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1.
J Control Release ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32422212

RESUMO

Chemotherapy post cancer surgery has important clinical significance for reducing the chance of recurrent-metastasis. However, postoperative chemotherapy efficacy is hampered by poor targeting capability and dose-limiting toxicity of chemo-drugs. Herein, we report a bio-mimetic platelet membrane-cloaked paclitaxel nanocrystal system (PPNCs), which consists of spherical paclitaxel nanocrystals (PNCs) as a high-dose drug core, polyethylene glycol-conjugated paclitaxel (PEG-PTX) as an amphiphilic molecule to adjust the surface hydrophilicity of PNCs and the shell of platelet membrane that can target surgical coagulation site. The in vitro characterization of PPNCs exhibited uniform particle size distribution, high drug loading, and good stability, which are crucial for effective drug delivery. At cell levels, PPNCs showed greater cellular uptake and higher cytotoxicity in 4T1 breast cancer cells than bare PNCs. In vivo, the nanoparticles could deliver high-dose chemo-drugs and target the coagulation site caused by surgery or vascular disrupting agents, resulting in enhanced anti-tumor efficacy and reduced systemic toxicities. In general, the PPNCs system can be served as a promising and efficient drug delivery system for postoperative chemotherapy.

2.
Biomed Chromatogr ; : e4898, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32428257

RESUMO

A rapid and sensitive method for the quantitative detection of busulfan in children's hemolysis samples by HPLC-MS/MS was established. In this study, the sample preparation procedure involved a one-step protein precipitation with acetonitrile solution, and the HPLC-MS/MS method used Hypersil GOLD C18. The mobile phase consisted of 10mM ammonium acetate solution (containing 0.1% formic acid)-acetonitrile with a flow rate of 0.4mL/min. Multiple reaction monitoring modes was used for quantitative analysis and the ion pairs of busulfan and busulfan-d8 were m/z 263.9→150.9 and 272.0→159.0, respectively. Busulfan had a good linearity in the range of 0.01~10 µg·mL-1 . The intra- and inter-day relative error (RE) was between -7.21% and 8.26%, and the coefficient of variation (CV) was less than 12.64%. The average extraction recovery rate in plasma samples was 99.76%±6.53%, and the matrix in normal plasma and hemolyzed plasma had no significant effect on the detection results. Normal and hemolysis samples could maintain good stability at 4°C, 25°C and -40°C. As a result, this method is particularly suitable for determining busulfan in hemolysis samples from children with HSCT, and this study provides the methodological basis for further research on the pharmacokinetics of busulfan in children with HSCT.

3.
Neurosci Lett ; 730: 135030, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32389612

RESUMO

PURPOSE: We used fractional amplitude of low-frequency fluctuations (fALFF) and gray matter volume (GMV) jointly to explore the mechanism of brain function and structure in unmedicated patients with bipolar disorder (BD). METHODS: Thirty first episode drug-naive patients with and thirty healthy controls (HCs) were recruited in this study; All the subjects underwent Magnetic Resonance Imaging (MRI) scanning and performed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), all the patients with MDD finished the 17-item Hamilton Depression Rating Scale (HAMD17). Data Processing and Analysis for Brain Imaging (DPABI) and SPM8 were used to find potential differences in fALFF and GMV between the two groups. A Pearson correlation model was used to analyze associations of functional and morphometric changes with clinical symptoms and cognitive tests. RESULTS: Compared to healthy controls, the BD group had significantly reduced fALFF values in the lingual gyrus and increased fALFF values in the bilateral superior frontal gyrus and superior frontal gyrus. With regards to VBM, patients with BD showed significant GMV decreases in the bilateral superior temporal gyrus, bilateral superior frontal gyrus, right superior frontal gyrus, right parahippocampal gyrus and precuneus. Additionally, we found an overlap of brain regions focused on the left SFG. Significant negative correlations were observed between abnormal GMV values in the left SFG and vocabulary memory. CONCLUSION: The superior frontal gyrus was the site of the most robust and reliable abnormality, with an overlap of abnormal structural and functional MRI features that play an important role in pathology in BD.

4.
J Affect Disord ; 273: 95-105, 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32421626

RESUMO

OBJECTIVE: It is common for major depressive disorder (MDD) to be accompanied by gastrointestinal (GI) symptoms, which are known to negatively impact the course and severity of the disease. Although previous studies have attempted to explore the neuropathology of MDD, few studies have focused on the pathogenesis of GI symptoms in MDD. In this study, we investigated the changes in regional gray matter volume (GMV) and regional homogeneity (ReHo) present in MDD accompanied by GI symptoms. METHOD: The following images were obtained and analyzed: Structural and functional magnetic resonance images (MRI) of 36 patients with MDD accompanied by GI symptoms (GI symptoms group), 22 patients without GI symptoms (Non-GI symptoms group), and 27 healthy controls (HC. The 24-item Hamilton Depression Rating Scale (HAMD) was administered. A correlation analysis was used to identify the possible associations between altered regional GMV, ReHo symptoms, GI symptoms, and depressive symptoms. RESULTS: The total scores from the HAMD-24 in the GI symptoms group were significantly higher than in the Non-GI symptoms group (P<0.05). Significant differences in both GMV and ReHo were observed among the three groups for the right parahippocampal gyrus, left precentral gyrus, left middle frontal gyrus, right superior frontal gyrus, right middle frontal gyrus, and left inferior orbitofrontal gyrus (AlphaSim correction, P <0.001). The GI symptoms group exhibited significantly decreased GMV and ReHo in the left middle frontal gyrus, precentral gyrus, right superior frontal gyrus, and middle frontal gyrus. Additionally, the GI symptoms group exhibited increased ReHo in the left superior temporal gyrus at a higher level than the non-GI symptoms group. (AlphaSim correction, P <0.001). These altered brain areas were correlated with GI symptoms (P<0.001) but not depressive symptoms (P>0.05). CONCLUSION: Patients with MDD accompanied by GI symptoms have more severe depressive symptoms. The structural and functional changes of the brain may be the pathogenesis for the GI symptoms in patients with MDD.

5.
J Int Med Res ; 48(5): 300060520922684, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32419554

RESUMO

BACKGROUND: Transcorporeal percutaneous endoscopic cervical discectomy (TcPECD) destroys the integrity of the vertebral body. We herein discuss its long-term risks and avoidance measures. Case presentation: A 44-year-old woman underwent TcPECD. Although her upper limb symptoms were relieved after the operation, the bone channel did not heal and the endplate of the segment was altered. She consequently developed chronic neck and shoulder discomfort. CONCLUSION: Careful preoperative planning is needed to avoid non-healing of the bone channel following TcPECD. The diameter of the bony channel should be as small as possible and the channel should be opened at the posterior edge of the upper endplate to avoid collapse.

6.
J Glob Health ; 10(1): 010423, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32426123

RESUMO

Background: To describe and compare the separate and combined prevalence of physical activity, active transportation, physical education, and sedentary behavior among adolescents 12-15 year-olds in low- and middle-income countries (LMICs). Methods: We used the latest data from the Global School-based Student Health Survey (GSHS), which collect data on the physical behaviors of young adolescents in LMICs. The weighted prevalence and 95% confidence intervals of separate, combined and all of the qualifying physical behaviors were calculated. Pooled overall and regional estimates were calculated using a random effects model. Results: In total, 154 559 young adolescents (45.90% boys) aged 12-15 from 54 countries covered in the GSHS were included in our analysis. Only 0.7% (95% confidence interval (CI) = 0.5%-1.0%) of the adolescents, comprising 0.9% (95% CI = 0.6%-1.3%) of the boys and 0.5% (95% CI = 0.3%-0.7%) of the girls, displayed all of the qualifying physical behaviors. The overall prevalence of physical activity, active transportation, physical education, and sedentary behavior was 15.2% (95% CI = 13.7%-16.7%), 39.5% (95% CI = 34.9%-44.0%), 18.8% (95% CI = 16.1%-21.5%), and 34.6% (95% CI = 28.4%-40.7%), respectively. The overall prevalence of high levels of combined physical behaviors was 6.6% (95% CI = 5.4%-7.8%), with lowest in the Eastern Mediterranean region (4.9%, 95% CI = 3.5%-6.2%) and highest in Southeast Asia (8.6%, 95% CI = 4.9%-12.3%). Conclusion: The prevalence of the separate physical behaviors and high levels of the combined physical behaviors was consistently low among young adolescents in LMICs, and that of all qualifying physical behaviors was even lower.

7.
PLoS One ; 15(5): e0233145, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32428041

RESUMO

This paper studied the relationship between personality traits and mental health conditions of medical personnel to provide a basis and reference for the implementation of targeted education on mental health. A self-report inventory, the Symptom Checklist-90 (SCL-90), was used to investigate the mental health status of 548 medical personnel dealing with the new coronavirus pneumonia in eight provinces and cities of China. The overall mean SCL-90 score and mean values of factors (somatization, obsessive-compulsive, anxiety, phobic anxiety, and psychoticism) of the medical personnel were significantly higher than in the norm group (p < 0.05), while their average interpersonal sensitivity score was significantly lower (p < 0.01). In addition, personal factors affecting the mental health status of medical personnel were identified (all p < 0.05). The overall mental health status of medical personnel responding to new coronavirus pneumonia is generally higher than that of the norm group in China. The results of this study should contribute to measures to alleviate the psychological pressures on medical personnel dealing with the new coronavirus epidemic in China.

8.
J Enzyme Inhib Med Chem ; 35(1): 1224-1232, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32420773

RESUMO

Novel antibacterial agents are urgently needed to address the infections caused by multi-drug resistant bacteria. Urinary tract infections are common infectious diseases in clinical. Most of these infections are caused by drug-resistant uropathogenic Escherichia coli. PPK1 is an essential kinase for bacterial motility, biofilm formation, quorum sensing, and virulence factors in the expression of uropathogenic E. coli. In the present study, two small molecules potentially targeting PPK1 were discovered through virtual screening and biological assays. The in vitro and in vivo results suggested that the interaction of these compounds with PPK1 can disrupt biofilm formation of uropathogenic E. coli and reduce invasive ability and resistance to oxidative stress of this strain. Moreover, the compounds exhibit good antibacterial bacterial activity in the mice with urinary tract infection. Taken together, our findings could provide a new chemotype for the development of antibacterials targeting PPK1.

9.
J Diabetes Res ; 2020: 5860417, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32309447

RESUMO

Background: There is no clear consensus on the effect of coculture of islets with mesenchymal stem cells (MSCs) on islet function and viability. Methods: We conducted a meta-analysis of relevant studies to evaluate the effect of coculture of islets with MSCs on the function and viability of islets, both in vitro and in vivo. We searched PubMed, Embase, and Web of Science databases for all relevant studies that compared the effect of coculture of islets with MSCs on the function and viability of islets (language of publication: English; reference period: January 2000-May 2019). Data pertaining to islet function and viability, concentrations of some cytokines, and in vivo experimental outcomes were extracted and compared. Results: Twenty-four articles were included in the meta-analysis. In comparison to islets cultured alone, coculture of islets with MSCs was associated with a significantly higher islet viability [weighted mean difference (WMD), -15.59; -22.34 to -8.83; P < 0.00001], insulin level (WMD, -5.74; -9.29 to -2.19; P = 0.002), insulin secretion index (WMD, -2.45; -3.70 to -1.21; P = 0.0001), and higher concentrations of interleukin-6 (WMD, -1225.66; -2044.47 to -406.86; P = 0.003) and vascular endothelial growth factor (WMD, -1.19; -2.25 to -0.14; P = 0.03). Direct coculture of islets and MSCs significantly increased islet viability (WMD, -19.82; -26.56 to -13.07; P < 0.00001). In the in vivo experiments, coculture of islets with MSCs induced lower fasting blood glucose level (on postoperative days 21 and 28, WMD, 102.60; 27.14 to 178.05; P = 0.008 and WMD, 121.19; 49.56 to 192.82; P = 0.0009) and better glucose tolerance (blood glucose at 30 minutes after intraperitoneal injection of glucose, WMD, 85.92; 5.33 to 166.51; P = 0.04). Conclusion: Coculture of islets with MSCs improves insulin secretory function of islets and enhances islet viability. Direct coculture of two cells significantly increased islet viability. MSC-based strategy may be beneficial for clinical islet transplantation for type 1 diabetes in the future.

10.
Am J Transplant ; 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32277602

RESUMO

This study aimed to determine the mechanism of isogeneic-induced pluripotent stem cells (iPSCs) homing to vascular transplants and their therapeutic effect on chronic allogeneic vasculopathy. We found that integrin ß1 (Intgß1) was the dominant integrin ß unit in iPSCs that mediates the adhesion of circulatory and endothelial cells (ECs). Intgß1 knockout or Intgß1-siRNAs inhibit iPSC adhesion and migration across activated endothelial monolayers. The therapeutic effects of the following were examined: iPSCs, Intgß1-knockout iPSCs, iPSCs transfected with Intgß1-siRNAs or nontargeting siRNAs, iPSC-derived ECs, iPSC-derived ECs simultaneously overexpressing Intgα4 and Intgß1, iPSCs precultured in endothelial medium for 3 days (endothelial-prone stem cells), primary aortic ECs, mouse embryonic fibroblasts, and phosphate-buffered saline (control). The cells were administered every 3 days for a period of 8 weeks. iPSCs, iPSCs transfected with nontargeting siRNAs, and endothelial-prone stem cells selectively homed on the luminal surface of the allografts, differentiated into ECs, and decreased neointimal proliferation. Through a single administration, we found that iPSCs trafficked to allograft lesions, differentiated into ECs within 1 week, and survived for 4-8 weeks. The therapeutic effect of a single administration was moderate. Thus, Intgß1 and pluripotency are essential for iPSCs to treat allogeneic vasculopathy.

11.
J Pediatr Urol ; 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32334969

RESUMO

INTRODUCTION: Laparoscopic pyeloplasty (LP) has been widely used in the treatment of pediatric ureteropelvic junction obstruction (UPJO). However, no prior reports with a large pediatric series have focused on the analysis of complications and impact factors of the outcomes. We hypothesized there were risk factors of higher Clavien grade postoperative complications. OBJECTIVE: To analyze the characteristics of complications and risk factors of high Clavien grade postoperative complications. PATIENTS AND METHODS: All children with UPJO treated with primary transperitoneal LP between July 2016 and July 2018 were retrospectively reviewed. The Clavien complication grades in groups with different weight, intraoperative complication (drainage methods), anteroposterior pelvic diameters (APPD), side, gender, title of surgeon, preoperative presentation and obstruction reason were compared. RESULTS: Of the 279 children, intraoperative complications in which the placement of double-J stents was not accomplished and conversion to open surgery (Satava grade II) occurred in 17 (6.09%) and 2 (0.72%) patients, respectively. A total of 270 patients (277 kidneys) were included in the analysis of postoperative complications. Postoperative complications occurred in 51 (18.89%) patients. The most frequent postoperative incident was febrile UTI in 27 patients. Of the 13 patients who required reoperations, 6 patients had kidney restenosis and were considered as failure of surgery. All complications with an exact onset time occurred within 10 months after surgery. In the univariate and multivariate analysis, weight <10 kg and having intraoperative complication with nephrostomy tube were risk factors of higher Clavien postoperative complication grade (P<0.05). DISCUSSION: Patients who were <10 kg in weight and having intraoperative complication with nephrostomy tube had a greater risk of a higher Clavien grade postoperative complication. To reduce high Clavien grade postoperative complications, asymptomatic patients under 10 kg in weight and having intraoperative complication with nephrostomy tube need close monitoring. In the 26 patients who had an exact time of the postoperative complications, the longest time we found was 10 months. Thus, we recommend the follow-up time required to observe postoperative complications in patients should be at least 10 months after surgery. CONCLUSIONS: LP has been proven to be safe and effective in children with a low rate of complications. Weight <10 kg and having intraoperative complications with nephrostomy tube were risk factors of higher Clavien grade postoperative complications. Children with low weight and intraoperative complications need more attention in terms of the occurrence of complications.

12.
Cancer Sci ; 2020 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-32279431

RESUMO

Absent, small or homeotic 2-like protein (ASH2L) is a core component of a multimeric histone methyltransferase complex that is involved in the maintenance of active transcription, participating in several cancers, however the biological function and molecular mechanism of ASH2L in endometrial cancer (ECa) are largely unknown. Endometrial cancer is a common malignant tumor in women and the incidence of this cancer is on the rise. Estrogen-ERα signaling, as an oncogenic pathway, plays a crucial role in endometrial carcinogenesis. Therefore, further exploration of the molecular mechanisms around ERα-mediated gene transcription in ECa would be helpful to the understanding of tumor development and to finding a new therapeutic target for ECa. Here, our study demonstrated that ASH2L was highly expressed in ECa samples, and higher expression of ASH2L was positively correlated with a poor prognosis. Moreover, we identified that ASH2L associated with ERα and that knockdown of ASH2L resulted in decreased expression of a subset of the estrogen-induced target genes, including paired box 2 (PAX2), an oncogenic gene in ECa. ASH2L was recruited to cis-regulatory elements in PAX2, thereby altering histone H3K4me3 and H3K27me3 levels, to enhance ERα-mediated transactivation. Finally, depletion of ASH2L suppressed endometrial cancer cell proliferation and migration. Our findings suggest that ASH2L participates in the promotion of ECa progression, if not totally at least partially, via upregulation of PAX2 transcription.

13.
Am J Hum Genet ; 106(4): 535-548, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32243820

RESUMO

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.


Assuntos
Grupos Étnicos/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Medicina de Precisão/métodos , Controle de Qualidade , Veteranos , Sequenciamento Completo do Genoma/métodos
15.
Acupunct Med ; : 964528419900789, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32309995

RESUMO

BACKGROUND: Acupuncture has been advocated for as a potentially effective therapy for patients with knee osteoarthritis (KOA) in systematic reviews and guidelines. However, there is still a lack of agreement on the optimal therapeutic protocol for acupuncture. This aim of this study was to develop an expert consensus regarding the therapeutic protocol of acupuncture to guide doctors in clinical practice. METHODS: An initial list of items was based on an overview of research evidence from four databases and clinical problem investigation with a multidisciplinary panel. A two-step process was used to optimize the list, including semi-structured interviews with three acupuncture clinical experts and a three-round Delphi consensus survey with the voting panel. A nine-point Likert-type scale (1 = strongly disagree, 9 = strongly agree) was used to measure agreement. RESULTS: In total, 52 professionals (response rate: 52%) confirmed their participation in the voting panel. The initial list including 28 items was evaluated. Following a three-round Delphi survey, a consensus was achieved including 37 items that can be broadly categorized into six domains: (1) main treatment principles, (2) acupuncture treatment, (3) dose of acupuncture intervention, (4) primary outcomes, (5) adverse events and (6) others. CONCLUSION: This expert consensus could be used to guide doctors in clinical practice and help patients with KOA gain access to appropriate and coordinated acupuncture treatment.

16.
Protein Cell ; 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32277346

RESUMO

Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. Whether BMAL1 plays a role in regulating human heart function remains unclear. Here we generated a BMAL1 knockout human embryonic stem cell (hESC) model and further derived human BMAL1 deficient cardiomyocytes. We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression. BMAL1 knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.

17.
Free Radic Biol Med ; 152: 248-254, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32217193

RESUMO

The diagnosis of frailty is usually subjective, which calls for objective biomarkers in clinical medicine. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGsn) and 8-oxo-7, 8-dihydroguanosine (8-oxoGsn) in urine are two aging biomarkers that have not been explored deeply in cases of frailty. A total of 508 elderly patients with cardiovascular disease (mean age 75.0 ± 6.5 years, 50.8% males) were enrolled consecutively. Frailty was assessed by the Fried phenotype (robust: 0 score; pre-frail: 1-2 scores; frail: 3-5 scores). The concentrations of 8-oxoGsn and 8-oxodGsn in urine were measured by improved ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Urinary creatinine (Cre) was tested to correct the 8-oxoGsn and 8-oxodGsn levels. According to the Fried phenotype score, the proportions of robust, pre-frail, and frail subjects were 20.5% (104/508), 53.9% (274/508), and 25.6% (130/508), respectively. The urinary 8-oxoGsn/Cre (P < 0.001) differed significantly among these 3 groups, but the urinary 8-oxodGsn/Cre (P = 0.600) showed no marked difference. Univariate and multivariate logistic regression showed that the age (odds ratio [OR] = 1.090, P < 0.001), systolic blood pressure (OR = 0.981, P = 0.008), 8-oxoGsn/Cre (OR = 1.203, P = 0.007), hemoglobin (OR = 0.980, P = 0.007), and sodium (OR = 0.915, P = 0.044) were independently associated with frailty. The sensitivity and specificity to identify frailty were 53.08% and 71.96%, respectively, for 8-oxoGsn/Cre at the optimal cut-off value of 3.879 µmol/mol according to the maximal Youden index. Urinary 8-oxoGsn, as a recognized biomarker of RNA oxidation, is independently associated with frailty in elderly patients with cardiovascular disease. However, the urinary 8-oxodGsn shows no obvious correlation with frailty. To obtain a better diagnostic performance for frailty, more biomarkers from different pathophysiological pathways should be explored in the future.

18.
Int J Biol Sci ; 16(7): 1166-1179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32174792

RESUMO

Carbon tetrachloride (CCl4), Concanavalin A (ConA), bile duct ligation (BDL), and liver resection (LR) are four types of commonly used mouse models of acute liver injury. However, these four models belong to different types of liver cell damage while their application situations are often confounded. In addition, the systematic changes of multiple extra-liver organs after acute liver injury and the crosstalk between liver and extra-liver organs remain unclear. Here, we aim to map the morphological, metabolomic and transcriptomic changes systematically after acute liver injury and search for the potential crosstalk between the liver and the extra-liver organs. Significant changes of transcriptome were observed in multiple extra-liver organs after different types of acute liver injury despite dramatic morphological damage only occurred in lung tissues of the ConA/BDL models and spleen tissues in the ConA model. Liver transcriptomic changes initiated the serum metabolomic alterations which correlated to transcriptomic variation in lung, kidney, and brain tissues of BDL and LR models. The potential crosstalk might lead to pulmonary damage and development of hepatorenal syndrome (HRS) and hepatic encephalopathy (HE) during liver injury. Serum derived from acute liver injury mice damaged alveolar epithelial cells and human podocytes in vitro. Our data indicated that different types of acute liver injury led to different transcriptomic changes within extra-liver organs. Integration of serum metabolomics and transcriptomics from multiple tissues can improve our understanding of acute liver injury and its effect on the other organs.

19.
iScience ; 23(3): 100968, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32199293

RESUMO

R-loops, three-stranded DNA-DNA:RNA hybrid structures, are best known for their deleterious effects on genome stability. The regulatory factors of this fundamental genetic structure remain unclear. Here, we reveal an epigenetic factor that controls R-loop stability. METTL8, a member of the methyltransferase-like protein family that methylates 3-methylcytidine (m3C), is a key factor in the R-loop regulating methyltransferase complex. Biochemical studies show that METTL8 forms a large SUMOylated nuclear RNA-binding protein complex (∼0.8 mega daltons) that contains well-reported R-loop related factors. Genetic ablation of METTL8 results in an overall reduction of R-loops in cells. Interaction assays indicated METTL8 binds to RNAs and is responsible for R-loop stability on selected gene regions. Our results demonstrate that the SUMOylated METTL8 promotes tumorigenesis by affecting genetic organization primarily in, or in close proximity to, the nucleolus and impacts the formation of regulatory R-loops through its methyltransferase activity on m3C.

20.
Eur J Med Chem ; 193: 112190, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32179332

RESUMO

EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.

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