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1.
Sci Total Environ ; 710: 136448, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32050374

RESUMO

Docosahexaenoic acid plays a vital role in human health as it is essential for the proper function of the nervous system and for visual functions. To decrease the cost of docosahexaenoic acid production by Schizochytrium, the cost of the medium should be further decreased. In this study, the use of tofu whey wastewater to culture Schizochytrium sp. for docosahexaenoic acid production was tested, with the goal of reducing the medium cost. The results indicated that tofu whey wastewater presented a better culture performance with respect to biomass, lipid, and docosahexaenoic acid production compared with three traditional media. Through simple pH adjustment, the biomass and docosahexaenoic acid productivity reached 1.89 and 0.24 g/L/day, respectively, which were much higher than those obtained using traditional medium. The removal efficiency of chemical oxygen demand, total nitrogen, and total phosphorus reached 64.7, 66.0, and 59.3%, respectively. Due to the rich nutrients in tofu whey wastewater, the use of extra nitrogen source was avoided and the total medium cost for docosahexaenoic acid production in cultures using tofu whey wastewater was <1/3 of that of traditional media. This result indicated that tofu whey wastewater is an effective and economic basal medium for docosahexaenoic acid production by Schizochytrium sp.

2.
Toxicol Lett ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31981688

RESUMO

Paraoxonase 1 (PON1) is a type of aromatic esterase widely existing in mammals. It can hydrolyze various kinds of compounds effectively in vivo and in vitro. Previous studies have confirmed that PON1 can be used as an antidote against organophosphorus poisoning. In this study, we obtained two subtype isozymes of recombinant human PON1 (rhPON1), which have gene polymorphisms in 192 locis, by gene recombination. We then investigated the differences between these two recombinant isozymes (i.e. rhPON1R192 and rhPON1Q192) in their detoxification effect against organophosphorus pesticide poisoning in rats. As antidotes against chlorpyrifos poisoning, the rhPON1R192 isozyme demonstrated better effect than the rhPON1Q192 isozyme; whereas, their detoxification activities against diazinon were on the contrary. Both isozymes showed poor detoxification activity against trithion. Therefore, we concluded that if the PON1 was used as a biological scavenger against organophosphate poisoning, better detoxification effect may be achieved by selecting the PON1 subtype isozyme with higher specific hydrolytic activity.

3.
Int J Biol Sci ; 16(1): 162-171, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31892853

RESUMO

Great quantity of intergenic noncoding RNAs (lncRNAs) have been identified in the mammalian genome and involved in various biological processes, especially in the development and metastasis of cancer. In this study, we identified one lncRNA, lncRNA NONHSAT028712 (Lnc712), was highly expressed in breast cancer cell lines and tissues based on microarray screening. Knockdown of Lnc712 largely inhibited breast cancer cell proliferation. Mechanistically, Lnc712 bound specifically to heat-shock protein 90 (HSP90). Interaction between Lnc712 and HSP90 is required for HSP90 binding to cell division cycle 37 (Cdc37). The Lnc712/HSP90/Cdc37 complex regulated cyclin-dependent kinase 2 (CDK2) activation and then triggered breast cancer cell proliferation. In summary, our results identified a new lncRNA regulate breast cancer proliferation though interaction with HSP90.

4.
Int J Mol Sci ; 21(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991733

RESUMO

: Heterosis is an interesting topic for both breeders and biologists due to its practical importance and scientific significance. Cultivated rice (Oryza sativa L.) consists of two subspecies, indica and japonica, and hybrid rice is the predominant form of indica rice in China. However, the molecular mechanism underlying heterosis in japonica remains unclear. The present study determined the genome sequence and conducted quantitative trait locus (QTL) analysis using backcross recombinant inbred lines (BILs) and BILF1 lines to uncover the heterosis-related loci for rice yield increase under a japonica genetic background. The BIL population was derived from an admixture variety Habataki and japonica variety Sasanishiki cross to improve the genetic diversity but maintain the genetic background close to japonica. The results showed that heterosis in F1 mainly involved grain number per panicle. The BILF1s showed an increase in grain number per panicle but a decrease in plant height compared with the BILs. Genetic analysis then identified eight QTLs for heterosis in the BILF1s; four QTLs were detected exclusively in the BILF1 population only, presenting a mode of dominance or super-dominance in the heterozygotes. An additional four loci overlapped with QTLs detected in the BIL population, and we found that Grains Height Date 7 (Ghd7) was correlated in days to heading in both BILs and BILF1s. The admixture genetic background of Habataki was also determined by subspecies-specific single nucleotide polymorphisms (SNPs). This investigation highlights the importance of high-throughput sequencing to elucidate the molecular mechanism of heterosis and provides useful germplasms for the application of heterosis in japonica rice production.

5.
Oncol Rep ; 43(1): 229-239, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31661146

RESUMO

Long non­coding RNAs (lncRNAs) are considered to be important regulators in breast cancer. In the present study, the potential mechanisms and functional roles of lncRNA PSMG3­antisense (AS)1 were investigated in vivo and in vitro. The relative expression levels of lncRNA PSMG3­AS1 and microRNA (miR)­143­3p were determined using reverse­transcription quantitative PCR. The protein expression levels of collagen type 1 alpha 1 (COL1A1) and proliferating cell nuclear antigen (PCNA) were obtained using western blot analysis. Bioinformatics analysis was used to identify the relationship between PSMG3­AS1, miR­143­3p and COL1A1. Colony forming and Cell Counting Kit­8 assays were used to detect cell proliferation. Transwell and wound­healing assays were used to determine cell migration. The results of the present study demonstrated that PSMG3­AS1 expression was increased in breast cancer tumor tissues and cell lines, and that of miR­143­3p was decreased. Knockdown of PSMG3­AS1 increased the level of miR­143­3p expression, which led to the mitigation of proliferation and migration capacity in breast carcinoma cells. Additionally, PSMG3­AS1 knockdown was demonstrated to reduce the mRNA and protein expression levels of COL1A1. miR­143­3p mimic transfection reduced proliferation and migration in MDA­MB­231 and MCF­7 cell lines. Furthermore, miR­143­3p inhibition significantly increased the proliferation and migration of breast cancer cells compared with the negative control group. The mRNA and protein expression levels of PCNA were reduced in the MCF­7 cell line when transfected with miR­143­3p mimics and si­PSMG3­AS1. However, PCNA expression was increased in cells transfected with a miR­143­3p inhibitor. In conclusion, the results of the present study identified a novel lncRNA PSMG3­AS1, which serves as a sponge for miR­143­3p in the pathogenesis of breast cancer. PSMG3­AS1 may be used as a potential therapeutic target gene in breast cancer treatment.

6.
J Pharm Biomed Anal ; 179: 113029, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31835125

RESUMO

Gansuibanxia decoction (GSBXD) is one of the most famous traditional Chinese medicine (TCM). It is a herbal formula used for treating hydrops, such as cancerous ascites, pleural effusion, pericardial effusion, etc. However, the chemical constituents of GSBXD were still unclear. In this study, an UHPLC-FT-ICR-MS method was established and applied to the separation and characterization of the chemical constituents of GSBXD. A total of 62 components were chemically defined or tentatively identified, including diterpenoids, triterpenoids, flavonoids, monoterpene glycosides and alkaloids. The results is meaningful for a better understanding of the material basis of GSBXD and can be the basis for its further in vitro and in vivo studies.

7.
J Affect Disord ; 260: 281-286, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521864

RESUMO

BACKGROUND: White matter abnormalities have been implicated in mental disorders including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ); however, the shared and distinct white matter integrity across mental disorders is still unclear. METHODS: A total of 290 participants (MDD = 85, BD = 42, SZ = 68, and healthy controls = 95) were included in the present study. Tract-based spatial statistics were performed to measure fractional anisotropy (FA) and characterize shared and distinguishing white matter changes across mental disorders. RESULTS: We found that decreased FA converged across MDD, BD and SZ in the body and genu of the corpus callosum, bilateral anterior and posterior corona radiata, and right superior corona radiata. By contrast, diagnosis-specific effect was only found in MDD in the anterior portion of anterior corona radiata. LIMITATIONS: The small and imbalanced sample size, and possible confounding effects of medication. CONCLUSIONS: Our findings suggest that abnormally reduced white matter integrity in the interhemispheric and thalamocortical circuit could be consistently involved in the pathogenesis of MDD, BD and SZ.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31776907

RESUMO

In view of the increasing attention on antibiotic contamination and their scarce data in the inland river (especially for the sediment), the occurrence of 28 antibiotics in sediments from the Xiangjiang River was comprehensively analyzed, and 22 antibiotics were detected with a total concentration ranging from 4.07 to 2090 ng g-1. The residue was almost at a moderate or higher level in the aquatic environment around the world. Fluoroquinolones and tetracyclines were the dominant detected antibiotics, and the maximum total concentration could reach to 2085 ng g-1, though that in surface water was just 33.4 ng L-1. Oxytetracycline and chlortetracycline could be detected with high concentration in areas with lower population density. Usage profile of each antibiotic may be responsible for the spatial variation. Principal component analysis-multiple linear regression model indicated that direct discharge of domestic wastewater and livestock or aquaculture sewage could contribute 94.2% of the pollution. Redundancy analysis was used to screen out the environment variables, which were closely related to the pseudo-partitioning coefficients (Kd) of antibiotics in sediment and surface water for the first time, and showed that the Kd was correlated with sediment pH negatively and organic carbon, total phosphorus, and conductivity of the sediments positively. High sedimentary organic carbon was considered to promote the higher Kd in this river. This study would deepen the understanding of the occurrence of antibiotics in sediments from the inland rivers and provide scientific support for controlling the antibiotic contamination.

9.
Oncogene ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740781

RESUMO

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) significantly prolong the survival time of non-small-cell lung cancer (NSCLC) patients with EGFR-activating mutations, but resistance develops universally. Activation of the phosphatidyl inositol-3 kinase (PI3K)/AKT signaling pathway and phenotypic alterations in epithelial-mesenchymal transition (EMT) are both mechanisms of acquired resistance to EGFR-TKIs. However, the mechanisms underlying this resistance remain unclear. In this study, EHD1 depletion significantly increased NSCLC cell sensitivity to EGFR-TKI, which was accompanied by EMT reversal. Microarray analysis showed that the PTEN/PI3K/AKT signaling pathway is a crucial pathway regulated by EHD1. Moreover, a PTEN inhibitor abolished EHD1 shRNA regulation of EGFR-TKI sensitivity, EMT, and cancer progression. Mass spectrometry showed that TUBB3 is a novel EHD1-interacting protein. EHD1 modulated microtubule stability by interacting with TUBB3. Furthermore, TUBB3 depletion significantly attenuated EHD1-induced EGFR-TKI resistance and EMT. Bioinformatics analysis revealed that EHD1 is significantly associated with the gene set, "Cellular Response to Interleukin-1ß (IL-1ß)". As expected, treatment with IL-1ß led to increased expression of EHD1, activation of PTEN/PI3K/AKT signaling, and induction of EMT in NSCLC cells. In patient specimens, EHD1 was highly expressed in EGFR-TKI-refractory specimens. EHD1 was positively associated with TUBB3 and IL-1R1 but negatively associated with PTEN. In addition, targeting the IL-1ß/EHD1/TUBB3 axis mitigated cancer progression by inhibiting cell proliferation and metastasis and promoting apoptosis. Our study demonstrates the involvement of the IL-1ß/EHD1/TUBB3 axis in EGFR-TKI resistance and provides a potential therapeutic approach for treating patients with NSCLC that has acquired EGFR-TKI resistance.

10.
PeerJ ; 7: e7714, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576246

RESUMO

Background: Alfalfa is the most widely cultivated forage legume and one of the most economically valuable crops in the world. Its survival and production are often hampered by environmental changes. However, there are few studies on stress-resistance genes in alfalfa because of its incomplete genomic information and rare expression profile data. The MYB proteins are characterized by a highly conserved DNA-binding domain, which is large, functionally diverse, and represented in all eukaryotes. The role of MYB proteins in plant development is essential; they function in diverse biological processes, including stress and defense responses, and seed and floral development. Studies on the MYB gene family have been reported in several species, but they have not been comprehensively analyzed in alfalfa. Methods: To identify more comprehensive MYB transcription factor family genes, the sequences of 168 Arabidopsis thaliana, 430 Glycine max, 185 Medicago truncatula, and 130 Oryza sativa MYB proteins were downloaded from the Plant Transcription Factor Database. These sequences were used as queries in a BLAST search against the M. sativa proteome sequences provided by the Noble Research Institute. Results: In the present study, a total of 265 MsMYB proteins were obtained, including 50 R1-MYB, 186 R2R3-MYB, 26 R1R2R3-MYB, and three atypical-MYB proteins. These predicted MsMYB proteins were divided into 12 subgroups by phylogenetic analysis, and gene ontology (GO) analysis indicated that most of the MsMYB genes are involved in various biological processes. The expression profiles and quantitative real-time PCR analysis indicated that some MsMYB genes might play a crucial role in the response to abiotic stresses. Additionally, a total of 170 and 914 predicted protein-protein and protein-DNA interactions were obtained, respectively. The interactions between MsMYB043 and MSAD320162, MsMYB253 and MSAD320162, and MsMYB253 and MSAD308489 were confirmed by a yeast two-hybrid system. This work provides information on the MYB family in alfalfa that was previously lacking and might promote the cultivation of stress-resistant alfalfa.

11.
Sensors (Basel) ; 19(18)2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31500222

RESUMO

The development of new bioelectronic platforms for direct interactions with oral fluid could open up significant opportunities for healthcare monitoring. A tongue depressor is a widely used medical tool that is inserted into the mouth, where it comes into close contact with saliva. Glucose is a typical salivary biomarker. Herein, we report-for the first time-a tongue depressor-based biosensor for the detection of glucose in both phosphate buffer and real human saliva. Carbon nanotubes (CNTs) are attractive electronic materials, with excellent electrochemical properties. The sensor is constructed by printing CNTs and silver/silver chloride (Ag/AgCl) to form three electrodes in an electrochemical cell: Working, reference, and counter electrodes. The enzyme glucose oxidase (GOD) is immobilized on the working electrode. The glucose detection performance of the sensor is excellent, with a detection range of 7.3 µM to 6 mM. The glucose detection time is about 3 min. The discretion between healthy people's and simulated diabetic patients' salivary samples is clear and easy to tell. We anticipate that the biosensor could open up new opportunities for the monitoring of salivary biomarkers and advance healthcare applications.


Assuntos
Técnicas Biossensoriais , Glucose Oxidase/química , Glucose/isolamento & purificação , Nanotubos de Carbono/química , Eletrodos , Enzimas Imobilizadas/química , Glucose/química , Humanos , Peróxido de Hidrogênio/química
12.
EBioMedicine ; 47: 543-552, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31420302

RESUMO

BACKGROUND: Current fMRI-based classification approaches mostly use functional connectivity or spatial maps as input, instead of exploring the dynamic time courses directly, which does not leverage the full temporal information. METHODS: Motivated by the ability of recurrent neural networks (RNN) in capturing dynamic information of time sequences, we propose a multi-scale RNN model, which enables classification between 558 schizophrenia and 542 healthy controls by using time courses of fMRI independent components (ICs) directly. To increase interpretability, we also propose a leave-one-IC-out looping strategy for estimating the top contributing ICs. FINDINGS: Accuracies of 83·2% and 80·2% were obtained respectively for the multi-site pooling and leave-one-site-out transfer classification. Subsequently, dorsal striatum and cerebellum components contribute the top two group-discriminative time courses, which is true even when adopting different brain atlases to extract time series. INTERPRETATION: This is the first attempt to apply a multi-scale RNN model directly on fMRI time courses for classification of mental disorders, and shows the potential for multi-scale RNN-based neuroimaging classifications. FUND: Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, National Institutes of Health Grants, National Science Foundation.

13.
Open Biol ; 9(7): 180227, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31337279

RESUMO

Non-small cell lung cancer (NSCLC) is considered to be the primary cause of cancer-related mortalities worldwide. Paclitaxel (PTX), either as a monotherapy or in combination with other drugs, is an alternative therapy for advanced NSCLC. However, cancer cell resistance against PTX represents a major clinical problem. This study aimed to investigate the role and underlying mechanism of miR-4262 in PTX-resistant NSCLC. The levels of miR-4262 were analysed by quantitative reverse transcription polymerase chain reaction. A luciferase reporter assay and bioinformatics were used to explore the potential target gene of miR-4262. Regulation of miR-4262 and PTEN expressions in NSCLC was conducted by transfection. PTX-resistant A549 and H1299 cells were established by stepwise screening through increasing the PTX concentration in the cultures. In vivo, tumorigenesis experiments were used to explore the effects of miR-4262 and PTX. Cell proliferation, apoptosis and cell migration were detected using a CCK-8 assay, flow cytometry and Transwell migration assay, respectively. PI3 K/Akt pathway-related proteins were detected by western blot. miR-4262 expression was significantly upregulated in NSCLC tissues and cell lines, and miR-4262 targeted PTEN. In addition, miR-4262 induced PTX chemoresistance by promoting survival and migration in A549/PTX and H1299/PTX cells. Moreover, miR-4262 expression and PI3 K/Akt signalling pathway-related proteins were upregulated and PTEN was downregulated in A549/PTX and H1299/PTX. Our results indicate that miR-4262 enhances PTX resistance in NSCLC cells through targeting PTEN and activating the PI3 K/Akt signalling pathway. The inhibition of miR-4262 expression might be an improved treatment to overcome PTX resistance in NSCLC.

14.
Brain Imaging Behav ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278651

RESUMO

Intelligence is a socially and scientifically interesting topic because of its prominence in human behavior, yet there is little clarity on how the neuroimaging and neurobiological correlates of intelligence differ between males and females, with most investigations limited to using either mass-univariate techniques or a single neuroimaging modality. Here we employed connectome-based predictive modeling (CPM) to predict the intelligence quotient (IQ) scores for 166 males and 160 females separately, using resting-state functional connectivity, grey matter cortical thickness or both. The identified multimodal, IQ-predictive imaging features were then compared between genders. CPM showed high out-of-sample prediction accuracy (r > 0.34), and integrating both functional and structural features further improved prediction accuracy by capturing complementary information (r = 0.45). Male IQ demonstrated higher correlations with cortical thickness in the left inferior parietal lobule, and with functional connectivity in left parahippocampus and default mode network, regions previously implicated in spatial cognition and logical thinking. In contrast, female IQ was more correlated with cortical thickness in the right inferior parietal lobule, and with functional connectivity in putamen and cerebellar networks, regions previously implicated in verbal learning and item memory. Results suggest that the intelligence generation of males and females may rely on opposite cerebral lateralized key brain regions and distinct functional networks consistent with their respective superiority in cognitive domains. Promisingly, understanding the neural basis of gender differences underlying intelligence may potentially lead to optimized personal cognitive developmental programs and facilitate advancements in unbiased educational test design.

15.
Clin Chim Acta ; 497: 67-75, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31276634

RESUMO

BACKGROUND: Asymptomatic hypercholanemia of pregnancy (AHP) is a controversial hypercholanemia, which is difficult to distinguish from intrahepatic cholestasis of pregnancy (ICP). Our aim is to elucidate the characteristics of urinary bile acid (BA) profiling of women with AHP and to find potential biomarkers for the diagnosis and differential diagnosis of AHP. METHODS: We developed a pseudo-targeted approach to perform metabolomics analysis of bile acids (BAs) using ultra-high performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Urinary BAs profiles were compared among AHP women (n = 20), ICP patients (n = 33) and normal controls (n = 35). RESULTS: The profiling of urinary BAs was significantly different among the AHP, ICP and control groups. Compared to the control group, the AHP group had higher levels of four possible sulfated BAs and trihydroxy BAs, including the species of muricholic acid (MCA), cholic acid (CA) and six possible BAs, whereas, 20 possible sulfated BAs, taurochenodeoxycholic acid (TCDCA), tetrahydrocannabinolic acid (THCA), and seven possible BAs were significantly lower in the AHP group than those in the ICP group. Based on the receiver operating characteristic (ROC) analysis, glycocholic acid (GCA) combined with T-ω-MCA were found to be the potential combination biomarker for the diagnosis (area under the curve was 0.960) of AHP, and mono-S, Gtri-S-2 combined with TLCA-S were found to be the potential combination biomarker for the differential diagnosis (area under the curve was 0.990) of AHP and ICP. CONCLUSIONS: The metabolisms of urinary Bas were altered in the AHP group compared with the ICP group and the control group. Urinary BA profiling analysis can serve as an effective tool for the diagnosis of AHP and the differential diagnosis of AHP and ICP.

16.
J Alzheimers Dis ; 70(3): 747-756, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256131

RESUMO

BACKGROUND: The Mild Behavioral Impairment Checklist (MBI-C), a screening scale for neuropsychiatric symptom evaluation, facilitates Alzheimer's disease (AD) screening. However, its validity and reliability for use as an AD screening tool have not been determined. OBJECTIVE: To develop an AD screening scale suitable for the Chinese population. METHODS: The MBI-C was translated into Chinese and back-translated with the original author's consent. Forty-six AD patients, attending the Xuanwu hospital memory clinic, and 50 sex- and education-matched controls from the community underwent a full neuropsychological evaluation, including MBI-C assessment. Among them, 15 AD patients were evaluated repeatedly, and eight were evaluated simultaneously by two different clinicians, to assess MBI-C reliability. RESULTS: The MBI-C demonstrated good internal consistency reliability, test-retest reliability, and inter-rater reliability. Its optimal cutoff point was 6/7 for identifying AD dementia, with a sensitivity of 86.96% and specificity of 86.00%, and its detection rate for moderate-severe AD dementia was higher than that of the Neuropsychiatric Inventory Questionnaire (NPI-Q). Pearson's correlation coefficients ranged from 0.702 to 0.831, indicating content validity. Seven factors were extracted during principal component analysis, with a cumulative contribution of 70.55%. Moreover, the Pearson's correlation coefficient was 0.758, indicating its criterion validity. The MBI-C could also distinguish AD dementia severity. MBI-C scores were significantly negatively correlated with MMSE and MoCA scores, and positively correlated with ADL scores. CONCLUSION: This study showed that the Chinese version of MBI-C has high reliability and validity, and could replace the NPI-Q for AD dementia screening in the Chinese population.

17.
Neurobiol Learn Mem ; 164: 107047, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31325495

RESUMO

Reactivation renders consolidated memory labile again, and the ensuing temporary reconsolidation process is highly susceptible to mnemonic modification. Here, we show that memories in such an unstable state could be influenced by sheer behavioral means, bypassing the need for pharmacological intervention. Across several experiments using a "face-location association" paradigm in which participants experienced a "Learning - New-learning - Final-test" procedure, we demonstrate that reactivated memory traces were hampered when the new learning was strategically administered at between 0-min and 20-min delay. Using fMRI, we further advance our theoretical understanding that this lability can be mechanistically explained by the differential activation in the hippocampal-amygdala memory system implicated by the post-activation new-learning whereas the mnemonic intrusion caused by newly learned memories is efficaciously reconciled by the left inferior frontal gyrus.

18.
Cancer Lett ; 460: 65-74, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31233836

RESUMO

Pds5b (precocious dissociation of sisters 5B) is involved in both tumorigenesis and cancer progression; however, the functions and molecular mechanisms of Pds5b in pancreatic cancer (PC) are unknown. Several approaches were conducted to investigate the molecular basis of Pds5b-related PC progression, including transfection, MTT, FACS, western blotting, wound healing assay, transwell chamber invasion assay, and immunohistochemical methods. Pds5b overexpression inhibited cell growth and induced apoptosis, whereas the inhibition of Pds5b promoted growth of PC cells. Moreover, Pds5b overexpression inhibited cell migration and invasion, while the downregulation of Pds5b enhanced cell motility. Furthermore, reduced Pds5b expression was associated with survival in PC patients. Mechanistically, Pds5b positively regulated the expression of Ptch2 to influence the Sonic hedgehog signaling pathway. Consistently, Ptch2 downregulation enhanced cell growth, migration, and invasion, while inhibiting cell apoptosis. Notably, the downregulation of Ptch2 abolished Pds5b-mediated anti-tumor activity in PC cells. Strikingly, Pds5b expression was positively associated with levels of Ptch2 in PC patient samples, suggesting that the Pds5b/Ptch2 axis regulates cell proliferation and invasion in PC cells. Our findings indicate that targeting Pds5b and Ptch2 may represent a novel therapeutic approach for PC.

19.
Anal Bioanal Chem ; 411(21): 5499-5507, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31179529

RESUMO

Anti-Müllerian hormone (AMH) is a biomarker for the assessment of female fertility. The accurate measurement of the concentration of AMH is relevant for the success of assisted reproductive therapies and diagnosis of clinical cases. In this study, we show that cytokines such as fetal liver tyrosine kinase 3 ligand (Flt3L), CC subtype chemokine ligand 20 (CCL20), granulocyte-macrophage colony-stimulating factor (GM-CSF), and ß2-microglobulin (ß2M) significantly enhance the immune response against AMH. Two anti-AMH monoclonal antibodies (mAbs) with high affinity were selected by biolayer interferometry (BLI) technology for application in a fully automated magnetic chemiluminescence immunoassay (CLIA). This robust and rapid assay can efficiently detect AMH in the range of 0.125~20 ng mL-1 with a detection limit of 0.099 ng mL-1. This immunoassay showed high specificity with no cross-reaction with structurally related proteins and some of the other members of the TGF-ß super family, such as inhibin A, activin A, follicle-stimulating hormone, and luteinizing hormone. The average recovery rates of three different batches were 100.19%, 102.72%, and 103.59%, respectively, with coefficients of variation of less than 12%. The developed assay was applied in the detection of AMH in 69 serum samples from randomly selected patients. Our data showed a high correlation with those obtained using commercially available ELISA kits (correlation coefficient, 0.9831). Hence, we suggest that this immunoassay could find application in the development of POCT for the diagnosis of AMH in clinical samples. Graphical abstract.


Assuntos
Hormônio Antimülleriano/metabolismo , Imunoensaio/métodos , Interferometria/métodos , Hormônio Antimülleriano/imunologia , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/imunologia , Calibragem , Citocinas/metabolismo , Feminino , Humanos
20.
Nat Commun ; 10(1): 2655, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201320

RESUMO

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.


Assuntos
Síndromes Epilépticas/patologia , Neurônios GABAérgicos/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/genética , Espasmos Infantis/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Códon sem Sentido , Modelos Animais de Doenças , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/genética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Memantina/farmacologia , Memantina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Proteínas Serina-Treonina Quinases/deficiência , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Resultado do Tratamento
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