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1.
Sci Rep ; 11(1): 7857, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846344

RESUMO

Given that a substantial proportion of the subgroup of COVID-19 patients that face a severe disease course are younger than 60 years, it is critical to understand the disease-specific characteristics of young COVID-19 patients. Risk factors for a severe disease course for young COVID-19 patients and possible non-linear influences remain unknown. Data were analyzed from COVID-19 patients with clinical outcome in a single hospital in Wuhan, China, collected retrospectively from Jan 24th to Mar 27th. Clinical, demographic, treatment and laboratory data were collected from patients' medical records. Uni- and multivariable analysis using logistic regression and random forest, with the latter allowing the study of non-linear influences, were performed to investigate the clinical characteristics of a severe disease course. A total of 762 young patients (median age 47 years, interquartile range [IQR] 38-55, range 18-60; 55.9% female) were included, as well as 714 elderly patients as a comparison group. Among the young patients, 362 (47.5%) had a severe/critical disease course and the mean age was statistically significantly higher in the severe subgroup than in the mild subgroup (59.3 vs. 56.0, Student's t-test: p < 0.001). The uni- and multivariable analysis suggested that several covariates such as elevated levels of serum amyloid A (SAA), C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased lymphocyte counts influence disease severity independently of age. Elevated levels of complement C3 (odds ratio [OR] 15.6, 95% CI 2.41-122.3; p = 0.039) are particularly associated with the risk of developing severe COVID-19 specifically in young patients, whereas no such influence seems to exist for elderly patients. Additional analysis suggests that the influence of complement C3 in young patients is independent of age, gender, and comorbidities. Variable importance values and partial dependence plots obtained using random forests delivered additional insights, in particular indicating non-linear influences of risk factors on disease severity. This study identified increased levels of complement C3 as a unique risk factor for adverse outcomes specific to young COVID-19 patients.

2.
Chin Med J (Engl) ; 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33840743

RESUMO

BACKGROUND: The association of lipids and cancer has varied greatly among different cancer types, lipid components and study populations. This study is aimed to investigate the association of serum lipids and the risk of malignant lesions in esophageal squamous epithelium. METHODS: In the "Endoscopic Screening for Esophageal Cancer in China" (ESECC) trial, serum samples were collected and tested for total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol at the time of subject enrollment. Cases were defined as malignant esophageal lesions identified by baseline endoscopic examination or by follow-up to May 31, 2018. Controls were randomly selected using incidence density sampling in the same cohort. Conditional logistic models were applied to identify the association of serum lipids and the risk of malignant esophageal lesions. Effect modification was evaluated by testing interaction terms of the factor under assessment and these serum lipid indicators. RESULTS: No consistent association between serum lipid levels and esophageal malignant lesions were found in a pooled analysis of 211 cases and 2101 controls. For individuals with a family history of esophageal cancer (EC), high TC, and LDL-C were associated with a significantly increased risk of having malignant lesions (odds ratio [OR]High vs. Low TC = 2.22, 95% confidence interval [CI]: 1.14-4.35; ORHigh vs. Low LDL-C = 1.93, 95% CI: 1.01-3.65). However, a negative association was observed in participants without an EC family history (ORHigh vs. Low TC = 0.69, 95% CI: 0.48-0.98 Pinteraction = 0.002; ORHigh vs. Low LDL-C = 0.50, 95% CI: 0.34-0.76 Pinteraction < 0.001). CONCLUSIONS: In this study, we found that the association of serum lipids and malignant esophageal lesions might be modified by EC family history. The stratified analysis would be crucial for population-based studies investigating the association of serum lipids and cancer. The mechanism by which a family history of EC modifies this association warrants further investigation.

3.
Nat Commun ; 12(1): 2114, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837182

RESUMO

Lack of detailed knowledge of SARS-CoV-2 infection has been hampering the development of treatments for coronavirus disease 2019 (COVID-19). Here, we report that RNA triggers the liquid-liquid phase separation (LLPS) of the SARS-CoV-2 nucleocapsid protein, N. By analyzing all 29 proteins of SARS-CoV-2, we find that only N is predicted as an LLPS protein. We further confirm the LLPS of N during SARS-CoV-2 infection. Among the 100,849 genome variants of SARS-CoV-2 in the GISAID database, we identify that ~37% (36,941) of the genomes contain a specific trio-nucleotide polymorphism (GGG-to-AAC) in the coding sequence of N, which leads to the amino acid substitutions, R203K/G204R. Interestingly, NR203K/G204R exhibits a higher propensity to undergo LLPS and a greater effect on IFN inhibition. By screening the chemicals known to interfere with N-RNA binding in other viruses, we find that (-)-gallocatechin gallate (GCG), a polyphenol from green tea, disrupts the LLPS of N and inhibits SARS-CoV-2 replication. Thus, our study reveals that targeting N-RNA condensation with GCG could be a potential treatment for COVID-19.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33721913

RESUMO

BACKGROUND AND AIM: Chemotherapy drugs do not work well in esophageal squamous cell carcinoma (ESCC), and none of the targeted drugs have been applied in clinic. This study aims to identify effective targeted drugs and related biomarkers for the treatment of ESCC. METHODS: The effect of 40 Food and Drug Administration-approved small-molecule inhibitors was first tested in five ESCC cell lines. CCK8 assays and xenografts derived from ESCC cell lines were performed to evaluate the anti-ESCC effects of inhibitors or chemotherapeutic agents in vitro and in vivo, respectively. Immunohistochemistry was utilized to analyze the p-EGFR expression in tissues. Western blot combining with gray analysis was conducted to detect the expression of interest protein. Flow cytometry and immunofluorescence assay were used to analyze apoptosis, cell cycle, and mitotic changes after drug treatment. RESULTS: Afatinib showed remarkable effects on inhibiting ESCC cells with higher expression of p-EGFR. Results from combinatorial screening in ESCC cells expressing lower phosphorylation level of EGFR showed that paclitaxel and afatinib presented a significant synergistic inhibitory effect (P < 0.001). Molecular analysis revealed that paclitaxel sensitized afatinib by activating EGFR, and afatinib in combination with paclitaxel effectively blocked MAPK pathway and induced G2/M cell arrest and apoptosis that is an indicator of mitotic catastrophe. CONCLUSIONS: Our data demonstrate that afatinib is an effective drug for patients with ESCC expressing higher phosphorylation level of EGFR. And for patients with lower p-EGFR in tumors, paclitaxel in combination with afatinib might be a promising therapeutic strategy in ESCC.

5.
Pharmacol Res ; 167: 105531, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33675964

RESUMO

Contrast-induced acute kidney injury (CI-AKI) is a main cause of hospital-acquired renal failure. Nevertheless, limited measures have been shown to be effective for the treatment of CI-AKI. Here, we demonstrated that αKlotho, which is highly expressed in kidney, has therapeutic activity in CI-AKI. Our data showed that αKlotho expression levels were decreased both in the kidney and serum of CI-AKI mice. Administration of αKlotho protein protected the kidney and HK-2 cells against contrast-induced injury. Mechanistically, αKlotho reduced contrast-induced renal tubular cells pyroptosis by limiting NLRP3 inflammasome activation. Meanwhile, αKlotho up-regulated autophagy via inhibiting the AKT/mTOR pathway and decreased mitochondrial ROS level. Inhibition of autophagy blunted the suppression effect of αKlotho on NLRP3 inflammasome activation and cell pyroptosis in contrast-treated HK-2 cells. Taken together, our data suggest that αKlotho protein protects against CI-AKI through inhibiting NLRP3 inflammasome-mediated pyroptosis, which is likely by promoting autophagy. αKlotho may be a promising therapeutic strategy for CI-AKI.

6.
Asia Pac J Clin Nutr ; 30(1): 140-152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33787050

RESUMO

BACKGROUND AND OBJECTIVES: Although fish consumption or omega-3 intake is associated with cardio- cerebrovascular disease including stroke, their correlation is still controversial. Therefore, this meta-analysis is to identify the relationship between the risk of stroke and fish consumption or omega-3 intake. METHODS AND STUDY DESIGN: We searched the PubMed, EMBASE and Cochrane Library databases as of May 2019. Multivariateadjusted risk ratios (RRs) with 95% confidence interval (CI) for stroke in different level intake of fish or Longchain omega-3 polyunsaturated fatty acids (LC ω3-PUFAs) were pooled using a random-effects meta-analysis. A dose-response analysis was conducted with the 2-stage generalized least-squares trend program. RESULTS: Our meta-analysis identified a total of 17 prospective cohort studies including 14986 strokes events in 672711 individuals. Meta-analysis revealed that the higher fish consumption was significantly associated with lower risk of stroke (RR=0.871, 95% CI: 0.779-0.975, p=0.016), especially with ischemic stroke (RR=0.808, 95% CI: 0.696- 0.937, p=0.005). Meantime, the combined RR of total stroke was 0.859 (95% CI: 0.769-0.959, p=0.007) for the highest versus lowest intake of LC ω3-PUFAs, and stratification analysis showed that higher LC ω3-PUFAs intake was associated with reduced stroke risk in women (RR=0.793, 95% CI: 0.706-0.891, p=0.000) but not in men. In addition, the dose-response analysis showed fish consumption with 1000g per month and LC ω3-PUFAs intake with 0.5g per month was associated with 17.3% (RR=0.927, 95% CI: 0.83-0.98) and 14% (RR=0.86, 95% CI: 0.78-0.95) lower risk of stroke, respectively. CONCLUSIONS: Both fish consumption and LC ω3-PUFAs intake were negatively associated with the risk of stroke, especially in women, which suggest that increased intake of fishery products and LC ω3-PUFAs may benefit primary prevention of stroke.

7.
J Orthop Surg Res ; 16(1): 212, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761974

RESUMO

BACKGROUND: To manage patellofemoral joint disorders, a complete understanding of the in vivo patellofemoral kinematics is critical. However, as one of the parameters of joint kinematics, the location and orientation of the patellofemoral finite helical axis (FHA) remains unclear. The purpose of this study is to quantify the location and orientation of the patellar FHA, both in vivo and non-invasively at various flexion angles, and evaluate the relationship of the FHA and the trans-epicondylar axis (TEA). METHODS: The magnetic resonance (MR) images of 18 unilateral knees were collected at full extension, 30°, 60°, 90°, and maximum angle of knee flexion. Three-dimensional models of the knee joint at different flexion angles were created using the MR images, and then used to calculate the patellar tracking and FHA with a spline interpolation algorithm. By using a coordinate system based on the TEA, the FHA tracking was quantified. Six parameters concerning the location and orientation of the patellar FHA were analysed. RESULTS: The average patellar FHA drew an L-shaped tracking on the midsagittal plane moving from the posteroinferior to the anterosuperior side of the TEA with knee flexion. Before 90° flexion, the patellar rotational radius decreased slightly, with an average value of 5.65 ± 1.09 cm. During 20° to 90° knee flexion, the average angle between the patellar FHA and the TEA was approximately 10° and that between the FHA and the coronal plane was maintained at about 0°, while that between the FHA and the level plane fluctuated between - 10° and 10°. CONCLUSIONS: This study quantitatively reported the continuous location and direction of the patellar FHA during knee flexion. The patellar FHA was close to but not coincident with the femoral TEA both in location and orientation, and the patellar rotational radius decreased slightly with knee flexion. These findings could provide a clear direction for further studies on the difference in patellofemoral FHA among various types of patellofemoral disorders, and provide a foundation for the application of FHA in surgical evaluation, preoperative planning and prosthesis design, thereby assisting in the diagnosis and treatment of patellofemoral disorders.

8.
Medicine (Baltimore) ; 100(12): e25017, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761657

RESUMO

ABSTRACT: Overweight and obesity may be associated with poor clinical outcome, including chronic kidney disease (CKD). However, whether body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC) are related to CKD is yet to be elucidated.A total of 7593 adults were divided into 4 groups based on the estimated glomerular filtration rate (eGFR) quartile. The eGFR was calculated with the CKD Epidemiology Collaboration. Multiple linear regression analyzed the association between eGFR and WHR, BMI, and WC. Logistic regression analysis determined whether the CKD patients were associated with WHR, BMI, and WC after adjusting for other variables.The mean age of the cohort was 72.34 ±â€Š7.30 years. Multiple linear regression analysis showed that WC (P = .006) was associated with eGFR, although adjusted by lifestyle factor and biochemical indicators. The individuals in the underweight, overweight, and obese groups had significantly lower eGFR value than those in the healthy weight group in moderate CKD. The eGFR in the overweight group with WHR ≤0.894 was higher than in the healthy weight group with WHR >0.894 group (P = .036). Overweight with WHR ≤0.894 group had a longer WC with a pronounced increase in the hip circumference. Logistic regression analysis showed that the WC (OR = 1.362, P < .001) and BMI (OR = 1.227, P = .031) were independent risk factors for moderate CKD patients. Each standard deviation (SD) of high BMI and WC level was associated with 23.0% and 17.3% higher odds of moderate CKD (OR = 1.230, P = .017 and OR = 1.173, P = .021, respectively).WC is an independent risk factor for eGFR. Combined BMI and WC are important factors that would predict moderate CKD patients.


Assuntos
Índice de Massa Corporal , Insuficiência Renal Crônica/diagnóstico , Circunferência da Cintura , Relação Cintura-Quadril , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Taxa de Filtração Glomerular , Humanos , Estilo de Vida , Modelos Logísticos , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Magreza/fisiopatologia , Adulto Jovem
9.
Antimicrob Resist Infect Control ; 10(1): 62, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33781329

RESUMO

BACKGROUND: The association between allogeneic blood transfusion and healthcare-associated infection (HAI) is considered dose-dependent. However, this association may be confounded by transfusion duration, as prolonged hospitalization stay increases the risk of HAI. Also, it is not clear whether specific blood products have different dose-response risks. METHODS: In this retrospective cohort study, a logistic regression was used to identify confounding factors, and the association between specific blood products and HAI were analyzed. Then Cox regression and restricted cubic spline regression was used to visualize the hazard of HAI per transfusion product. RESULTS: Of 215,338 inpatients observed, 4.16% were transfused with a single component blood product. With regard to these transfused patients, 480 patients (5.36%) developed a HAI during their hospitalization stay. Logistic regression showed that red blood cells (RBCs) transfusion, platelets transfusion and fresh-frozen plasmas (FFPs) transfusion were risk factors for HAI [odds ratio (OR) 1.893, 95% confidence interval (CI) 1.656-2.163; OR 8.903, 95% CI 6.646-11.926 and OR 1.494, 95% CI 1.146-1.949, respectively]. However, restricted cubic spline regression analysis showed that there was no statistically dose-response relationship between different transfusion products and the onset of HAI. CONCLUSIONS: RBCs transfusion, platelets transfusion and FFPs transfusion were associated with HAI, but there was no dose-response relationship between them.

10.
Zhongguo Zhong Yao Za Zhi ; 46(2): 426-435, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33645132

RESUMO

This study aimed to explore the effect of Salviae Miltiorrhizae Radix et Rhizoma, its stems and leaves on the diversity of intestinal microflora in rats with diabetic kidney injury. Diabetic rats model was established by feeding high glucose and high fat diet and 5% glucose solution with intraperitoneal injection of 30 mg·kg~(-1) streptozocin(STZ). The rats were randomly divided into normal group, model group, irbesartan control group, Huangkui Capsules control group, as well as low, middle and high dose groups of Sal-viae Miltiorrhizae Radix et Rhizoma, its stems and leaves. After administration for 2 weeks, 16 S rRNA technique was used to analyze the diversity of intestinal microflora in the feces of each group. The results showed rats in the model group developed renal tubular epithelial vacuole degeneration and a large amount of inflammatory cell infiltration in the renal interstitium. A small amount of inflammatory cell infiltration was seen in each administration group. The kidney structure of rats in irbesartan group, Huangkui Capsules group, high-dose group of Salviae Miltiorrhizae Radix et Rhizoma and its stem water extract, as well as high dose group of Salviae Miltiorrhizae Radix et Rhizoma and its stem ethnol extract group was close to the normal group. The diversity and structure of intestinal flora in the model group were significantly different from those in the normal group. Each administration group improved the fecal flora diversity in rats with diabetic kidney injury to a certain extent, especially the high dose of Salviae Miltiorrhizae Radix et Rhizoma and its stems water extract. Different flora were found in feces of diabetic nephropathy model rats on class, order, family and genus levels. On families and genera levels, the relative abundance of Bifidobacterium, Turicibacter, Peptostreptococcaceae, Desulfovibrio, and SMB53 showed an upward trend in model group, but that of Lactobacillus, Clostridium, Rikenella, Rumen fungi showed a downward trend. The administration groups can improve the relative abundance of the above intestinal flora in the model rats to a normal-like level. The results of this study provide a reference for resource utilization and further development of Salviae Miltiorrhizae Radix et Rhizoma.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Salvia miltiorrhiza , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Ratos
11.
Food Res Int ; 140: 110037, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33648263

RESUMO

As a widely used Asian starter culture, the quality of daqu can significantly affect the organoleptic characteristics of the final products, yet the microbial metabolic network involved in flavor development remains unclear. This study aims to investigate that network based on the dynamics of physicochemical properties, microbial community, and volatile compounds in medium-temperature daqu (MT-daqu) during spontaneous fermentation. Analyses using the metagenomic data set facilitated the gene repertoire overview of this ecosystem, indicating that Lactobacillales (mainly Weissella, Lactobacillus, and Pediococcus), Mucorales (mainly Lichtheimia), and Eurotiales (mainly Aspergillus, Rasamsonia and Byssochlamys) were the potential predominant populations successively responsible for the production of lytic enzymes and flavor precursors/compounds in MT-daqu. Flavor-relevant pathways were found to exist in multiple species, but only bacteria showed the potential to participate in butane-2,3-diol (e.g. Weissella, Lactobacillus, and Staphylococcus) and butanoate (Thermoactinomyces) metabolism, and only fungi were potentially involved in biosynthesis of guaiacol (Byssochlamys) and 4-vinylguaiacol (Aspergillus). Furthermore, a combined analysis revealed that the acidic thermal environment present in early phases was mainly due to the catabolic activities of Lactobacillales and Lichtheimia, which could contribute to the effective self-domestication of microbiota. The study helps elucidate the different metabolic roles of microorganisms and disclose the formation mechanism of daqu's partial functions, namely providing various aromatic substances/precursors and enzymes.

12.
Am J Clin Nutr ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33675348

RESUMO

BACKGROUND: The dietary polyphenol resveratrol prevents various malignancies in preclinical models, including prostate cancer. Despite attempts to translate findings to humans, gaps remain in understanding pharmacokinetic-pharmacodynamic relations and how tissue concentrations affect efficacy. Such information is necessary for dose selection and is particularly important given the low bioavailability of resveratrol. OBJECTIVES: This study aimed to determine concentrations of resveratrol in prostate tissue of men after a dietary-achievable (5 mg) or pharmacological (1 g) dose. We then examined whether clinically relevant concentrations of resveratrol/its metabolites had direct anticancer activity in prostate cell lines. METHODS: A window trial was performed in which patients were allocated to 5 mg or 1 g resveratrol daily, or no intervention, before prostate biopsy. Patients (10/group) ingested resveratrol capsules for 7-14 d before biopsy, with the last dose [14C]-labeled, allowing detection of resveratrol species in prostate tissue using accelerator MS. Cellular uptake and antiproliferative properties of resveratrol/metabolites were assessed in cancer and nonmalignant cell cultures using HPLC with UV detection and cell counting, respectively. RESULTS: [14C]-Resveratrol species were detectable in prostate tissue of all patients analyzed, with mean ± SD concentrations of 0.08 ± 0.04 compared with 22.1 ± 8.2 pmol/mg tissue for the 5 mg and the 1 g dose, respectively. However, total [14C]-resveratrol equivalents in prostate were lower than we previously reported in plasma and colorectum after identical doses. Furthermore, resveratrol was undetectable in prostate tissue; instead, sulfate and glucuronide metabolites dominated. Although resveratrol reduced prostate cell numbers in vitro over 7 d, the concentrations required (≥10 µM) exceeded the plasma maximum concentration. Resveratrol mono-sulfates and glucuronides failed to consistently inhibit cell growth, partly due to poor cellular uptake. CONCLUSIONS: Low tissue concentrations of resveratrol species, coupled with weak antiproliferative activity of its conjugates, suggest daily doses of ≤1 g may not have direct effects on human prostate.This trial was registered at clinicaltrialsregister.eu as EudraCT 2007-002131-91.

13.
J Alzheimers Dis ; 80(2): 695-713, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33579843

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. OBJECTIVE: The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice. METHODS: Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aß plaques and neuroinflammation in the brain. IL-1ß, TNF-α, and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting. RESULTS: DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aß deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1ß and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κB activation in the hippocampus of APP/PS1 mice. CONCLUSION: DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD.

14.
Sci Rep ; 11(1): 3253, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547384

RESUMO

Tenofovir and entecavir are currently designated as the preferred oral antiviral drugs for chronic hepatitis B. However, only less than 40% of patients can achieve HBeAg seroconversion. We aim at investigating the role of intestinal microbiome in HBeAg seroconversion induced by oral antiviral therapy and describe multi-omics characteristics of HBeAg seroconversion associated intestinal flora. In this study, we prospectively collected fecal samples at baseline from the patients with HBeAg positive chronic hepatitis B who would have oral antiviral therapy. 16S rDNA sequencing and metabolomics were performed. We identified HBeAg seroconversion-related microbial signature and constructed prediction model for HBeAg seroconversion. Thirty-seven of these subjects achieved HBeAg seroconversion within 156 weeks after the initiation of oral antiviral therapy, while 41 subjects remained HBeAg positive even after over 156 weeks of therapy. A computational statistical and machine learning approach allowed us to identify a microbial signature for HBeAg seroconversion. Using random forest method, we further constructed a classifier based on the microbial signature, with area under curve being 0.749 for the test set. Patients who achieved HBeAg seroconversion tended to have lower abundance of certain fecal metabolites such as essential amino acids, and several dipeptides. By analyzing the fecal microbiota from the patients with and without HBeAg seroconversion, we showed intestinal microbiome play a critical role in HBeAg seroconversion induced by oral antiviral therapy. We also identified intestinal microbial signature that is associated with HBeAg seroconversion after oral antiviral therapy.

15.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(1): 68-71, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33554799

RESUMO

OBJECTIVE: To explore the effects of costunolide on the proliferation and apoptosis of human chronic myeloid leukemia drug resisitant cell line K562/ADR and its mechanism. METHODS: The proliferation of the cells was assessed by CCK-8 assay, while flow cytometry was used to detect the apoptosis of the cells. The related-proteins were detected by using Western blot. RESULTS: The proliferation of K526/ADR cells was significantly inhibited by costunolide in a dose-dependent manner (r=0.9886) after treated by 0.01, 0.1, 0.25, 0.5, 1, 2.5, 5, 10, 25, 50 and 100 µmol/L costunolide for 72 h, and IC50 value of costunolide on K562/ADR cells was about (10.86±0.99) µmol/L (P<0.05). The apoptosis of K562/ADR cells could be induced by costunolide (10 and 15 µmol/L) significantly, the rate of apoptosis was 14.80%±3.27%, 33.2%±5.03%, respectively, which in comparison with a significantly difference as compared with the control group (4.30%±0.62%) (P<0.05). Western blot showed that costunolide could down-regulated the expression of p-AKT, p-PI3K, BCL-2, and up-regulated the expression of cleaved-caspase-3, cleaved-PARP significantly. CONCLUSION: Costunolide could inhibit the proliferation and apoptosis of K562/ADR cells through regulation of PI3K/AKT pathway.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Apoptose , Proliferação de Células , Humanos , Células K562 , Sesquiterpenos
16.
J Biomed Sci ; 28(1): 13, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33557829

RESUMO

BACKGROUND: Although the availability of therapeutic options including temozolomide, radiotherapy and some target agents following neurosurgery, the prognosis of glioma patients remains poor. Thus, there is an urgent need to explore possible targets for clinical treatment of this disease. METHODS: Tissue microarrays and immunohistochemistry were used to detect FKBP10, Hsp47, p-AKT (Ser473), p-CREB (Ser133) and PCNA expression in glioma tissues and xenografts. CCK-8 tests, colony formation assays and xenograft model were performed to test proliferation ability of FKBP10 in glioma cells in vitro and in vivo. Quantitative reverse transcriptase-PCR, western-blotting, GST-pull down, co-immunoprecipitation and confocal-immunofluorescence staining assay were used to explore the molecular mechanism underlying the functions of overexpressed FKBP10 in glioma cells. RESULTS: FKBP10 was highly expressed in glioma tissues and its expression was positively correlates with grade, poor prognosis. FKBP10-knockdown suppressed glioma cell proliferation in vitro and subcutaneous/orthotopic xenograft tumor growth in vivo. Silencing of FKBP10 reduced p-AKT (Ser473), p-CREB (Ser133), PCNA mRNA and PCNA protein expression in glioma cells. FKBP10 interacting with Hsp47 enhanced the proliferation ability of glioma cells via AKT-CREB-PCNA cascade. In addition, correlation between these molecules were also found in xenograft tumor and glioma tissues. CONCLUSIONS: We showed for the first time that FKBP10 is overexpressed in glioma and involved in proliferation of glioma cells by interacting with Hsp47 and activating AKT-CREB-PCNA signaling pathways. Our findings suggest that inhibition of FKBP10 related signaling might offer a potential therapeutic option for glioma patients.

17.
Nat Commun ; 12(1): 1028, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589610

RESUMO

Upon binding to DNA breaks, poly(ADP-ribose) polymerase 1 (PARP1) ADP-ribosylates itself and other factors to initiate DNA repair. Serine is the major residue for ADP-ribosylation upon DNA damage, which strictly depends on HPF1. Here, we report the crystal structures of human HPF1/PARP1-CAT ΔHD complex at 1.98 Å resolution, and mouse and human HPF1 at 1.71 Å and 1.57 Å resolution, respectively. Our structures and mutagenesis data confirm that the structural insights obtained in a recent HPF1/PARP2 study by Suskiewicz et al. apply to PARP1. Moreover, we quantitatively characterize the key residues necessary for HPF1/PARP1 binding. Our data show that through salt-bridging to Glu284/Asp286, Arg239 positions Glu284 to catalyze serine ADP-ribosylation, maintains the local conformation of HPF1 to limit PARP1 automodification, and facilitates HPF1/PARP1 binding by neutralizing the negative charge of Glu284. These findings, along with the high-resolution structural data, may facilitate drug discovery targeting PARP1.


Assuntos
Proteínas de Transporte/química , DNA/química , Histonas/química , Proteínas Nucleares/química , Poli(ADP-Ribose) Polimerase-1/química , Serina/metabolismo , ADP-Ribosilação , Sequência de Aminoácidos , Animais , Sítios de Ligação , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Clonagem Molecular , Cristalografia por Raios X , DNA/genética , DNA/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Glutamina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Camundongos , Modelos Moleculares , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Eletricidade Estática
18.
Artigo em Inglês | MEDLINE | ID: mdl-33635343

RESUMO

CD133 + cancer stem cells mediate chemoresistance in multiple aggressive cancers, and anti-CD133 chimeric antigen receptor T (CAR-T) cells are designed to selectively target cisplatin-resistant gastric cancer stem cells in this investigation. The relative CD133 expression was detected in gastric cancer patients before and after cisplatin treatment. Anti-CD133 CAR-T cells were incubated with cisplatin-exposed CD133+ BGC-823 cells to evaluate the killing efficacy. At the same time, the canonical T cell activation markers were assayed by fluorescence-activated cell sorting, and the functional cytokine profile was detected with enzyme-linked immunosorbent assays. In addition to the percentage of CD133 positive stem cell-like cells, the volume and weight of subcutaneous tumors in BGC-823, KATO III and MKN-28 xenograft models were measured to evaluate the anti-tumor activity of cisplatin and anti-CD133 CAR-T combination strategy. After cisplatin treatment, both human samples and BGC-823 cells showed up-regulated CD133 expression. Anti-CD133 CAR-T cells exhibited pronounced killing efficiency against cisplatin-exposed CD133+ BGC-823 cells with up-regulated activation markers and cytotoxicity cytokine production. Moreover, cisplatin and anti-CD133 CAR-T combination treatment inhibited tumor progression in three different xenograft models with diminished CD133 positive stem cell-like cell infiltration. These results indicate that cisplatin and anti-CD133 CAR-T combination strategy can simultaneously target normal and stem cell-like gastric cancer cells to improve the treatment outcome.

19.
Sleep Breath ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619665

RESUMO

BACKGROUND: Sleep deprivation (SD) has become a serious concern worldwide. This study aimed to identify key modules and candidate hub genes correlated with diseases caused by SD, using co-expression analysis. METHODS: The weighted gene co-expression network analysis was performed to construct a co-expression network of hub genes correlated with SD. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to search for signaling pathways. The protein-protein interaction network analysis of central genes was performed to recognize the interactions among central genes. Molecular Complex Detection, a plugin in Cytoscape, was used to discover the hub gene clusters involved in SD. RESULTS: A total of 564 genes in the yellow module were identified based on the results of topological overlap measure-based clustering. The yellow module showed a pivotal correlation with SD. Six hub gene clusters prominently associated with SD were identified. Heat shock protein family and circadian clock genes among them may be the hub genes involved in SD. CONCLUSIONS: These genes and pathways might become therapeutic targets with clinical usefulness in the future.

20.
BMC Musculoskelet Disord ; 22(1): 8, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397348

RESUMO

BACKGROUND: Guillain-Barré syndrome (GBS) is the most common and serious acute paralytic neuropathy and is usually caused by infection. It is thought to be the result of an aberrant response of the immune system. To our knowledge, GBS, especially severe GBS, after orthopaedic surgery has rarely been reported. CASE PRESENTATION: We herein report the case of a 58-year-old man who developed quadriplegia and respiratory failure on the 6th day after surgery for multiple fractures. The patient had no symptoms of respiratory or gastrointestinal tract infection within 4 weeks before the onset. The white blood cell count was normal, and there was no redness, swelling, heat or pain in the surgical incision. Brain, cervical and thoracic magnetic resonance imaging were normal, albuminocytological dissociation was found on cerebrospinal fluid examination, and electrophysiological examination showed that sensory and motor nerve evoked potentials could not be elicited. A diagnosis of post-traumatic GBS was made, and the patient was treated with intravenous immunoglobulin and plasma exchange, as well as supportive care and rehabilitation exercise. The length of stay was 18 months, and the in-hospital-related costs amounted to $127,171. At the last follow-up, the patient had recovered only grade 3 power in the upper limbs and grade 2 power in the lower limbs. CONCLUSIONS: Severe GBS is a rare complication after orthopaedic surgery. When progressive weakness occurs in trauma patients, the possibility of GBS should be considered, and cerebrospinal fluid and electrophysiological examinations should be performed in a timely manner. For patients with severe GBS after trauma, the treatment costs may be high, and the prognosis may be poor.

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