: TLR4-/- mice fed a VAN diet (KO VAN), TLR4-/- mice fed a VAD diet (KO VAD), WT mice fed a VAN diet (WT VAN), and WT mice fed a VAD diet (WT VAD). Then, the mice from each experimental group were mated with male mice with the same genetic background. The pups in the KO VAD and WT VAD groups were subsequently fed the VAD diet after weaning, while the pups in the KO VAN and WT VAN groups were fed the VAN diet continuously after weaning. The serum retinol levels of 7-week-old offspring were determined using high-performance liquid chromatography, and colons were collected from mice in each group and analyzed via 16S rRNA gene sequencing using an Illumina MiSeq platform to characterize the overall microbiota of the samples. Results: The abundance and evenness of the colon mucosa-associated microbiota were unaffected by dietary VA and TLR4 KO. VAD decreased the abundance of Anaerotruncus (Firmicutes), Oscillibacter (Firmicutes), Lachnospiraceae _NK4A136 _group (Firmicutes) and Mucispirillum (Deferribacteres) and increased the abundance of Parasutterella (Proteobacteria). TLR4 KO decreased the abundance of Bacteroides (Bacteroidetes) and Alloprevotella (Bacteroidetes). However, the abundance of Allobaculum (Firmicutes), Ruminiclostridium_9 (Firmicutes), Alistipes (Bacteroidetes), and Rikenellaceae_RC9 (Bacteroidetes) impacted the interaction between VA and TLR4. Conclusion: TLR4 may play a pivotal role in regulation of the intestinal mucosa-associated microbiota by VA to maintain the intestinal microecology.

18.
Molecules ; 24(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925820

RESUMO

The goal of this investigation was to determine the processes and mechanism of intestinal absorption for capilliposide B (CAPB) and capilliposide C (CAPC) from the Chinese herb, Lysimachia capillipes Hemsl. An analysis of basic parameters, such as drug concentrations, time, and behavior in different intestinal segments was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). The susceptibility of CAPB and CAPC to various inhibitors such as P-glycoprotein (P-gp) inhibitor (verapamil); multidrug resistance-associated protein 2 (MRP2) inhibitor (indomethacin); cytochrome P450 protein 3A4 (CYP3A4) inhibitor (ketoconazole); and the co-inhibitor of P-gp, MRP2 and CYP3A4 (cyclosporine A) were assessed using both caco-2 cell monolayer and single-pass intestinal perfusion (SPIP) models. As a result, CAPB and CAPC are both poorly absorbed in the intestines and exhibited segment-dependent permeability. The intestinal permeability of CAPB and CAPC were significantly increased by the co-treatment of verapamil, indomethacin. In addition, the intestinal permeability of CAPB was also enhanced by ketoconazole and cyclosporine A. It can be concluded that the intestinal absorption mechanisms of CAPB and CAPC involve processes such as facilitated passive diffusion, efflux transporters, and enzyme-mediated metabolism. Both CAPB and CAPC are suggested to be substrates of P-gp and MRP2. However, CAPB may interact with the CYP3A4 system.


Assuntos
Absorção Intestinal/efeitos dos fármacos , Primulaceae/química , Saponinas/farmacologia , Triterpenos/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/efeitos dos fármacos , Células CACO-2 , Cromatografia Líquida , Citocromo P-450 CYP3A/metabolismo , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Permeabilidade , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
19.
Gene ; 697: 184-193, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30797995

RESUMO

BACKGROUNDS: The pathophysiology of hydrocephalus induced brain damage remains unclear. Long non-coding RNAs (lncRNAs) have been demonstrated to be implicated in many central nervous system diseases. However, the roles of lncRNAs in hydrocephalus injury are poorly understood. METHODS: The present study depicted the expression profiles of lncRNAs and messenger RNAs (mRNAs) in C57BL/6 mice with kaolin-induced hydrocephalus and saline controls using high-throughput RNA sequencing. Afterward, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify potential targets that correlated with hydrocephalus. In addition, co-expression networks and cis- and trans-regulation were predicted using bioinformatics methods. Finally, representative lncRNAs and mRNAs were further validation using quantitative real-time polymerase chain reaction. RESULTS: A total of 1575 lncRNAs and 1168 mRNAs were differentially expressed (DE) in hydrocephalus. GO and KEGG analyses indicated several immune and inflammatory response-associated pathways may be important in the hydrocephalus. Besides, functional enrichment analysis based on co-expression network showed several similar pathways, such as chemokine signaling pathway, phagosome, MAPK signaling pathway and complement and coagulation cascade. Cis-regulation prediction revealed 5 novel lncRNAs might regulate their nearby coding genes, and trans-regulation revealed several lncRNAs participate in pathways regulated by transcription factors, including BPTF, FOXM1, NR5A2, P2RX5, and NR6A1. CONCLUSIONS: In conclusion, our results provide candidate genes involved in hydrocephalus and suggest a new perspective on the modulation of lncRNAs in hydrocephalus.


Assuntos
Hidrocefalia/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Animais , Biologia Computacional , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Genoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hidrocefalia/induzido quimicamente , Caulim/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante/análise , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma/genética
20.
Neuroradiology ; 61(1): 103-107, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30488255

RESUMO

PURPOSE: Identifying previous chronic cerebral hemorrhage (PCH), especially asymptomatic cases in patients with ischemic stroke, is essential for proper antithrombotic management. The study aimed to further clarify the prevalence of PCH and the associated factors in patients with acute ischemic stroke using multi-modal neuroimaging including susceptibility-weighted MR imaging (SWI). METHODS: This was a retrospective cross-sectional study of 382 patients with acute ischemic stroke. All patients underwent 3.0-T MRI for cranial SWI, 1.5-T or 3.0-T conventional cranial MRI, and cranial CT. Patients found with PCH were matched 1:4 with patients without PCH. Clinical manifestation, computed tomography, conventional cranial MRI, and cranial SWI were used to determine PCH. Clinical and neuroimaging findings between the patients with symptomatic vs. asymptomatic PCH were compared. RESULTS: Thirty-six patients (36/382, 9.4%) were determined to have had a PCH. Of these 36 patients, 17 (17/36, 47.2%, or 17/382, 4.5%) had asymptomatic PCH. Multivariable analysis showed that serum total cholesterol (OR = 0.510, 95%CI 0.312-0.832, P = 0.007), cerebral microbleeds (OR = 6.251, 95%CI 2.220-17.601, P = 0.001), and antithrombotic drugs history (OR = 3.213, 95%CI 1.018-10.145, P = 0.047) were independently associated with PCH. Asymptomatic PCH had similar clinical and neuroimaging characteristics with symptomatic PCH. CONCLUSION: PCH is not uncommon in acute ischemic stroke patients. Total serum cholesterol, cerebral microbleeds on SWI, and history of antithrombotic drugs were independently associated with PCH in patients with acute ischemic stroke. Asymptomatic PCH, which is easier to be missed and has similar characteristics with symptomatic PCH, should draw much attention.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Imagem Multimodal , Neuroimagem/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Doença Crônica , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
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