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1.
J Exp Med ; 218(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33045063

RESUMO

KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33201813

RESUMO

Existing RGB-D salient object detection methods treat depth information as an independent component to complement RGB and widely follow the bistream parallel network architecture. To selectively fuse the CNN features extracted from both RGB and depth as a final result, the state-of-the-art (SOTA) bistream networks usually consist of two independent subbranches: one subbranch is used for RGB saliency, and the other aims for depth saliency. However, depth saliency is persistently inferior to the RGB saliency because the RGB component is intrinsically more informative than the depth component. The bistream architecture easily biases its subsequent fusion procedure to the RGB subbranch, leading to a performance bottleneck. In this paper, we propose a novel data-level recombination strategy to fuse RGB with D (depth) before deep feature extraction, where we cyclically convert the original 4-dimensional RGB-D into DGB, RDB and RGD. Then, a newly lightweight designed triple-stream network is applied over these novel formulated data to achieve an optimal channel-wise complementary fusion status between the RGB and D, achieving a new SOTA performance.

3.
Int J Cancer ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33197272

RESUMO

Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1,197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41 to 2.31]) and Cirrus (1.72 [1.38 to 2.14]); Cirrus (1.49 [1.32 to 1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27 to 1.68]), respectively. The AUCs were: 0.73 [0.68 to 0.77], 0.63 [0.60 to 0.66], and 0.72 [0.69 to 0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P<10-12 ), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening.

4.
Stem Cell Res ; 49: 102058, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33189042

RESUMO

Severe mycological epilepsy of infancy is a catastrophic disease with preferential dysfunction of interneurons, frequentepisoderate, cognitive and sudden death. The disease is mainly caused by heterozygous loss-of-function mutation of SCN1A gene encoding α subunit of the sodium channel Nav1.1. To generate mutations in normal iPSC, Transcription activator-like effector nucleases was used to introduce the epilepsy-causing mutation A5768G into the endogenous locus of SCN1A gene. The gene editing induced pluripotent stem cell line and normal iPSC were obtained from the same donor to eliminate significantly the genetic background noise.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33181061

RESUMO

Background: Anastomotic leak (AL) rates gradually decreased with surgical skills and perioperative management progression, but it is still inevitable. As the traditional management of AL after the pull-through procedure of Hirschsprung's disease (HD), enterostomy could lead to multiple surgeries, repeated hospitalizations, increased costs, and enterostomy-associated complications. This study aimed to explore the safety and feasibility of resuturing without enterostomy treating early AL after the laparoscopic Soave procedure. Methods: From October 2014 to June 2019, 10 patients who had AL after the laparoscopic Soave procedure were included. Six patients underwent simply resuturing with presacral drainage; the reoperation time was 1-5 days after primary surgery. Four patients who had diffused peritonitis or severe inflammations received resuturing with an ileostomy, and the reoperation time was 6-11 days. Results: Common early symptoms of AL included persistent fever, sacrococcygeal pain, and abdominal pain. The median delay to reoperation was 1.0 (0-2.25) day. Five patients had leaks at the 3-6 o'clock position, two had leaks at the 6-9 o'clock, and the other three had leaks at the 6 o'clock. The median postoperative fever durations were similar in patients without or with an ileostomy, and the median length of intensive care unit (ICU) stays, duration of antibiotic use, and postoperative length of stay were significantly longer in patients with ileostomy. The mean follow-up time was 38.5 ± 16.7 months (15-69 m). As of the time of writing, no reoccurrence was identified. Conclusion: For patients without diffuse peritonitis, severe inflammations, early diagnosis and timely resuturing of AL within 5 days after the laparoscopic Soave procedure of HD could be a safe, effective, and pleasing treatment.

6.
Nanotechnology ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33181499

RESUMO

CuInSe2 quantum dots (QDs) is one of the most important Cd-free fluorescent probes, which usually exhibited low fluorescence intensity, suggesting considerable amount of absorbed photon energy was lost as heat. In this study, we aimed to improve the fluorescence intensity of CuInSe2 QDs and investigate their photoacoustic (PA) signal that resulted from the heat dissipation. Cu-In-Zn-Se/ZnSe QDs was synthesized by adopting two strategies of Zn doping and ZnSe shell growth. It was found that there was an upper limit for Zn concentration beyond which the fluorescence intensity began to decrease. In addition, blue shift of emission peak of Cu-In-Zn-Se/ZnSe QDs was also observed at high concentration of ZnSe precursor due to the diffusion of excessive Zn. To prepare the dual-modal fluorescence and PA imaging probe, poly(maleic anhydride-alt-1-octadecene) (PMAO) modified with PEG was coated on the QDs, which led to a slight fluorescence reduction. Cellular labeling on HeLa cells was performed to demonstrate utility of these probes for fluorescence imaging. We further measured the in vitro PA imaging capabilities of the Cu-In-Zn-Se/ZnSe/PMAO-g-PEG nanoparticles, which showed distinct PA signal beyond 1.0 mg/mL. The in vitro PA imaging demonstrated that in addition to an effective fluorescence probe, the Cu-In-Zn-Se/ZnSe/PMAO-g-PEG nanoparticle was also a potential PA imaging contrast agent.

7.
Microbiome ; 8(1): 156, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176883

RESUMO

BACKGROUND: The human microbiota are complex systems with important roles in our physiological activities and diseases. Sequencing the microbial genomes in the microbiota can help in our interpretation of their activities. The vast majority of the microbes in the microbiota cannot be isolated for individual sequencing. Current metagenomics practices use short-read sequencing to simultaneously sequence a mixture of microbial genomes. However, these results are in ambiguity during genome assembly, leading to unsatisfactory microbial genome completeness and contig continuity. Linked-read sequencing is able to remove some of these ambiguities by attaching the same barcode to the reads from a long DNA fragment (10-100 kb), thus improving metagenome assembly. However, it is not clear how the choices for several parameters in the use of linked-read sequencing affect the assembly quality. RESULTS: We first examined the effects of read depth (C) on metagenome assembly from linked-reads in simulated data and a mock community. The results showed that C positively correlated with the length of assembled sequences but had little effect on their qualities. The latter observation was corroborated by tests using real data from the human gut microbiome, where C demonstrated minor impact on the sequence quality as well as on the proportion of bins annotated as draft genomes. On the other hand, metagenome assembly quality was susceptible to read depth per fragment (CR) and DNA fragment physical depth (CF). For the same C, deeper CR resulted in more draft genomes while deeper CF improved the quality of the draft genomes. We also found that average fragment length (µFL) had marginal effect on assemblies, while fragments per partition (NF/P) impacted the off-target reads involved in local assembly, namely, lower NF/P values would lead to better assemblies by reducing the ambiguities of the off-target reads. In general, the use of linked-reads improved the assembly for contig N50 when compared to Illumina short-reads, but not when compared to PacBio CCS (circular consensus sequencing) long-reads. CONCLUSIONS: We investigated the influence of linked-read sequencing parameters on metagenome assembly comprehensively. While the quality of genome assembly from linked-reads cannot rival that from PacBio CCS long-reads, the case for using linked-read sequencing remains persuasive due to its low cost and high base-quality. Our study revealed that the probable best practice in using linked-reads for metagenome assembly was to merge the linked-reads from multiple libraries, where each had sufficient CR but a smaller amount of input DNA. Video Abstract.

8.
Genomics ; 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33144217

RESUMO

DIRIGENT (DIR) genes play important roles in regulating plant growth and development and have been studied in many plant species. However, information on DIR genes in soybean is limited. Here, we identified and characterized 54 GmDIRs and studied the characteristics of GmDIRs. Most of the GmDIRs contained a classical gene structure, one exon; 26 conserved motifs were found among these GmDIRs. The GmDIRs were grouped into four subfamilies, DIR-a, DIR-b, DIR-e and DIR-f, based on a phylogenetic analysis, and 24 duplicated gene pairs were identified. Differences in the cis-acting elements in the GmDIR promoter regions might result in distinct expression patterns of GmDIRs in different tissues. In addition, GmDIR27 had a close relationship with the pod dehiscence gene GmPdh1, and overexpression of GmDIR27 increased pod dehiscence by affecting several pod dehiscence-related gene expressions. Generally, our results provide essential information that aids future efforts to functionally characterize soybean GmDIR genes.

9.
Acad Radiol ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33162318

RESUMO

RATIONALE AND OBJECTIVE: To investigate the significance of magnetic resonance imaging (MRI)-based radiomics model in differentiating local recurrence of rectal cancer from nonrecurrence lesions at the site of anastomosis. MATERIALS AND METHODS: A total of 80 patients with clinically suspected lesions of anastomosis underwent 3.0T pelvic MRI consisting of T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast-enhanced T1-weighted volume interpolated body examination (VIBE) imaging. Radiomics features were extracted from volumes of interest (VOIs), delineated manually on multiple MRI sequences. Subsequently, principal component analysis reduced the dimensionality of features for T2WI, DWI, VIBE, and combined multisequences, respectively. On this basis, the extreme gradient boosting (XGBoost) classifier was trained to build ModelT2WI, ModelDWI, ModelVIBE, and Modelcombination. Receiver operating characteristic curves were generated to determine the diagnostic performance of various models. RESULTS: Principal component analysis selected eight, four, seven, and six principal components to construct the radiomics model for T2WI, DWI, VIBE, and combined multisequences, respectively. Modelcombination had an area under the receiver operating characteristic curve of 0.864, with sensitivity and specificity of 81.82% and 75.86% in the validation set, demonstrating a more optimal performance compared to other models (p< 0.05). The decision curve analysis confirmed the clinical usefulness of the model. CONCLUSION: This study demonstrated that MRI-based radiomics is a sophisticated and noninvasive tool for accurately distinguishing LR from nonrecurrence lesions at the site of anastomosis. Combining multiple sequences significantly improves its performance.

10.
Mol Neurobiol ; 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33222146

RESUMO

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterised by the selective loss of motor neurons, muscular atrophy, and degeneration. Statins, as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely prescribed drugs to lower cholesterol levels and used for the treatment of cardiovascular and cerebrovascular diseases. However, statins are seldom used in muscular diseases, primarily because of their rare statin-associated myopathy. Recently, statins have been shown to reduce muscular damage and improve its function. Here, we investigated the role of statins in myopathy using G93ASOD1 mice. Our results indicated that simvastatin significantly increased the autophagic flux defect and increased inflammation in the skeletal muscles of G93ASOD1 mice. We also found that increased inflammation correlated with aggravated muscle atrophy and fibrosis. Nevertheless, long-term simvastatin treatment promoted the regeneration of damaged muscle by activating the mammalian target of rapamycin pathway. However, administration of simvastatin did not impede vast muscle degeneration and movement dysfunction resulting from the enhanced progressive impairment of the neuromuscular junction. Together, our findings highlighted that simvastatin exacerbated skeletal muscle atrophy and denervation in spite of promoting myogenesis in damaged muscle, providing new insights into the selective use of statin-induced myopathy in ALS.

11.
J Asian Nat Prod Res ; : 1-8, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225748

RESUMO

A new homo-aro-cholestane glycoside parispolyside H, along with nine known compounds, were isolated from 75% ethanolic extract of the rhizome of Paris polyphylla var. chinensis. Their chemical structures were elucidated on the basic of analysis of detailed spectroscopic and physicochemical properties. In addition, the isolated compounds (1, 6-9) were evaluated for their cytotoxic activity against HepG2 human liver cancer cell lines. Among them, four known compounds (6-9) showed cytotoxicity with IC50 values ranging from 0.41 to 3.6 µM.

12.
Breast ; 54: 235-241, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33166784

RESUMO

Co-expression of human epidermal growth factor receptor-2 (HER2) and hormone receptor (HR) predicted worse prognosis in early breast cancer before trastuzumab was developed. We aimed to investigate whether HER2 positivity was still associated with worse outcome in high-risk estrogen receptor (ER) positive patients treated with trastuzumab and chemotherapy. In the present study, 227 ER+/HER2+ patients treated with trastuzumab and chemotherapy (HER2-pos-T group) and 1097 ER+/HER2-patients treated with chemotherapy alone (HER2-neg group) during 2009 and 2015 were retrospectively enrolled for the comparison of disease-free survival (DFS) and overall survival (OS). At a median follow-up of 59 months, 174 DFS events and 69 deaths were observed. The estimated 5-year DFS rate was 94.2% in the HER2-pos-T group and 87.4% in the HER2-neg group (Log-rank P = 0.014). HER2-pos-T group was associated with significantly better DFS in multivariate analysis (HR 0.38, 95% CI: 0.22-0.67, Log-rank P = 0.001). The estimated 5-year OS rates for the two groups were 97.2% and 95.7%, respectively (Log-rank P = 0.183). In multivariable analysis, patients in the HER2-pos-T group had significantly better OS compared with those in the HER2-neg group (HR 0.40, 95% CI: 0.17-0.95, Log-rank P = 0.037). We concluded that high-risk ER+/HER2+ breast cancer patients treated with chemotherapy and trastuzumab had superior prognosis compared with ER+/HER2-patients. Therefore, HER2 positivity itself may not be considered as an unfavorable factor for ER + patients in the era of trastuzumab.

13.
BMC Genomics ; 21(Suppl 10): 618, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208097

RESUMO

BACKGROUND: Single-cell RNA-sequencing (scRNA-seq) is becoming indispensable in the study of cell-specific transcriptomes. However, in scRNA-seq techniques, only a small fraction of the genes are captured due to "dropout" events. These dropout events require intensive treatment when analyzing scRNA-seq data. For example, imputation tools have been proposed to estimate dropout events and de-noise data. The performance of these imputation tools are often evaluated, or fine-tuned, using various clustering criteria based on ground-truth cell subgroup labels. This limits their effectiveness in the cases where we lack cell subgroup knowledge. We consider an alternative strategy which requires the imputation to follow a "self-consistency" principle; that is, the imputation process is to refine its results until there is no internal inconsistency or dropouts from the data. RESULTS: We propose the use of "self-consistency" as a main criteria in performing imputation. To demonstrate this principle we devised I-Impute, a "self-consistent" method, to impute scRNA-seq data. I-Impute optimizes continuous similarities and dropout probabilities, in iterative refinements until a self-consistent imputation is reached. On the in silico data sets, I-Impute exhibited the highest Pearson correlations for different dropout rates consistently compared with the state-of-art methods SAVER and scImpute. Furthermore, we collected three wetlab datasets, mouse bladder cells dataset, embryonic stem cells dataset, and aortic leukocyte cells dataset, to evaluate the tools. I-Impute exhibited feasible cell subpopulation discovery efficacy on all the three datasets. It achieves the highest clustering accuracy compared with SAVER and scImpute. CONCLUSIONS: A strategy based on "self-consistency", captured through our method, I-Impute, gave imputation results better than the state-of-the-art tools. Source code of I-Impute can be accessed at https://github.com/xikanfeng2/I-Impute .

14.
Korean J Parasitol ; 58(5): 583-587, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33202512

RESUMO

Blastocystis sp. is a kind of protozoa living in the intestinal tract of human and animals, which will cause intestinal diseases such as diarrhea, abdominal distension and vomiting. This paper was aimed to understand the infection of Blastocystis sp. In golden monkeys and the transmission path in North China. Thirty-seven feces samples from golden monkeys and 116 cockroach samples from Shijiazhuang Zoo were collected from July to October 2019 for PCR analysis of Blastocystis sp. Genetic diversity analysis was further conducted on the samples with positive PCR results. The results showed that the infection rate was 48.7% (18/37) in golden monkeys and 82.8% (96/116) in cockroaches, respectively. The genetic evolution analysis based on small subunit ribosomal RNA demonstrated that three subtypes (ST) of Blastocystis sp. including ST1, ST2, and ST3 existed in the intestinal tract of golden monkeys, while only ST2 was detected in the intestinal tract of cockroaches. This paper may provide supports for the quarantine and control of Blastocystis sp. for the zoo in Northern China.

15.
Bioorg Chem ; 104: 104312, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33142424

RESUMO

Approximately 17 compounds were isolated from a 60% EtOH aqueous extract of the roots and rhizomes of Clematis hexapetala Pall., including three new guaianolide sesquiterpenoids with 5/7/5-fused rings and 3S-configuration (1-3), five new prenylated tetra-substituted phenolic glycosides (4-8) with 6/6-fused 9H-benzopyran skeleton (5) and 6/7-fused 7,10-dihydro-benzoxepin skeleton (6-8), one new isoferulyl glucoside (9), two new furofuran lignan diglucosides (10-11), and six known compounds. The chemical structures of the new compounds were elucidated via spectroscopic data and electronic circular dichroism (ECD) analyses in combination with a modified Mosher's method. The possible biosynthetic relationships of prenylated tetra-substituted phenols were postulated. In the in vitro assays, compound 16 exhibited moderate TNF-α secretion inhibitory activity with IC50 value of 3.419 µM. Compounds 14-16 displayed potent PTP1B enzymatic inhibitory activities with inhibition ratios of 48.30-86.00%. And compound 16 showed significant PTP1B enzymatic inhibition with IC50 value of 4.623 µM.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33090958

RESUMO

In this brief, the problem of synchronization control is investigated for a class of fractional-order chaotic systems with unknown dynamics and disturbance. The controller is constructed using neural approximation and disturbance estimation where the system uncertainty is modeled by neural network (NN) and the time-varying disturbance is handled using disturbance observer (DOB). To evaluate the estimation performance quantitatively, the serial-parallel estimation model is constructed based on the compound uncertainty estimation derived from NN and DOB. Then, the prediction error is constructed and employed to design the composite fractional-order updating law. The boundedness of the system signals is analyzed. The simulation results show that the proposed new design scheme can achieve higher synchronization accuracy and better estimation performance.

17.
Chem Soc Rev ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33118560

RESUMO

Chiroptical switches, whose chiral optical signals such as optical rotatory dispersion (ORD), circular dichroism (CD) and circularly polarized luminescence (CPL) are reversibly interchangeable between two states, offer many promising applications in the fields of chiral sensing, optical displays, information storage, asymmetric catalysis and so on. Through various non-covalent interactions, supramolecular chiroptical switches have been constructed by combining the chiral and responsive functional components. This review summarizes the recent progress in the construction of supramolecular chiroptical switchable systems that reversibly respond to various stimuli, such as light, electricity, magnetic fields, mechanical force, solvents, pH, temperature, and chemical additives. The switching of supramolecular chirality in the forms of on/off, amplification/weakening and chirality inversion is shown. Additionally, the design of chiroptical switchable systems for chiral logic gates, data communication, chiral separation and asymmetric catalysis has been demonstrated. Future challenges in developing supramolecular chiroptical switches are also discussed.

18.
Nanoscale ; 12(41): 21440-21446, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33079127

RESUMO

Cerium dioxide (CeO2) nanocatalysts were initially grown in situ on 2D graphitic carbon nitride (g-C3N4) nanosheets to yield the nanocomposites g-C3N4/CeO2 with a spherical structure for the catalysis-based colorimetric analysis of Hg2+ ions in blood and wastewater. As the synergetic introduction of g-C3N4 nanosheets might promote the electron transfer in CeO2, the resulting g-C3N4/CeO2 nanozyme was found to present greatly enhanced catalytic activity, as demonstrated by the steady-state kinetic studies, which is nearly 4-fold higher than that of pure CeO2. Moreover, the g-C3N4/CeO2 nanozymes would aggregate in the presence of Hg2+ ions due to the strong interaction between Hg2+ and the nitrogen of g-C3N4, leading to a decrease of catalysis rationally depending on the Hg2+ ion concentration. A colorimetric analysis strategy is therefore developed for the selective detection of Hg2+ ions separately in the complex samples of blood and wastewater, showing a linear concentration range from 0.50 nM to 800 nM with the LOD of 0.23 nM as exemplified for Hg2+ ions in blood. Also, the recovery tests indicated that the developed colorimetric method can allow for the accurate analysis of Hg2+ ions in wastewater and blood. Such a route for the fabrication of composite nanozymes by growing catalytic nanomaterials on conductive 2D substrates may be extended to the design of other kinds of nanozymes with enhanced catalytic performances for developing catalysis-based detection platforms.

19.
Nat Prod Res ; : 1-8, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33121294

RESUMO

Two new phenylpropanoid glycosidic compounds (a pair of epimers), named pleionosides K (1) and L (2), were isolated from the pseudobulbs of Pleione bulbocodioides (Franch.) Rolfe. Their structures, including absolute configurations, were elucidated by a combination of MS, NMR data, chemical methods and the comparison of experimental and calculated electronic circular dichroism (ECD). Their possible biosynthetic pathway was discussed in the text. Furthermore, the two compounds exhibited moderate hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced HepG2 cell damage in in vitro assays, with cell survival rates of 25.83% and 28.82% at 10 µM, respectively, and antioxidant effect against H2O2-induced toxicity in human SK-N-SH cell, with increasing viability at 10 µM of 24.9% and 34.6%, respectively.

20.
Anesth Analg ; 131(5): 1616-1625, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33079886

RESUMO

BACKGROUND: Anesthesia in pregnant rodents causes neurotoxicity in fetal and offspring rodents. However, the underlying mechanisms and targeted treatments remain largely to be determined. Isoflurane and propofol are among commonly used anesthetics. Thus, we set out to investigate whether propofol can mitigate the isoflurane-induced neurotoxicity in mice. METHODS: Pregnant C57BL/6 mice at gestational day 15 (G15) were randomly assigned to 4 groups: control, isoflurane, propofol, and isoflurane plus propofol. Levels of interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment were measured in the brains of G15 embryos, and levels of postsynaptic density (PSD)-95 and synaptophysin were determined in the hippocampal tissues of postnatal day 31 (P31) offspring using Western blotting and immunohistochemical staining. Learning and memory functions in P31 offspring were determined using a Morris water maze test. RESULTS: Isoflurane anesthesia in pregnant mice at G15 significantly increased brain IL-6 (222.6% ± 36.45% vs 100.5% ± 3.43%, P < .0001) and PARP fragment (384.2% ± 50.87% vs 99.59% ± 3.25%, P < .0001) levels in fetal mice and reduced brain PSD-95 (30.76% ± 2.03% vs 100.8% ± 2.25%, P < .0001) and synaptophysin levels in cornu ammonis (CA) 1 region (57.08% ± 4.90% vs 100.6% ± 2.20%, P < .0001) and dentate gyrus (DG; 56.47% ± 3.76% vs 99.76% ± 1.09%, P < .0001) in P31 offspring. Isoflurane anesthesia also impaired cognitive function in offspring at P31. Propofol significantly mitigated isoflurane-induced increases in brain IL-6 (117.5% ± 10.37% vs 222.6% ± 36.45%, P < .0001) and PARP fragment (205.1% ± 35.99% vs 384.2% ± 50.87%, P < .0001) levels in fetal mice, as well as reductions in PSD-95 (49.79% ± 3.43% vs 30.76% ± 2.03%, P < .0001) and synaptophysin levels in CA1 region (85.57% ± 2.97% vs 57.08% ± 4.90%, P < .0001) and DG (85.05% ± 1.87% vs 56.47% ± 3.76%, P < .0001) in hippocampus of P31 offspring. Finally, propofol attenuated isoflurane-induced cognitive impairment in offspring. CONCLUSIONS: These findings suggest that gestational isoflurane exposure in mice induces neuroinflammation and apoptosis in embryos and causes cognitive impairment in offspring. Propofol can attenuate these isoflurane-induced detrimental effects.

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