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1.
Zhongguo Zhong Yao Za Zhi ; 46(2): 420-425, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33645131

RESUMO

Gastrodiae Rhizoma-Uncariae Ramulus cum Uncis is the most frequently used herbal pair in the treatment of Parkinson's disease(PD). Gastrodin and isorhynchophylline are important components of Gastrodiae Rhizoma-Uncariae Ramulus cum Uncis herb pair with anti-Parkinson mechanism. This study aimed to investigate the effect of gastrodin combined with isorhynchophylline on 1-methyl-4-phenylpyridinium(MPP~+)-induced apoptosis of PC12 cells and their antioxidant mechanism. The leakage of lactate dehydrogenase(LDH) from cells to media was analyzed by spectrophotometry. Apoptotic cells were labeled with Annexin V-fluorescein isothiocyanate(FITC) and propidium iodide(PI) and analyzed by flow cytometry. The cell cycle was analyzed using propidium iodide(PI) staining. Lipid peroxidation(LPO) level was analyzed by spectrophotometry. The mRNA expression of caspase-3 was examined by Real-time RT-PCR. The protein expressions of heme oxygenase 1(HO-1) and NADPH: quinoneoxidore-ductase 1(NQO-1) were determined by Western blot. Gastrodin combined with isorhynchophylline reduced the percentage of Annexin V-positive cells and cell cycle arrest in MPP~+-induced PC12 cells. Gastrodin combined with isorhynchophylline down-regulated the mRNA expression of caspase-3, up-regulated the protein expressions of HO-1 and NQO-1, and reduced LPO content in MPP~+-induced PC12 cells. PD98059, LY294002 or LiCl could partially reverse these changes pretreated with gastrodin combined with isorhynchophylline, suggesting that gastrodin combined with isorhynchophylline inhibited MPP~+-induced apoptosis of PC12 cells and oxidative stress through ERK1/2 and PI3 K/GSK-3ß signal pathways. Our experiments showed that gastrodin combined with isorhynchophylline could down-re-gulate the mRNA expression of caspase-3 and up-regulate the protein expressions of HO-1 and NQO-1, so as to reduce oxidative stress and inhibit apoptosis.

2.
Nutr Metab Cardiovasc Dis ; 31(3): 852-859, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33546947

RESUMO

BACKGROUND AND AIMS: High serum netrin-1 levels decrease the risk of ischemic stroke and are negatively associated with outcomes after ischemic stroke. However, it remains unclear whether the association between netrin-1 and ischemic stroke prognosis is modified by lipid component levels. METHODS AND RESULTS: We measured baseline serum netrin-1 levels in 3065 ischemic stroke patients from China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 3 months after ischemic stroke. Total cholesterol (TC) levels could modify the association between netrin-1 and prognosis of ischemic stroke (Pinteraction = 0.040). After multivariate adjustment, the odds ratios of the primary outcome associated with the highest quartile of netrin-1 were 0.39 (95%CI, 0.17-0.90; Ptrend = 0.004) for the patients with high TC levels and 0.82 (95%CI, 0.61-1.11; Ptrend = 0.149) for those with normal TC levels. Adding netrin-1 to conventional risk factors improved risk prediction for the primary outcome in the patients with high TC levels (net reclassification improvement: 26.8%, P = 0.015; integrated discrimination index: 1.6%, P = 0.028) but not in those with normal TC levels. CONCLUSIONS: Elevated netrin-1 is associated with improved prognosis at 3 months after ischemic stroke in the patients with high TC levels but not in those with normal TC levels. Further prospective studies from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms.

3.
Mol Biol Rep ; 48(2): 1269-1279, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33547532

RESUMO

Auxin is an important endogenous hormone in plants. The YUCCA gene encodes a flavin monooxygenase, which is an important rate-limiting enzyme in the auxin synthesis pathway and involved in the regulation of plant growth and development. In the study, we identified 63 wheat TaYUCCA genes; among them, some genes appeared in clusters. By constructing phylogenetic trees, we found that the TaYUCCA genes could be divided into six groups. In the WheatExp database, there were 22 differential expressed TaYUCCA genes, among which the TaYUCCA10 gene was abundantly expressed in the endosperm and medium milk stage, the TaYUCCA2 gene was abundantly expressed in the roots of three leaves and meiosis and transfer cells at 20 days post anthesis and the others 16 TaYUCCA genes had different expression level at different developmental stages in wheat, and there were 15 TaYUCCA genes induced by drought and heat stress, among which the TaYUCCA2-D, TaYUCCA3-B, and TaYUCCA9-D might be upregulated induced by drought stress, TaYUCCA10.1 might be upregulated induced drought and heat stress, TaYUCCA6-A was upregulated induced both drought and heat stress and the others 9 TaYUCCA genes were downregulated induced by drought and heat stress. Transcriptome and qRT-PCR analysis showed that TaYUCCA7-A was upregulated significantly after induced by powdery mildew. The comprehensive annotation and expression profiling of the TaYUCCA genes in this study enhanced our understanding of TaYUCCA family gene expression in wheat growth and development and laid the foundation for the further study of TaYUCCA gene mechanism.

4.
Stroke ; 52(3): 868-877, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33517703

RESUMO

BACKGROUND AND PURPOSE: Complement C3 has been implicated in inflammation and ischemia/reperfusion injury, but its impact on the prognosis of ischemic stroke remains unclear. Aim of this study was to prospectively investigate the association between serum complement C3 and adverse clinical outcomes after ischemic stroke. METHODS: We measured serum complement C3 levels for 3474 patients with ischemic stroke in 26 participating hospitals and collected data of clinical outcomes at 3 months after ischemic stroke. The primary outcome was composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset and secondary outcomes included major disability, death, and vascular events. RESULTS: During 3 months of follow-up, 866 participants (25.4%) developed primary outcome. After multivariate adjustment, elevated serum complement C3 levels were associated with increased risk of primary outcome (odds ratio, 1.30 [95% CI, 1.02-1.65]; Ptrend=0.038) when 2 extreme tertiles were compared. Each SD increase of log-transformed complement C3 was associated with 13% (95% CI, 2%-25%) increased risk of primary outcome. Multivariable-adjusted spline regression model showed a linear relationship between serum complement C3 and the risk of primary outcome (Plinearity=0.022). Addition of serum complement C3 to conventional risk factors significantly improved the risk prediction of primary outcome (net reclassification index: 8.87%, P=0.028; integrated discrimination index: 0.19%, P=0.029). CONCLUSIONS: High serum complement C3 levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that serum complement C3 may be a valuable prognostic biomarker for ischemic stroke.

5.
J Tradit Chin Med ; 41(1): 167-180, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33522210

RESUMO

OBJECTIVE: To investigate the targets and mechanisms of action of Qingkailing injection (,QKL) in the treatment of cholestatic hepatitis. METHODS: A network pharmacology method was implemented using drug and disease databases to target QKL and cholestasis hepatitis, respectively. The functional protein association network STRING database was used to construct a protein-protein interaction network using R language and the Bioconductor toolkit. The org.Hs.eg.db and clusterProfiler packages were used for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, which explored biological functions and pathways of potential targets. Targets were then visualized using Cytoscape 3.6.0 software. RESULTS: We screened 121 compounds in QKL and identified 112 targets for the treatment of cholestatic hepatitis. QKL played a role in the treatment of cholestatic hepatitis through 305 biology process terms, 15 cellular component and 29 molecular function terms. The mechanism of QKL action was mainly related to tumor necrosis factor, mitogen-activated protein kinase, and PI3K-Akt signaling pathways. CONCLUSION: The treatment of cholestatic hepatitis by QKL involved multiple targets, biological functions, and signaling pathways that are closely associated with the disease.

6.
Lasers Med Sci ; 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33389306

RESUMO

This study is to determine the role of the fractional CO2 laser in topical drug delivery and the impact of local immune responses. Experimental rabbit nails were treated with fractionated CO2 laser at varied fluencies of 20 mJ, 25 mJ, and 30 mJ and half of which were coated with rhodamine B (RhB). Histological examination was performed by hematoxylin and eosin staining; the penetration of RhB was assessed by the use of confocal laser scanning microscopy; and the expressions of IFN-γ and IL-4 mRNA in situ were detected by means of qPCR at 12 h, 24 h, 3 days, and 7 days post-laser irritation. The fractional CO2 laser could generate microscopic treatment zones in nail plates, and the depths of these micropores as well as the permeation of RhB in nails increased significantly in an energy-dependent manner. Importantly, the laser irritation led an upregulation of local IFN-γ mRNA expression accompanied by a downregulation of IL-4 mRNA expression. The ultrapulsed ablative fractionated CO2 laser may assist topical drug delivery, and may drive stronger local Th1 responses due to an imbalance of IFN-γ/IL-4 expressions, suggesting that the combination of ablative fractionated CO2 laser with topical agents would be an effective option for the treatment of onychomycosis.

7.
J Asian Nat Prod Res ; : 1-8, 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33502251

RESUMO

A pair of new enantiomeric trinorsesquiterpenes, (+)-genpenterpene A (1a) and (-)-genpenterpene A (1b), together with seven known compounds (2-8), were isolated from the aerial parts of Justicia gendarussa Burm.f.. All of these known compounds were isolated from this plant for the first time. Racemic genpenterpene A was separated by chiral HPLC column. Their chemical structures were elucidated based on extensive spectroscopic analysis, single crystal X-ray diffraction, and ECD calculations. (+)-genpenterpene A (1a) exhibited potent inhibitory effect against nitric oxide production in lipopolysaccharide-activated RAW 264.7 mouse macrophage cells with an IC50 value of 9.54 ± 1.02 µM.

8.
Food Res Int ; 139: 109907, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33509475

RESUMO

Sesame is an oil crop with high nutritional value. Protein is one of the main ingredients of sesame, however research on protein of cold-pressed sesame cake is limited. This study aimed to investigate the effects of ultrasonic pre-treatment (UPT) on physicochemical properties of proteins (yield, solubility, amino acid composition, surface properties, structural and thermal stability) extracted from the cold-pressed sesame cake, after removing lignans by ultrasonic-assisted extraction. By comparison, the extraction yield of protein was significantly (p < 0.05) increased from 22.24% (without UPT) to 25.95% (with UPT), while the purity (54.08% without UPT, 55.43% with UPT), total amount of essential amino acids (22.48% without UPT, 23.10% with UPT) and non-essential amino acids (37.48% without UPT, 36.54% with UPT) were not significantly influenced. Besides, UPT slightly reduced the solubility, foaming capacity and stability (FC and FS) of protein. In addition, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR) and thermal stability (TG) analysis demonstrated that UPT could disorder and loose protein molecular structure, resulting in the change of morphology, secondary structure and thermal stability. In conclusion, this study provides a way for the separation and future application of sesame cake protein. UPT is a good option to remove the lignans from sesame cake proteins.

9.
Nutr Metab Cardiovasc Dis ; 31(1): 209-215, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33342644

RESUMO

BACKGROUND AND AIMS: Whether the prognostic value of matrix metalloproteinase-9 (MMP-9) is modified by patients' dyslipidemia status is unknown. The aim of present study was to evaluate the prognostic effect of MMP-9 among ischemic stroke patients stratified by dyslipidemia status. METHODS AND RESULTS: MMP-9 levels were measured for 2977 acute ischemic stroke patients from 26 participating hospitals across China, and data of clinical outcomes within one year after ischemic stroke was collected. The primary outcome was a composite outcome of major disability and death at one year after stroke onset, and secondary outcomes were major disability, death, vascular events and recurrent stroke. The association between MMP-9 and primary outcome was appreciably modified by dyslipidemia status (Pinteraction = 0.048). After multivariate adjustment, increased MMP-9 level was associated with increased risk of primary outcome at one year after ischemic stroke in the patients with dyslipidemia (odds ratio, 1.34; 95% confidence interval, 1.06-1.79), but not in those without dyslipidemia (odds ratio, 1.23; 95% confidence interval, 0.90-1.68). Increased MMP-9 was also significantly associated with major disability, death and vascular events in the patients with dyslipidemia but not in those without dyslipidemia (P for interaction < 0.05 for all). CONCLUSION: Increased MMP-9 was associated with poor prognosis within one-year after stroke only in patients with dyslipidemia, suggesting that the prognostic value of MMP-9 be modified by dyslipidemia status of ischemic stroke patients. Further prospective study from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms.

10.
Biomaterials ; 268: 120564, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33296794

RESUMO

Glioma stem cells (GSCs), as a subpopulation of stem cell-like cells, have been proposed to play a crucial role in the progression of drug-resistance in glioblastoma (GBM). Therefore, the targeted eradication of GSCs can serve as a promising therapeutic strategy for the reversal of drug-resistance in GBM. Herein, the effects of silencing c-Myc and m-TOR on primary GBM cells extracted from patients were investigated. Results confirmed that dual inhibition treatment significantly (p < 0.05) and synergistically suppressed GSCs, and consequently reversed TMZ-resistance when compared with the single treatment group. Subsequently, to facilitate effective crossing of the BBB, a biological camouflaged cascade brain-targeting nanosystem (PMRT) was created. The PMRT significantly inhibited tumor growth and extended the lifespan of orthotopic transplantation TMZ-resistant GBM-grafted mice. Our data demonstrated that PMRT could precisely facilitate drug release at the tumor site across the BBB. Simultaneously, c-Myc and m-TOR could serve as synergistic targets to eradicate the GSCs and reverse GBM resistance to TMZ.

11.
J Cell Mol Med ; 2020 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-33280245

RESUMO

YKL-40 was reported to be associated with the risk of hypertension. Whether the variants of CHI3L1 gene were associated with both YKL-40 levels and hypertension needs to be further elucidated. In a 1:1 matched case-control study of 507 pairs with available YKL-40 levels and DNA samples nested in a prospective cohort of Chinese subjects, the 15 tag single nucleotide polymorphisms (SNPs) of CHI3L1 gene were genotyped. The levels of YKL-40 among different genotypes of each SNP were compared after false discovery rate adjustment. Multivariable conditional logistic regression analyses were used to explore the association between the genotypes and the risk of hypertension. Subjects with the genetic variants for rs10399931, rs1538372, rs2071580, rs2297839 and rs4950928 had lower YKL-40 levels. The genetic variant for rs10399805 was associated with higher YKL-40 level. Subjects with the genotype of GA/AA of rs10399805 had a 1.34-fold risk of hypertension compared with those with GG genotype in the total population (P = .05). Subjects with heterozygote/rare homozygote genotype of rs4950928 and rs2297839 both had a significantly lower risk of hypertension compared with those with major homozygote genotype among men. The ORs (95% CIs) were 0.46 (0.23-0.89) and 0.49 (0.26-0.91), respectively. The above three SNPs could significantly improve the accuracy of risk prediction for hypertension based on the conventional factors. The genotypes of rs10399805, rs4950928 and rs2297839 may hopefully become stable biomarkers for predicting the risk of hypertension.

12.
Transl Neurodegener ; 9(1): 44, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33280613

RESUMO

Deficits in synaptic transmission and plasticity are thought to contribute to the pathophysiology of Alzheimer's disease (AD) and Parkinson's disease (PD). Several brain stimulation techniques are currently available to assess or modulate human neuroplasticity, which could offer clinically useful interventions as well as quantitative diagnostic and prognostic biomarkers. In this review, we discuss several brain stimulation techniques, with a special emphasis on transcranial magnetic stimulation and deep brain stimulation (DBS), and review the results of clinical studies that applied these techniques to examine or modulate impaired neuroplasticity at the local and network levels in patients with AD or PD. The impaired neuroplasticity can be detected in patients at the earlier and later stages of both neurodegenerative diseases. However, current brain stimulation techniques, with a notable exception of DBS for PD treatment, cannot serve as adequate clinical tools to assist in the diagnosis, treatment, or prognosis of individual patients with AD or PD. Targeting the impaired neuroplasticity with improved brain stimulation techniques could offer a powerful novel approach for the treatment of AD and PD.

13.
Anal Chem ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33263984

RESUMO

Top-down proteomics (TDP) aims to delineate proteomes in a proteoform-specific manner, which is vital for accurately understanding protein function in cellular processes. It requires high-capacity separation of proteoforms before mass spectrometry (MS) and tandem MS (MS/MS). Capillary isoelectric focusing (cIEF)-MS has been recognized as a useful tool for TDP in the 1990s because cIEF is capable of high-resolution separation of proteoforms. Previous cIEF-MS studies concentrated on measuring the protein's mass without MS/MS, impeding the confident proteoform identification in complex samples and the accurate localization of post-translational modifications on proteoforms. Herein, for the first time, we present automated cIEF-MS/MS-based TDP for large-scale delineation of proteoforms in complex proteomes. Single-shot cIEF-MS/MS identified 711 proteoforms from an Escherichia coli (E. coli) proteome consuming only nanograms of proteins. Coupling two-dimensional size-exclusion chromatography (SEC)-cIEF to ESI-MS/MS enabled the identification of nearly 2000 proteoforms from the E. coli proteome. Label-free quantitative TDP of zebrafish male and female brains using SEC-cIEF-MS/MS quantified thousands of proteoforms and revealed sex-dependent proteoform profiles in brains. Particularly, we discovered several proteolytic proteoforms of pro-opiomelanocortin and prodynorphin with significantly higher abundance in male zebrafish brains as potential endogenous hormone proteoforms. Multilevel quantitative proteomics (TDP and bottom-up proteomics) of the brains revealed that the majority of proteoforms having statistically significant difference in abundance between genders showed no abundance difference at the protein group level. This work represents the first multilevel quantitative proteomics study of sexual dimorphism of the brain.

14.
Appl Opt ; 59(35): 11070-11075, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33361933

RESUMO

Different from ordinary planar waveguide structure, we designed a double-metal-cladding waveguide (DMCW) for easier light coupling into the guiding layer from free space. In contrast to evanescent waves in a surface plasmon polariton waveguide, an oscillating wave is generated in the guiding layer. and a similar Fabry-Perot (FP) cavity can be formed by the DMCW. In past work, the FP cavity excited by the DMCW was used to study the refractive index of light, while in this work, the FP cavity is used to excite the photothermal effect of the metal substrate. It is a good connection between light and heat. The photothermal effect is investigated to promote the galvanic replacement reaction in the substrate. Although the experiment process is destructive to the DMCW structure, a surface-enhanced Raman scattering (SERS) chip is prepared on the basis of the photothermal effect in the DMCW. It shows that the DMCW can convert the energy of incident light into thermal energy, and then prepare the SERS chip. The chip has better uniformity, stronger activity, and higher sensitivity. The results demonstrate that the morphology of the SERS substrate created via the DMCW is far more elaborate than that via the surface plasmon polariton waveguide.

15.
Cancer Manag Res ; 12: 11063-11075, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173339

RESUMO

Background: Early detection is essential to improve the survival and life quality of lung cancer (LC) patients. Changes of peripheral blood DNA methylation could be associated with malignancy but were mostly studied in Caucasians. Methods: Here, in a Chinese population, we performed mass spectrometry assays to investigate the association between very early stage LC and methylation levels of RAPSN in the peripheral blood by a case-control cohort using of 221 LC patients (93.2% LC at stage I) and 285 unrelated cancer free control individuals. Results: The odds ratios (ORs) of all CpG sites were evaluated for their risk to LC using inter-quartile analyses by logistic regression. In general, we observed an association between very early LC and decreased methylation of RAPSN_CpG_1.15 and RAPSN_CpG_3.4 (referring to Q4, OR range from 1.64 to 1.81, p<0.05). Stratified by gender, while hypomethylation of RAPSN_CpG_1.15, RAPSN_CpG_3.4 and RAPSN_CpG_7.14 were associated with LC in males (referring to Q4, ORs range from 1.94 to 2.31, p<0.05), RAPSN_CpG_2 and RAPSN_CpG_5 showed significantly lower methylation in female LC patients comparing to controls (referring to Q4, ORs range from 2.49 to 3.60, p<0.05). The risk of RAPSN hypomethylation to LC was enhanced by aging, and typically for people older than 55 years (referring to Q4, ORs range from 2.17 to 3.61 in six out of all 10 analyzed CpG groups, p<0.05). Conclusion: Our study reveals an association between RAPSN hypomethylation in peripheral blood and LC and suggests the occurrence of altered blood-based methylation at the early stage of cancer.

16.
Am J Transl Res ; 12(10): 6954-6964, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194085

RESUMO

BACKGROUND: To delineate the clinical characteristics associated with long-term viral shedding (>21 days) in patients with coronavirus disease 2019 (COVID-19). METHODS: In this retrospective study, factors associated with long-term (>21 days) severe acute respiratory coronavirus 2 (SARS-CoV-2) RNA shedding were evaluated in a conhort of 609 patients from two hospitals in Wuhan. RESULTS: The median duration of SARS-CoV-2 viral shedding was 19 days (interquartile range, 10-28 days) among all patients. There were 42% of patients having prolonged viral shedding time (>21 days), in which the longest viral shedding time was 58 days. When comparing patients with early (≤21 days) and late viral RNA clearance (>21 days), prolonged viral shedding was associated with age <65 (P=0.015), female sex (P=0.028), cough (P=0.025), fatigue (P=0.035), sore throat (P=0.013), aspartate aminotransferase (P=0.038), procalcitonin (P=0.010), albumin (P=0.003), D-dimer (P=0.011), lung involvement (P=0.014), reticular shadow (P<0.001) and lung consolidation (P=0.004). Age range (<65 years) (odds ratio [OR], 1.46 [95% CI, 1.05-2.03]) and female sex (odds ratio [OR], 1.40 [95% CI, 1.00-1.94]) were independent risk factors. CONCLUSIONS: Long-term viral shedding (>21 days) is not a rare phenomenon among COVID-19 infectious patients. Age range (<65) and female sex are independent risk factors for long-term viral shedding. Early antiviral treatment should be considered for COVID-19 patients with such risk factors. Further study should be conducted to know the infectivity of patients with long-term viral shedding in order to develop reasonable control measures.

17.
Cell Rep ; 33(6): 108369, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33176141

RESUMO

Nerve injury in somatosensory pathways may lead to neuropathic pain, which affects the life quality of ∼8% of people. Long-term enhancement of excitatory synaptic transmission along somatosensory pathways contributes to neuropathic pain. Caspase 3 (Casp3) plays a non-apoptotic role in the hippocampus and regulates internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. Whether Casp3-AMPAR interaction is involved in the maintenance of peripheral hypersensitivity after nerve injury remained unknown. Here, we show that nerve injury suppresses long-term depression (LTD) and downregulates Casp3 in the anterior cingulate cortex (ACC). Interfering with interactions between Casp3 and AMPAR subunits or reducing Casp3 activity in the ACC suppresses LTD induction and causes peripheral hypersensitivity. Overexpression of Casp3 restores LTD and reduces peripheral hypersensitivity after nerve injury. We reveal how Casp3 is involved in the maintenance of peripheral hypersensitivity. Our findings suggest that restoration of LTD via Casp3 provides a therapeutic strategy for neuropathic pain management.

18.
Carcinogenesis ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33151304

RESUMO

c-Met hyperactivity has been observed in numerous neoplasms. Several researchers have shown that the abnormal activation of c-Met is mainly caused by transcriptional activation. However, the molecular mechanism behind this transcriptional regulation is poorly understood. Here, we suggest that Smad3 negatively regulates the expression and activation of c-Met via a transcriptional mechanism. We explore the molecular mechanisms that underlie Smad3-induced c-Met transcription inhibition. We found in contrast to the high expression of c-Met, Smad3 showed low protein and mRNA levels. Smad3 and c-Met expression was inconsistent between lung cancer tissues and cell lines. We also found that Smad3 overexpression suppresses whereas Smad3 knockdown significantly promotes EMT and production of the angiogenic factors VEGF, CTGF and COX-2 through the ERK1/2 pathway. In addition, Smad3 overexpression decreases whereas Smad3 knockdown significantly increases protein and mRNA levels of invasion related ß-catenin and FAK through the PI3K/Akt pathway. Furthermore, using the ChIP analysis method, we demonstrate that a transcriptional regulatory complex consisting of HDAC1, Smad3 and mSin3A binds to the promoter of the c-Met gene. By either silencing endogenous mSin3A expression with siRNA or by pretreating cells with a specific HDAC1 inhibitor (MS-275), Smad3-induced transcriptional suppression of c-Met could be effectively attenuated. These results demonstrate that Smad3-induced inhibition of c-Met transcription depends on of a functional transcriptional regulatory complex that includes Smad3, mSin3A and HDAC1 at the c-Met promoter. Collectively, our findings reveal a new regulatory mechanism of c-Met signaling, and suggest a potential molecular target for the development of anticancer drugs.

19.
Sci Rep ; 10(1): 19106, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154423

RESUMO

Deep learning analysis of images and text unfolds new horizons in medicine. However, analysis of transcriptomic data, the cause of biological and pathological changes, is hampered by structural complexity distinctive from images and text. Here we conduct unsupervised training on more than 20,000 human normal and tumor transcriptomic data and show that the resulting Deep-Autoencoder, DeepT2Vec, has successfully extracted informative features and embedded transcriptomes into 30-dimensional Transcriptomic Feature Vectors (TFVs). We demonstrate that the TFVs could recapitulate expression patterns and be used to track tissue origins. Trained on these extracted features only, a supervised classifier, DeepC, can effectively distinguish tumors from normal samples with an accuracy of 90% for Pan-Cancer and reach an average 94% for specific cancers. Training on a connected network, the accuracy is further increased to 96% for Pan-Cancer. Together, our study shows that deep learning with autoencoder is suitable for transcriptomic analysis, and DeepT2Vec could be successfully applied to distinguish cancers, normal tissues, and other potential traits with limited samples.

20.
Circ J ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33208593

RESUMO

BACKGROUND: This study explored the value of cystatin C (CysC) in predicting stroke recurrence in patients with acute ischemic stroke.Methods and Results:This was a post hoc analysis of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) on 3,474 acute ischemic stroke patients with documented serum CysC and high-sensitivity C-reactive protein (hsCRP) concentrations. Study outcomes included stroke recurrence and combined vascular events within 2 years after stroke. In stroke patients with higher (i.e., ≥4.8ng/mL), but not lower, hsCRP concentrations, a higher CysC concentration (i.e., ≥0.78 mg/L) was associated with a 2.48-fold increase in the risk of recurrent stroke (95% confidence interval [CI] 1.37-4.51; P=0.003) and a 2.04-fold increase in the risk of vascular events (95% CI 1.27-3.28; P=0.003). Serum hsCRP concentrations significantly modified the association of serum CysC with recurrent stroke (Pinteraction=0.001) and vascular events (Pinteraction=0.007). Moreover, CysC may improve reclassification of stroke recurrence (net reclassification improvement [NRI] 42.9%, P=0.001; integrated discrimination improvement [IDI] 1.2%, P=0.001) and vascular events (NRI 35.8%, P=0.001; IDI 1.1%, P=0.004). CONCLUSIONS: In ischemic stroke patients with high hsCRP concentrations, higher CysC concentrations increased the risk of stroke recurrence and vascular events. This indicates that the predictive value of CysC on stroke recurrence may depend on the inflammation status of patients.

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