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1.
Cell Biol Toxicol ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33950334

RESUMO

Adipogenesis is a multi-step process orchestrated by activation of numerous TFs, whose cooperation and regulatory network remain elusive. Activating transcription factor 4 (ATF4) is critical for adipogenesis, yet its regulatory network is unclarified. Here, we mapped genome-wide ATF4 binding landscape and its regulatory network by Chip-seq and RNA-seq and found ATF4 directly modulated transcription of genes enriching in fat cell differentiation. Motifs of TFs especially CTCF were found from ATF4 binding sites, suggesting a direct role of ATF4 in regulating adipogenesis associated with CTCF and other TFs. Deletion of CTCF attenuated adipogenesis while overexpression enhanced adipocyte differentiation, indicating CTCF is indispensable for adipogenesis. Intriguingly, combined analysis of Chip-seq data of these two TFs showed that ATF4 co-localized with CTCF in the promoters of key adipogenic genes including Cebpd and PPARg and co-regulated their transactivation. Moreover, ATF4 directly regulated CTCF expression and interacted with CTCF in differentiated 3T3-L1 cells. In vivo, downregulation of ATF4 suppressed the expression of CTCF, Cebpd, and PPARg, leading to reduced adipose tissue expansion in refeeding mice. Consistently, mRNA expression of ATF4 and CTCF was positively correlated with each other in human subcutaneous adipose tissue and inversely associated with BMI, indicating a possible involvement of these two TFs in adipose development. Taken together, our data propose for the first time that ATF4 and CTCF work cooperatively to control adipogenesis and adipose development via orchestrating transcription of adipogenic genes. Our findings reveal novel therapeutic targets in obesity treatment.

2.
Clin Transl Med ; 11(4): e379, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33931972

RESUMO

BACKGROUND AND AIMS: 4-phenylbutyric acid (4-PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown. METHODS: 4-PBA was administered alone or in combination with diethylnitrosamine to investigate its long-term effect on liver tumorigenesis. The role of 4-PBA in oncogene-induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co-expressed with hMet and ß-catenin point mutation (S45Y) was also observed. RNA-seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4-PBA on liver and validate the underlying mechanism. RESULTS: 4-PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b-Fzd5 mediating ß-catenin signaling. Peroxisome proliferator-activated receptors (PPAR)-α induced by 4-PBA was responsible for the activation of ß-catenin signaling. Thus, intervention of PPAR-α reversed 4-PBA-induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4-PBA could not only upregulate the expression of PPAR-α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR-α expression predicted poor prognosis in HCC patients. CONCLUSIONS: 4-PBA could upregulate PPAR-α to initiate LCSCs by activating ß-catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor-promoting effect of 4-PBA under HCC-inducing environment.

3.
J Exp Clin Cancer Res ; 40(1): 157, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962657

RESUMO

BACKGROUND: Medullary thyroid cancer (MTC) represents 13.4 % of all thyroid cancers-related deaths. The treatments for MTC are very limited especially for patients with distal metastasis. Therefore, it is critical to understand the mechanisms of MTC to pursue novel therapeutic avenues. Here, we studied the function of circPVT1/miR-455-5p in MTC. METHODS: Human MTC tissues and cell lines were used. qRT-PCR and Western blotting were employed to measure expression levels of miR-455-5p, circPVT1, CXCL12, and epithelial mesenchymal transformation (EMT)-related proteins. Colony formation assay, flow cytometry, transwell assay, and scratch wound healing assay were used to assess the abilities of cell proliferation, apoptosis, migration and invasion, respectively. Dual luciferase assay and RNA immunoprecipitation were employed to validate interactions of circPVT1/miR-455-5p and miR-455-5p/CXCL12. Nude mouse xenograft model was used to evaluate the effects of shcircPVT1 and miR-455-5p mimics on tumor growth and metastasis in vivo. RESULTS: miR-455-5p was reduced in MTC tissues and cells while circPVT1 was elevated. Their levels were correlated with prognosis of MTC. Overexpression of miR-455-5p or sh-circPVT1 suppressed EMT and MTC cell proliferation, migration and invasion. miR-455-5p targeted CXCL12 while circPVT1 sponged miR-455-5p. Knockdown of CXCL12 or CXCL12/CXCR4 signaling inhibitor reversed the effects of circPVT1 overexpression or miR-455-5p inhibitor on EMT and MTC cell proliferation, migration and invasion. Knockdown of circPVT1 or miR-455-5p overexpression repressed MTC tumor growth and lung metastasis in vivo. CONCLUSIONS: miR-455-5p suppresses MTC growth and metastasis by targeting CXCL12/CXCR4 signaling pathway while circPVT1 promotes MTC by sponging miR-455-5p. Our study sheds light on the mechanisms of MTC growth and metastasis.

4.
Orthop Surg ; 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33942537

RESUMO

OBJECTIVE: To clarify the regulatory effect of Calcyclin (S100A6) on chondrocytes apoptosis and its relationship with progression of osteoarthritis in an effort to explore potential therapeutic targets for osteoarthritis. METHOD: Immunofluorescence assay was produced to identify the rat chondrocyte sample and western blots assay was detected the expression changes of S100A6 between control group and osteoarthritis model which induced by interleukin-1ß. Adenovirus were transfected into the chondrocytes in vitro, in order to regulate the S100A6 expression. The influence of S100A6 on inflammatory reaction of osteoarthritis was detected by RT-PCR. Also, Caspase-3 activity assay and TUNEL assay were performed to evaluate the apoptosis changes. In addition, RT-PCR and western blots were performed to verify that S100A6 mediated the PI3K/AKT signaling pathway. Through the usage of pathway regulator, we detected S100A6 produced the effect by mediating the PI3K/AKT pathway. RESULTS: We determined the expression of S100A6 decreased in osteoarthritis model, the relative expression level in osteoarthritis model was about 0.5 fold compared with control group. Through adenovirus transfection we revealed that the inflammatory factors of osteoarthritis (interleukin-6 and matrix metalloproteinase-13) showed a negative correlation with the S100A6 expression. The relative expression level of interleukin-6 and matrix metalloproteinase-13 were 1.534 and 1.259 when S100A6 was up-regulated and the values were up to 2.445 and 2.074, respectively, when S100A6 was down-regulated. Also, the data verified the apoptosis could be reduced when the S100A6 was up-regulated and be activated when the S100A6 was down-regulated, the Caspase-3 activity was 16.512 U/µg and 24.45 U/µg respectively. Similar results were shown in TUNEL assay, the apoptosis index was 4.46% and 31.44%, respectively. Additionally, the results of polymerase chain reaction and western blots both demonstrated that the expression level of PI3K and AKT were increased when S100A6 was up-regulated, conversely the expression level of those two signal modules were reduced if the S100A6 was down-regulated. More importantly, the apoptosis triggered by S100A6 can be offset by the PI3K/AKT pathway inhibitor and activator (LY294002 and IGF-1), the values of Caspase-3 activity and apoptosis index became close to the untreated osteoarthritis group. The experimental results in this study were statistically significant. CONCLUSION: We investigated that Calcyclin (S100A6) relieved the inflammation and mediated the chondrocyte apoptosis through PI3K/AKT pathway and we confirmed that S100A6 might be an attractive therapeutic target.

5.
Int J Mol Med ; 47(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33846765

RESUMO

Bladder cancer (BC) is among the most common urinary system tumors with a high morbidity and mortality worldwide. Despite advancements being made in the diagnosis and treatment of bladder cancer, targeted therapy remains the most promising treatment, and novel therapeutic targets are urgently required in to improve the outcomes of patients with BC. Kinesin family member 4A (KIF4A) is a plus­end directed motor protein involved in the regulation of multiple cellular processes, such as mitosis and axon growth. Notably, KIF4A plays important roles in tumor growth and progression, and its expression is associated with the prognosis of several types of cancer. However, the potential role and molecular mechanisms of KIF4A in bladder cancer development remain unclear. The present study demonstrated that KIF4A was highly expressed in human BC tissues, and its expression was associated with patient clinicopathological characteristics, such as tumor stage (P=0.012) and with the prognosis of patients with BC. It was further found that KIF4A promoted the cell proliferation of bladder cancer both in vitro and in vivo. On the whole, the data presented herein provide evidence that KIF4A promotes the development of BC through the transcriptional activation of the expression of CDCA3. The present study indicates the involvement of KIF4A in the progression of BC and suggests that KIF4A may be a promising therapeutic target for the treatment of BC.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33856760

RESUMO

Transition-metal sulfide is pursued for replacing scare platinum-group metals for oxygen electrocatalysis and is of great importance in developing low-cost, high-performance rechargeable metal-air batteries. We report herein a facile cationic-doping strategy for preparing nickel-doped cobalt sulfide embedded into a mesopore-rich hydrangea-like carbon nanoflower. Nickel cations are introduced to induce the formation of Co3+-active species and more oxygen vacancies due to higher electronegativity and smaller ionic radius, thereby strengthening the intrinsic activity for oxygen electrocatalysis. Moreover, hydrangea-like superstructure composed of interconnected carbon cages provides abundant accessible active sites and hierarchical porosity. As a result, it shows excellent catalytic performance with a superior mass activity for the oxygen reduction reaction to the state-of-the-art Pt/C catalyst and a low overpotential of 314 mV at 10 mA cm-2 for the oxygen evolution reaction. When used as an air cathode for the rechargeable Zn-air battery, it delivers a peak power density of 96.3 mW cm-2 and stably operates over 214 h. This work highlights the importance of cationic doping in strengthening the electrocatalytic performance of 3d-transition-metal chalcogenides.

7.
World J Pediatr ; 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33844176

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging disease. The consequences of SARS-CoV-2 exposure in infants remain unknown. Therefore, this study aims to investigate whether neonates born to mothers with COVID-19 have adverse brain development. METHODS: This multicenter observational study was conducted at two designated maternal and children's hospitals in Hubei Province, mainland China from February 1, 2020 to May 15, 2020. Neonates born to mothers with COVID-19 were enrolled. Brain magnetic resonance imaging (MRI) findings, and volumes of grey and white matters, and physical growth parameters were observed at 44 weeks corrected gestational age. RESULTS: Of 72 neonates born to mothers with COVID-19, 8 (11%) were diagnosed with COVID-19, 8 (11%) were critically ill, and no deaths were reported. Among the eight neonates that underwent brain MRI at corrected gestational age of 44 weeks, five neonates were diagnosed with COVID-19. Among these five neonates, three presented abnormal MRI findings including abnormal signal in white matter and delayed myelination in newborn 2, delayed myelination and brain dysplasia in newborn 3, and abnormal signal in the bilateral periventricular in newborn 5. The other three neonates without COVID-19 presented no significantly changes of brain MRI findings and the volumes of grey matter and white matter compared to those of healthy newborns at the equivalent age (P > 0.05). Physical growth parameters for weight, length, and head circumference at gestational age of 44 weeks were all above the 3rd percentile for all neonates. CONCLUSIONS: Some of the neonates born to mothers with COVID-19 had abnormal brain MRI findings but these neonates did not appear to have poor physical growth. These findings may provide the information on the follow-up schedule on the neonates exposed to SARS-CoV-2, but further study is required to evaluate the association between the abnormal MRI findings and the exposure to SARS-CoV-2.

8.
Plant Signal Behav ; : 1913310, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33853500

RESUMO

Phosphate (Pi) deficiency is one of the major adverse factors limiting plant growth and production. Enhanced RH development is thought to be the typical root morphological response under Pi deficiency, which will enhance the utilization of Pi resources from soil. Here, we report that MYB30-EIN3 module is functionally implicated in Pi deficiency-induced RH development in Arabidopsis. MYB30 and EIN3 antagonistically regulate RH growth via transcriptional regulation of RSL4 as well as other PSR genes, resulting in fine-tuned Pi uptake under Pi deficiency.

9.
Food Chem ; 356: 129678, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33812185

RESUMO

This study investigated the effect of frozen storage periods (0, 2, 4, 6, or 8 weeks) of raw meat and stewing on the flavor of chicken broth. With the increased storage duration of frozen raw material, the contents of the free amino acids, nucleotides and mineral elements in the broth decreased significantly, especially within the first 4 weeks, and then increased significantly. Meanwhile, the volatile compounds showed the reverse trend. The results from the E-nose, E-tongue and sensory evaluation indicated a progressive difference in overall flavor profiles between the samples. The sensory scores of the meaty and fatty traits reached a maximum as raw chicken meat was stored for 4 weeks at -18 °C, which should be related to the increased contents of aldehydes and 2-pentyl furan. Overall, the limited storage duration of frozen raw meat can enhance the flavor of chicken broth.

10.
Nano Lett ; 2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33872030

RESUMO

Fe-N-C with atomically dispersed Fe single atoms is the most promising candidate to replace platinum for the oxygen reduction reaction (ORR) in fuel cells. However, the conventional synthesis procedures require quantities solvents and metal precursors, sluggish adsorption process, and tedious washing, resulting in limited metal doping and uneconomical for large-scale production. For the first time, Fe2O3 is adopted as the Fe precursor to derive abundant single Fe atoms dispersed on carbon surfaces. The Fe-N-C catalyst synthesized by this simple method shows an excellent ORR activity with half-wave potentials of 0.82 and 0.90 V in acidic and alkaline solutions, respectively. A single fuel cell with an optimized Fe-N-C cathode shows a high peak power density of 0.84 W cm-2. The solid-state transformation synthesis method developed in this study may shed light on mass production of single-atom-based catalysts.

11.
Medicine (Baltimore) ; 100(17): e25492, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907098

RESUMO

ABSTRACT: rbBNP has positive cardiac effects in patients with acute decompensated heart failure, but its effects on the systemic venous circulation are not known.A single-center retrospective, self-controlled study was conducted on 14 patients undergone recombinant human brain natriuretic peptide (rhBNP) treatment between January 1, 2015 to December 31, 2018.The cardiac output (CO) significantly increased from 3.75 ±â€Š1.14 L min-1 to 4.24 ±â€Š0.97 L min-1 30 minutes after rbBNP infusion, and to 4.20 ±â€Š1.19 L min-1 3 hours later. The systemic vascular resistance significantly decreased from 18.85 ±â€Š7.66 mm Hg min L-1 to 14.62 ±â€Š6.13 mm Hg min L-1 30 minutes. The resistance to venous return (VR) significantly decreased from 5.93 ±â€Š4.97 mm Hg min L-1 to 4.46 ±â€Š1.53 mmHg min L-1 3 hours later. The mean systemic filling pressure significantly decreased from 32.71 ±â€Š20.00 mm Hg to 28.254 ±â€Š6.09 mm Hg 3 hours later.The role of rhBNP on CO was to reduce the peripheral circulation resistance at 30 minutes after rhBNP infusion and to reduce the resistance to VR at 3 hours later.This trial is registered at ChiCTR: ID ChiCTR1900024562.


Assuntos
Débito Cardíaco/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Modelos Cardiovasculares , Peptídeo Natriurético Encefálico/uso terapêutico , Resistência Vascular/efeitos dos fármacos , Doença Aguda , Idoso , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
12.
Bioorg Chem ; 112: 104845, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33812268

RESUMO

Steroidal alkaloids (1-11), including one new 24-hydroxylated cevanine-type steroidal alkaloid, named yibeinone F (1), were isolated from the bulbs of Fritillaria pallidiflora Schrenk. Their structures were elucidated by analyses of extensive spectroscopic data and comparison of the NMR data with those reported previously, and the structures of compounds 1, 7 and 11 were further confirmed by X-ray single crystal diffraction analyses. The anti-inflammatory effects of all the isolated alkaloids were evaluated in LPS-activated RAW264.7 macrophages. Among them, compounds 9 (stenanzine) and 10 (hapepunine) showed significant inhibitory effects against LPS-induced NO production with IC50 values of 8.04 µM and 20.85 µM, respectively. Furthermore, compound 9 effectively inhibited the release of cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2), and suppressed the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) in LPS-stimulated RAW264.7 cells. Further experiments revealed the underlying mechanism that 9 blocked LPS-induced phosphorylation and degradation of inhibitor-α of nuclear transcription factor κB (IκBα) and c-Jun N-terminal kinase (JNK) in RAW264.7 cells. Taken together, compound 9 may be a valuable candidate for the treatment of inflammatory diseases.

13.
Signal Transduct Target Ther ; 6(1): 155, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859163

RESUMO

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.


Assuntos
/sangue , Descoberta de Drogas , Lipidômica , Proteômica , /metabolismo , Biomarcadores/sangue , Feminino , Humanos , Masculino
14.
Insects ; 12(4)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810421

RESUMO

The sensilla on the antennae and maxillary palps are the most important olfactory organs, via which the insect can perceive the semiochemicals to adjust their host seeking and oviposition behaviors. The oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae), is a major agricultural quarantine pest infesting more than 250 different fruits and vegetables. However, the sensilla involved in olfaction have not been well documented even though a variety of control practices based on chemical communication have already been developed. In this study, the ultrastructure of the sensilla, especially the olfactory sensilla on the antennae and maxillary palps of both males and females, were investigated with field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). Three types of olfactory sensillum types including trichodea, basiconica, and coeloconica, and two non-olfactory sensilla including both chaetica and microtrichia, were observed. Each of these three types of olfactory sensilla on the antennae of B. dorsalis were further classified into two subtypes according to the morphology and number of receptor cells. For the first time, the pores on the sensilla trichodea and basiconica cuticular wall were observed in this species, suggesting they are involved in semiochemical perception. This study provides new information on B. dorsalis olfaction, which can be connected to other molecular, genetic, and behavioral research to construct an integral olfactory system model for this species.

15.
Clin Respir J ; 2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33866688

RESUMO

PURPOSE: To evaluate the feasibility and safety of CT-guided microcoil localization for pulmonary nodules in the scapula-shadowed area before video-assisted thoracic surgery (VATS). MATERIALS AND METHODS: Forty-seven patients (18 males, 19 females; mean age 57.5 years) with 48 pulmonary nodules covered by the scapulae were consecutively enrolled in this study. Successful targeting, localization, and VATS were defined as implantation of microcoil at the target site on CT image obtained immediately after the marking procedure, visualization of nodule location during VATS, and complete resection of the target nodule with adequate margin, respectively. Meanwhile, the procedure-related complication rate was also recorded. RESULTS: The rates of successful targeting and localization were 95.8% (46/48) and 89.6% (43/48), respectively. Of all nodules, 47 were successfully resected with VATS (30 wedge resections; 17 anatomic resections) and 1 nodule was converted to open thoracotomy for diffuse pleural adhesion, thus the successful VATS rate was 97.9% (47/48). With respect to procedure-related complications, only minor complications (including localized pneumothorax and intrapulmonary hemorrhage) were developed and the rate of overall procedure-related complications was 37.5% (18/48), including minor pneumothorax developed in 15 of 48 nodules (31.3%) and intrapulmonary hemorrhage in 6 of 48 nodules (12.5%). CONCLUSIONS: CT-guided microcoil technique is a safe and effective localization method prior to VATS for the nodules in the scapula-shadowed area.

16.
Anal Chim Acta ; 1158: 338420, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33863406

RESUMO

In this work, we developed a novel and facile strategy for the synthesis of a highly active and stable electrocatalyst based on PdCu alloy nanoparticles (PdCu-ANPs) embedded in 3D nitrogen-doped carbon (NC) nanofoam arrays (NFAs), which were assembled on flexible carbon fiber (CF) microelectrode for in situ sensitive electrochemical detection of biomarker H2O2 in cancer cells. Our results showed that NC-NFAs support possessed a unique hierarchically porous architecture by integrating the macrospores in arrays scaffold within mesopores in individual NC nanofoam, which offered exceptionally large surface area for embedding high-density PdCu-ANPs in it as well as facilitated the mass transfer and molecular diffusion during the electrochemical reaction. Taking the advantages of the unique structural merit of NC-NFAs support and excellent electrocatalyitc properties of PdCu-ANPs that embedded in it, the resultant PdCu-ANPs/NC-NFAs modified CF microelectrode exhibited good electrochemical sensing performances towards H2O2 including a wide linear range from 2.0 µM to 3.44 mM, a low detection limit of 500 nM, as well as good reproducibility, stability and anti-interference ability. When used in real-time in situ tracking H2O2 secreted from different types of human colorectal cancer cells, i.e., HCT116, HT29, SW48 and LoVo, it can distinguish the types of cancer cells by measuring the number of extracellular H2O2 molecules released per cell, which demonstrates its great promise in cancer diagnose and management.

17.
J Thromb Haemost ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33825327

RESUMO

BACKGROUND: Pulmonary embolism (PE) is a leading cause of cardiovascular mortality worldwide. Rapid and accurate diagnosis and risk stratification are crucial for timely treatment options, especially in high-risk PE. OBJECTIVES: The study aims to profile the comprehensive changes of plasma proteomes in PE patients and identify the potential biomarkers for both diagnosis and risk stratification. PATIENTS/METHODS: Based on the data-independent acquisition mass spectrometry and antibody array proteomic technology, we screened the plasma samples (13 and 32 proteomes, respectively) in two independent studies consisting of high-risk PE patients, non-high-risk PE patients, and healthy controls. Some significantly differentially expressed proteins were quantified by ELISA in a new study group with 50 PE patients and 26 healthy controls. RESULTS: We identified 207 and 70 differentially expressed proteins in PE and high-risk PE. These proteins were involved in multiple thrombosis-associated biological processes including blood coagulation, inflammation, injury, repair, and chemokine-mediated cellular response. It was verified that five proteins including SAA1, S100A8, TNC, GSN, and HRG had significant change in PE and/or in high-risk PE. The receiver operating characteristic curve analysis based on binary logistic regression showed that the area under the curve (AUC) of SAA1, S100A8, and TNC in PE diagnosis were 0.882, 0.788, and 0.795, and AUC of S100A8 and TNC in high-risk PE diagnosis were 0.773 and 0.720. CONCLUSION: As predictors of inflammation or injury repair, SAA1, S100A8, and TNC are potential plasma biomarkers for the diagnosis and risk stratification of PE.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33893110

RESUMO

Exploring unknown glycosyltransferases (GTs) is important for compound structural glycodiversification during the search for drug candidates. Piericidin glycosides have been reported to have potent bioactivities; however, the GT responsible for piericidin glucosylation remains unknown. Herein, BmmGT1, a macrolide GT with broad substrate selectivity and isolated from Bacillus methylotrophicus B-9987, was found to be able to glucosylate piericidin A1 in vitro Next, the codon-optimized GT gene, sbmGT1, which was designed based on BmmGT1, was heterologously expressed in the piericidin producer Streptomyces youssoufiensis OUC6819. Piericidin glycosides were thus significantly accumulated, leading to the identification of four new glucopiericidins (compounds 3, 4, 6, 7). Furthermore, using BmmGT1 as the probe, GT1507 was identified in the genome of S. youssoufiensis OUC6819 and demonstrated to be associated with piericidin glucosylation; the overexpression of this gene led to the identification of another new piericidin glycoside, N-acetyl glucosamine-piericidin (compound 8). Compounds 4, 7, and 8 displayed cytotoxic selectivity toward A549, A375, HCT-116, and HT-29 solid cancer cell line over THP-1 lymphoma cell line. Moreover, database mining of GT1507 homologs revealed their wide distribution in bacteria, mainly in those belonging to the High GC Gram+ and Firmicutes -clades, thus representing the potential for identification of novel tool enzymes for compound glycodiversification.IMPORTANCENumerous bioactive natural products are appended with sugar moieties, and are often critical for their bioactivities. Glycosyltransferases (GTs) are powerful tools for the glycodiversification of natural products. Although piericidin glycosides display potent bioactivities, the GT involved in glucosylation is unclear. In this study, five new piericidin glycosides (compounds 3, 4, 6, 7, and 8) were generated following the overexpression of GT-coding genes in a piericidin producer. Three of them (compounds 4, 7 and 8) displayed cytotoxic selectivity. Notably, GT1507 was demonstrated to be related to piericidin glucosylation in vivo Furthermore, mining of GT1507 homologs from the GenBank database revealed their wide distribution across numerous bacteria. Our findings would greatly facilitate the exploration of GTs to glycodiversify small molecules in the search of drug candidates.

19.
Radiat Oncol ; 16(1): 79, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882972

RESUMO

BACKGROUND: The optimal dose and fractionation scheme of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) remains unclear due to different tolerated liver volumes and degrees of cirrhosis. In this study, we aimed to verify the dose-survival relationship to optimize dose selection for treatment of HCC. METHODS: This multicenter retrospective study included 602 patients with HCC, treated with SBRT between January 2011 and March 2017. The SBRT dosage was classified into high dose, moderate dose, and low dose levels: SaRT (BED10 ≥ 100 Gy), SbRT (EQD2 > 74 Gy to BED10 < 100 Gy), and ScRT (EQD2 < 74 Gy). Overall survival (OS), progression-free survival (PFS), local control (LC), and intrahepatic control (IC) were evaluated in univariable and multivariable analyses. RESULTS: The median tumor size was 5.6 cm (interquartile range [IQR] 1.1-21.0 cm). The median follow-up time was 50.0 months (IQR 6-100 months). High radiotherapy dose correlated with better outcomes. After classifying into the SaRT, SbRT, and ScRT groups, three notably different curves were obtained for long-term post-SBRT survival and intrahepatic control. On multivariate analysis, higher radiation dose was associated with improved OS, PFS, and intrahepatic control. CONCLUSIONS: If tolerated by normal tissue, we recommend SaRT (BED10 ≥ 100 Gy) as a first-line ablative dose or SbRT (EQD2 ≥ 74 Gy) as a second-line radical dose. Otherwise, ScRT (EQD2 < 74 Gy) is recommended as palliative irradiation.

20.
Atherosclerosis ; 325: 24-29, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33887530

RESUMO

BACKGROUND AND AIMS: Serum calcium abnormality is associated with adverse cardiovascular outcomes, but the effects of serum calcium level on stroke outcomes remain unknown. We aimed to assess the relationship between serum calcium level and 1-year outcomes in patients with acute ischemic stroke and transient ischemic attack. METHODS: We included 9375 stroke patients from the China National Stroke Registry III for analysis. Participants were divided into 4 groups according to albumin corrected-calcium quartiles. Composite end point comprised recurrent stroke, myocardial infarction, other ischemic vascular events, and all-cause mortality. Multivariable Cox or logistic regression was used to evaluate the independent association of albumin corrected-calcium with all-cause mortality, recurrent stroke, composite end point, and poor functional outcome (modified Rankin Scale score ≥3). RESULTS: Compared with the lowest calcium quartile (<2.16 mmol/L), the adjusted hazard ratio (95% CI) of the top quartile (≥2.31 mmol/L) was 1.56 (1.11-2.18) for all-cause mortality, 1.06 (0.87-1.28) for recurrent stroke and 1.08 (0.90-1.01) for composite end point, and the adjusted odds ratio for poor functional outcome was 1.18 (0.96-1.44). The addition of serum calcium to conventional risk factors improved risk prediction of all-cause mortality, leading to a small but significant increase in C-statistics and reclassification with non-significant integrated discrimination improvement (C-statistics, p = 0.02; net reclassification index 11.8%, p = 0.038; integrated discrimination improvement 0.08%, p = 0.42). CONCLUSIONS: High serum calcium levels at baseline were associated with all-cause mortality at 1-year after ischemic stroke, suggesting that serum calcium may be a potential prognostic biomarker and therapeutic target for ischemic stroke.

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