Publications by authors named "Qingbo Liu"

62 Publications

A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention.

MAbs 2021 Jan-Dec;13(1):1946918

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve VRC01-class antibodies, we combined structure-based design with a matrix-based approach to generate VRC01-class variants that filled an interfacial cavity, used diverse third-complementarity-determining regions, reduced potential steric clashes, or exploited extended contacts to a neighboring protomer within the envelope trimer. On a 208-strain panel, variant VRC01.23LS neutralized 90% of the panel at a geometric mean IC less than 1 μg/ml, and in transgenic mice with human neonatal-Fc receptor, the serum half-life of VRC01.23LS was indistinguishable from that of the parent VRC01LS, which has a half-life of 71 d in humans. A cryo-electron microscopy structure of VRC01.23 Fab in complex with BG505 DS-SOSIP.664 Env trimer determined at 3.4-Å resolution confirmed the structural basis for its ~10-fold improved potency relative to VRC01. Another variant, VRC07-523-F54-LS.v3, neutralized 95% of the 208-isolated panel at a geometric mean IC of less than 1 μg/ml, with a half-life comparable to that of the parental VRC07-523LS. Our matrix-based structural approach thus enables the engineering of VRC01 variants for HIV-1 therapy and prevention with improved potency, breadth, and pharmacokinetics.
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http://dx.doi.org/10.1080/19420862.2021.1946918DOI Listing
July 2021

Identification of natural compounds extracted from crude drugs as novel inhibitors of hepatitis C virus.

Biochem Biophys Res Commun 2021 Aug 12;567:1-8. Epub 2021 Jun 12.

Department of Virology II, National Institute of Infectious Diseases, 162-8640, Tokyo, Japan. Electronic address:

Natural product-derived crude drugs are expected to yield an abundance of new drugs to treat infectious diseases. Hepatitis C virus (HCV) is an oncogenic virus that significantly impacts public health. In this study, we sought to identify anti-HCV compounds in extracts of natural products. A total of 110 natural compounds extracted from several herbal medicine plants were examined for antiviral activity against HCV. Using a Huh7-mCherry-NLS-IPS reporter system for HCV infection, we first performed a rapid screening for anti-HCV compounds extracted from crude drugs. The compounds threo-2,3-bis(4-hydroxy-3-methoxyphenyl)-3-butoxypropan-1-ol (#106) and medioresinol (#110), which were extracted from Crataegus cuneate, exhibited anti-HCV activity and significantly inhibited HCV production in a dose-dependent manner. Analyses using HCV pseudoparticle and subgenomic replicon systems indicated that compounds #106 and #110 specifically inhibit HCV RNA replication but not viral entry or translation. Interestingly, compound #106 also inhibited the replication and production of hepatitis A virus. Our findings suggest that C. cuneate is a new source for novel anti-hepatitis virus drug development.
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http://dx.doi.org/10.1016/j.bbrc.2021.06.022DOI Listing
August 2021

Investigation on the interaction of acrylamide with soy protein isolate: Exploring the binding mechanism in vitro.

J Food Sci 2021 Jun 1;86(6):2766-2777. Epub 2021 May 1.

Key Laboratory of Dairy Science, Ministry of Education, College of Food Science, Northeast Agricultural University, Harbin, China.

Acrylamide (AA), which is a carcinogen in humans, has been a research focus in terms of food risk assessment. However, few published studies have explored protein strategies to reduce the health risks of AA. The objective of this study was to investigate the binding of AA with soy protein isolate (SPI) and elucidate the binding mechanism. The results showed that AA could bind with nontreated, heat-treated, high-pressure homogenization-treated, and ultrasound-treated SPI in vitro. Fourier-transform infrared spectroscopy suggested that secondary structure of SPI changed significantly after binding with AA in the nontreated and different treated groups. Moreover, fluorescence quenching experiments suggested that the quenching of SPI by AA was static quenching and hydrogen bonds, hydrophobic interactions, and van der Waals forces were involved in this process. PRACTICAL APPLICATION: The study of SPI and AA binding could provide a new perspective for reducing the bioaccessibility of AA in human body by using protein. The results showed that SPI could potentially be used as a novel health strategy to reduce the harm of AA in the human body.
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http://dx.doi.org/10.1111/1750-3841.15733DOI Listing
June 2021

Flavonoid-triazolyl hybrids as potential anti-hepatitis C virus agents: Synthesis and biological evaluation.

Eur J Med Chem 2021 Jun 31;218:113395. Epub 2021 Mar 31.

Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address:

A series of flavonoid-triazolyl hybrids were synthesized and evaluated as novel inhibitors of hepatitis C virus (HCV). The results of anti-HCV activity assays showed that most of the synthesized derivatives at a concentration of 100 μg/mL inhibited the generation of progeny virus. Among these derivatives, 10m and 10r exhibited the most potent anti-HCV activity and inhibited the production of HCV in a dose-dependent manner. Interestingly, 10m and 10r had no significant inhibitory effect on viral translation or replication. Additional action mechanism studies revealed that the most potent compounds, 10m and 10r, significantly inhibited viral entry to 34.0% and 52.0%, respectively, at 10 μM. These results suggest further effective application of 10m and 10r as potential HCV preventive agents.
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http://dx.doi.org/10.1016/j.ejmech.2021.113395DOI Listing
June 2021

Rational Engraftment of Quaternary-Interactive Acidic Loops for Anti-HIV-1 Antibody Improvement.

J Virol 2021 05 24;95(12). Epub 2021 May 24.

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA

Broadly neutralizing antibodies (bNAbs) are the focus of increasing interest for human immunodeficiency virus type 1 (HIV-1) prevention and treatment. Although several bNAbs are already under clinical evaluation, the development of antibodies with even greater potency and breadth remains a priority. Recently, we reported a novel strategy for improving bNAbs against the CD4-binding site (CD4bs) of gp120 by engraftment of the elongated framework region 3 (FR3) from VRC03, which confers the ability to establish quaternary interactions with a second gp120 protomer. Here, we applied this strategy to a new series of anti-CD4bs bNAbs (N49 lineage) that already possess high potency and breadth. The resultant chimeric antibodies bound the HIV-1 envelope (Env) trimer with a higher affinity than their parental forms. Likewise, their neutralizing capacity against a global panel of HIV-1 Envs was also increased. The introduction of additional modifications further enhanced the neutralization potency. We also tried engrafting the elongated CDR1 of the heavy chain from bNAb 1-18, another highly potent quaternary-binding antibody, onto several VRC01-class bNAbs, but none of them was improved. These findings point to the highly selective requirements for the establishment of quaternary contact with the HIV-1 Env trimer. The improved anti-CD4bs antibodies reported here may provide a helpful complement to current antibody-based protocols for the therapy and prevention of HIV-1 infection. Monoclonal antibodies represent one of the most important recent innovations in the fight against infectious diseases. Although potent antibodies can be cloned from infected individuals, various strategies can be employed to improve their activity or pharmacological features. Here, we improved a lineage of very potent antibodies that target the receptor-binding site of HIV-1 by engineering chimeric molecules containing a fragment from a different monoclonal antibody. These engineered antibodies are promising candidates for development of therapeutic or preventive approaches against HIV/AIDS.
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http://dx.doi.org/10.1128/JVI.00159-21DOI Listing
May 2021

Functional Anatomy of the Trimer Apex Reveals Key Hydrophobic Constraints That Maintain the HIV-1 Envelope Spike in a Closed State.

mBio 2021 03 30;12(2). Epub 2021 Mar 30.

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA

The human immunodeficiency virus type 1 (HIV-1) envelope trimer maintains a closed, metastable configuration to protect vulnerable epitopes from neutralizing antibodies. Here, we identify key hydrophobic constraints at the trimer apex that function as global stabilizers of the HIV-1 envelope spike configuration. Mutation of individual residues within four hydrophobic clusters that fasten together the V1V2, V3, and C4 domains at the apex of gp120 dramatically increases HIV-1 sensitivity to weak and restricted neutralizing antibodies targeting epitopes that are largely concealed in the prefusion Env spike, consistent with the adoption of a partially open trimer configuration. Conversely, the same mutations decrease the sensitivity to broad and potent neutralizing antibodies that preferentially recognize the closed trimer. Sera from chronically HIV-infected patients neutralize open mutants with enhanced potency, compared to the wild-type virus, suggesting that a large fraction of host-generated antibodies target concealed epitopes. The identification of structural constraints that maintain the HIV-1 envelope in an antibody-protected state may inform the design of a protective vaccine. Elucidating the structure and function of the HIV-1 envelope proteins is critical for the design of an effective vaccine. Despite the availability of many high-resolution structures, key functional correlates in the envelope trimer remain undefined. We utilized a combination of structural analysis, energy calculation, mutagenesis, and neutralization profiling to dissect the functional anatomy of the trimer apex, which acts as a global regulator of the HIV-1 spike conformation. We identify four hydrophobic clusters that stabilize the spike in a tightly closed configuration and, thereby, play a critical role in protecting it from the reach of neutralizing antibodies.
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http://dx.doi.org/10.1128/mBio.00090-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092198PMC
March 2021

Predictive value of stress hyperglycemia ratio for the occurrence of acute kidney injury in acute myocardial infarction patients with diabetes.

BMC Cardiovasc Disord 2021 Mar 30;21(1):157. Epub 2021 Mar 30.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Yongan Road 95, Xicheng District, 100050, Beijing, China.

Background: Acute hyperglycemia has been recognized as a robust predictor for occurrence of acute kidney injury (AKI) in nondiabetic patients with acute myocardial infarction (AMI), however, its discriminatory ability for AKI is unclear in diabetic patients after an AMI. Here, we investigated whether stress hyperglycemia ratio (SHR), a novel index with the combined evaluation of acute and chronic glycemic levels, may have a better predictive value of AKI as compared with admission glycemia alone in diabetic patients following AMI.

Methods: SHR was calculated with admission blood glucose (ABG) divided by the glycated hemoglobin-derived estimated average glucose. A total of 1215 diabetic patients with AMI were enrolled and divided according to SHR tertiles. Baseline characteristics and outcomes were compared. The primary endpoint was AKI and secondary endpoints included all-cause death and cardiogenic shock during hospitalization. The logistic regression analysis was performed to identify potential risk factors. Accuracy was defined with area under the curve (AUC) by a receiver-operating characteristic (ROC) curve analysis.

Results: In AMI patients with diabetes, the incidence of AKI (4.4%, 7.8%, 13.0%; p < 0.001), all-cause death (2.7%, 3.6%, 6.4%; p = 0.027) and cardiogenic shock (4.9%, 7.6%, 11.6%; p = 0.002) all increased with the rising tertile levels of SHR. After multivariate adjustment, elevated SHR was significantly associated with an increased risk of AKI (odds ratio 3.18, 95% confidence interval: 1.99-5.09, p < 0.001) while ABG was no longer a risk factor of AKI. The SHR was also strongly related to the AKI risk in subgroups of patients. At ROC analysis, SHR accurately predicted AKI in overall (AUC 0.64) and a risk model consisted of SHR, left ventricular ejection fraction, N-terminal B-type natriuretic peptide, and estimated glomerular filtration rate (eGFR) yielded a superior predictive value (AUC 0.83) for AKI.

Conclusion: The novel index SHR is a better predictor of AKI and in-hospital mortality and morbidity than admission glycemia in AMI patients with diabetes.
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http://dx.doi.org/10.1186/s12872-021-01962-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008672PMC
March 2021

Predictive effect of triglyceride‑glucose index on clinical events in patients with type 2 diabetes mellitus and acute myocardial infarction: results from an observational cohort study in China.

Cardiovasc Diabetol 2021 02 11;20(1):43. Epub 2021 Feb 11.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Beijing, 100050, China.

Background: Triglyceride glucose (TyG) index is considered a reliable alternative marker of insulin resistance and an independent predictor of cardiovascular (CV) outcomes. However, the prognostic value of TyG index in patients with type 2 diabetes mellitus (TDM) and acute myocardial infarction (AMI) remains unclear.

Methods: A total of 1932 consecutive patients with TDM and AMI were enrolled in this study. Patients were divided into tertiles according to their TyG index levels. The incidence of major adverse cardiac and cerebral events (MACCEs) was recorded. The TyG index was calculated as the ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2].

Results: Competing risk regression revealed that the TyG index was positively associated with CV death [2.71(1.92 to 3.83), p < 0.001], non-fatal MI [2.02(1.32 to 3.11), p = 0.001], cardiac rehospitalization [2.42(1.81 to 3.24), p < 0.001], revascularization [2.41(1.63 to 3.55), p < 0.001] and composite MACCEs [2.32(1.92 to 2.80), p < 0.001]. The area under ROC curve of the TyG index for predicting the occurrence of MACCEs was 0.604 [(0.578 to 0.630), p < 0.001], with the cut-off value of 9.30. The addition of TyG index to a baseline risk model had an incremental effect on the predictive value for MACCEs [net reclassification improvement (NRI): 0.190 (0.094 to 0.337); integrated discrimination improvement (IDI): 0.027 (0.013 to 0.041); C-index: 0.685 (0.663 to 0.707), all p < 0.001].

Conclusions: The TyG index was significantly associated with MACCEs, suggesting that the TyG index may be a valid marker for risk stratification and prognosis in patients with TDM and AMI. Trial registration Retrospectively registered.
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http://dx.doi.org/10.1186/s12933-021-01236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879620PMC
February 2021

High Triglyceride-Glucose Index is Associated with Poor Cardiovascular Outcomes in Nondiabetic Patients with ACS with LDL-C below 1.8 mmol/L.

J Atheroscler Thromb 2021 Feb 3. Epub 2021 Feb 3.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University.

Aim: To evaluate the prognostic value of triglyceride-glucose (TyG) index in nondiabetic patients with acute coronary syndrome (ACS) with low-density lipoprotein cholesterol (LDL-C) below 1.8 mmol/L.

Methods: A total of 1655 nondiabetic patients with ACS with LDL-C below 1.8 mmol/L were included in the analysis. Patients were stratified into two groups. The incidence of acute myocardial infarction (AMI), infarct size in patients with AMI, and major adverse cardiac and cerebral event during a median of 35.6-month follow-up were determined and compared between the two groups. The TyG index was calculated using the following formula: ln [fasting triglycerides (mg/dL)×fasting plasma glucose (mg/dL)/2].

Results: Compared with the TyG index <8.33 group, the TyG index ≥ 8.33 group had a significantly higher incidence of AMI (21.2% vs. 15.2%, p=0.014) and larger infarct size in patients with AMI [the peak value of troponin I: 10.4 vs. 4.8 ng/ml, p=0.003; the peak value of Creatine kinase MB: 52.8 vs. 22.0 ng/ml, p=0.006; the peak value of myoglobin: 73.7 vs. 46.0 ng/ml, p=0.038]. Although there was no significant difference in mortality between the two groups, the incidence of revascularization of the TyG index ≥ 8.33 group was significantly higher than that of the TyG index <8.33 group (8.9% vs. 5.0%, p=0.035). A multivariable Cox regression revealed that the TyG index was positively associated with revascularization [hazard ratio, 1.67; 95% confidence interval, 1.02-2.75; p=0.043].

Conclusions: In nondiabetic patients with ACS with LDL-C below 1.8 mmol/L, a high TyG index level was associated with higher incidence of AMI, larger infarct size, and higher incidence of revascularization. A high TyG index level might be a valid predictor of subsequent revascularization.
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http://dx.doi.org/10.5551/jat.61119DOI Listing
February 2021

Pseudogene Annexin A2 Pseudogene 1 Contributes to Hepatocellular Carcinoma Progression by Modulating Its Parental Gene ANXA2 via miRNA-376a-3p.

Dig Dis Sci 2021 Jan 4. Epub 2021 Jan 4.

Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), No. 1 Jiazi Road, Lunjiao, Shunde District, Foshan, 528308, Guangdong Province, China.

Background: Pseudogenes are defined as key regulators in cancer initiation and progression. But their biological function and clinical significance in hepatocellular carcinoma (HCC) remain to be elucidated. In the current study, we identified a novel pseudogene, Annexin A2 pseudogene 1 (ANXA2P1), in HCC and explored its underlining molecular mechanism.

Methods And Results: We analyzed the expression pattern of ANXA2P1 in a TCGA dataset and an HCC sample cohort and evaluated its clinical significance. The biological effects on HCC cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process were assessed by Cell Counting Kit-8 assay, Transwell assay and Western blot, respectively. The ANXA2P1/miR-376a-3p/ANXA2 axis was determined by bioinformatics analysis and dual-luciferase reporter assays. ANXA2P1 exerted as an oncogene that was significantly overexpressed in HCC tissues and was associated with disease progression and unfavorable prognosis of HCC patients. ANXA2P1 knockdown suppressed cell growth, cell migration and invasion and reversed EMT phenotype in HCC. Mechanistically, ANXA2P1 acts as a competing endogenous RNA for miR-376a-3p, thereby leading to the upregulation of its cognate gene ANXA2.

Conclusions: ANXA2P1/miR-376a-3p/ANXA2 axis plays an important role in the progression of HCC. Our findings may provide valuable therapeutic target for treating HCC.
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http://dx.doi.org/10.1007/s10620-020-06734-0DOI Listing
January 2021

Development of GLUT1-targeting alkyl glucoside-modified dihydroartemisinin liposomes for cancer therapy.

Nanoscale 2020 Nov;12(42):21901-21912

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.

The antitumor activity of artemisinin derivatives has attracted much attention. However, lack of tumor targeting limits the anti-tumor activity of artemisinin derivatives. It is reported that tumor cells acquire energy through the glycolysis pathway. To meet their elevated glucose requirements, high expressions of glucose transporters (GLUTs) are observed in many malignant cells. On this basis, novel alkyl glycoside-modified dihydroartemisinin liposomes were successfully prepared with GLUT1 as the target and the glucose segment of an alkyl glycoside as the targeting head on the surface of liposomes. The particle size of the liposomes was 100.67 ± 1.25 nm, zeta potential was -22.93 ± 0.92 mV and encapsulation efficiency was 75.28 ± 0.73%, meanwhile the liposomes had good stability. In vitro targeting of liposomes was evaluated by fluorescence microscopy and flow cytometry. Compared with human L02 hepatocyte cells, the liposomes showed better targeting ability to human liver carcinoma cells HepG2 with the help of the glucose segment modified on the liposomes. In vivo targeting evaluation also showed that the tumor targeting of alkyl glycoside-modified liposomes was significantly improved, as well as the anti-tumor activity. These findings provide a research and theoretical basis for the development of artemisinin derivatives and other drug targeted antitumor nano-agents.
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http://dx.doi.org/10.1039/d0nr05138aDOI Listing
November 2020

High triglyceride-glucose index is associated with adverse cardiovascular outcomes in patients with acute myocardial infarction.

Nutr Metab Cardiovasc Dis 2020 11 2;30(12):2351-2362. Epub 2020 Aug 2.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular Disease, Beijing, China; Department of Geriatrics, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China. Electronic address:

Background And Aims: Triglyceride glucose (TyG) index is considered a new surrogate marker of insulin resistance that associated with the development of vascular disease. The aim of this study was to evaluate the prognostic value of TyG index in patients with acute myocardial infarction (AMI).

Methods And Results: A total of 3181 patients with AMI were included in the analysis. Patients were stratified into 2 groups according to their TyG index levels: the TyG index <8.88 group and the TyG index ≥8.88 group. The incidence of major adverse cardiovascular events (MACEs) during a median of 33.3-month follow-up were recorded. Multivariable Cox regression models revealed that the TyG index was positively associated with all-cause death [HR (95% CI): 1.51 (1.10,2.06), p = 0.010], cardiac death [HR (95% CI): 1.68 (1.19,2.38), p = 0.004], revascularization [HR (95% CI): 1.50 (1.16,1.94), p = 0.002], cardiac rehospitalization [HR (95% CI): 1.25 (1.05,1.49), p = 0.012], and composite MACEs [HR (95% CI): 1.19 (1.01,1.41), p = 0.046] in patients with AMI. The independent predictive effect of TyG index on composite MACEs was mainly reflected in the subgroups of male gender and smoker. The area under the curve (AUC) of the TyG index predicting the occurrence of MACEs in AMI patients was 0.602 [95% CI 0.580,0.623; p < 0.001].

Conclusion: High TyG index levels appeared to be associated with an increased risk of MACEs in patients with AMI. The TyG index might be a valid predictor of cardiovascular outcomes of patients with AMI.

Trial Registration: Retrospectively registered.
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http://dx.doi.org/10.1016/j.numecd.2020.07.041DOI Listing
November 2020

Role of peroxisome proliferators-activated receptor-gamma in advanced glycation end product-mediated functional loss of voltage-gated potassium channel in rat coronary arteries.

BMC Cardiovasc Disord 2020 07 14;20(1):337. Epub 2020 Jul 14.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xicheng, Beijing, 100050, P. R. China.

Background: High blood glucose impairs voltage-gated K (Kv) channel-mediated vasodilation in rat coronary artery smooth muscle cells (CSMCs) via oxidative stress. Advanced glycation end product (AGE) and receptor for AGE (RAGE) axis has been found to impair coronary dilation by reducing Kv channel activity in diabetic rat small coronary arteries (RSCAs). However, its underlying mechanism remain unclear. Here, we used isolated arteries and primary CSMCs to investigate the effect of AGE incubation on Kv channel-mediated coronary dilation and the possible involvement of peroxisome proliferators-activated receptor (PPAR) -γ pathway.

Methods: The RSCAs and primary CSMCs were isolated, cultured, and treated with bovine serum albumin (BSA), AGE-BSA, alagrebrium (ALA, AGE cross-linking breaker), pioglitazone (PIO, PPAR-γ activator) and/or GW9662 (PPAR-γ inhibitor). The groups were accordingly divided as control, BSA, AGE, AGE + ALA, AGE + PIO, or AGE + PIO + GW9662. Kv channel-mediated dilation was analyzed using wire myograph. Histology and immunohistochemistry of RSCAs were performed. Western blot was used to detect the protein expression of RAGE, major Kv channel subunits expressed in CSMCs (Kv1.2 and Kv1.5), PPAR-γ, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2).

Results: AGE markedly reduced Forskolin-induced Kv channel-mediated dilation of RSCAs by engaging with RAGE, and ALA or PIO significantly reversed the functional loss of Kv channel. In both RSCAs and CSMCs, AGE reduced Kv1.2/1.5 expression, increased RAGE and NOX-2 expression, and inhibited PPAR-γ expression, while ALA or PIO treatment partially reversed the inhibiting effects of AGE on Kv1.2/1.5 expression, accompanied by the downregulation of RAGE and decreased oxidative stress. Meanwhile, silencing of RAGE with siRNA remarkably alleviated the AGE-induced downregulation of Kv1.2/1.5 expression in CSMCs.

Conclusion: AGE reduces the Kv channel expression in CSMCs and further impairs the Kv channel-mediated dilation in RSCAs. The AGE/RAGE axis may enhance oxidative stress by inhibiting the downstream PPAR-γ pathway, thus playing a critical role in the dysfunction of Kv channels.
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http://dx.doi.org/10.1186/s12872-020-01613-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362521PMC
July 2020

Hepatic venous pressure gradient-guided laparoscopic splenectomy and pericardial devascularisation versus endoscopic therapy for secondary prophylaxis for variceal rebleeding in portal hypertension (CHESS1803): study protocol of a multicenter randomised controlled trial in China.

BMJ Open 2020 06 23;10(6):e030960. Epub 2020 Jun 23.

CHESS Center, Institute of Portal Hypertension, The First Hospital of Lanzhou University, Lanzhou, China

Introduction: Gastro-oesophageal variceal bleeding is one of the most common and severe complications with high mortality in cirrhotic patients who developed portal hypertension. Hepatic venous pressure gradient (HVPG) is a globally recommended golden standard for the portal pressure assessment and an HVPG ≥16 mm Hg indicates a higher risk of death and rebleeding. This study aims to compare the effectiveness and safety of splenectomy and pericardial devascularisation (laparoscopic therapy) plus propranolol and endoscopic therapy plus propranolol for variceal rebleeding in cirrhotic patients with HVPG between 16 and 20 mm Hg.

Methods And Analysis: This is a multicenter, randomised, controlled clinical trial. Participants will be 1:1 assigned randomly into either laparoscopic or endoscopic groups. Forty participants whose transjugular HVPG lies between 16 and 20 mm Hg with a history of gastro-oesophageal variceal bleeding will be recruited from three sites in China. Participants will receive either endoscopic therapy plus propranolol or laparoscopic therapy plus propranolol. The primary outcome measure will be the occurrence of gastro-oesophageal variceal rebleeding. Secondary outcome measures will include overall survival, occurrence of hepatocellular carcinoma, the occurrence of venous thrombosis, the occurrence of adverse events, quality of life and tolerability of treatment. Outcome measures will be evaluated at baseline, 12 weeks, 24 weeks, 36 weeks, 48 weeks and 60 weeks. Multivariate COX regression model will be introduced for analyses of occurrence data and Kaplan-Meier analysis with the log-rank test for intergroup comparison.

Ethics And Dissemination: Ethical approval was obtained from all three participating sites. Primary and secondary outcome data will be submitted for publication in peer-reviewed journals and widely disseminated.

Trial Registration Number: NCT03783065; Pre-results.

Trial Status: Recruitment for this study started in December 2018 while the first participant was randomised in January 2019. Recruitment is estimated to stop in October 2019.
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http://dx.doi.org/10.1136/bmjopen-2019-030960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312451PMC
June 2020

Protective effect of seabuckthorn berry juice against acrylamide-induced oxidative damage in rats.

J Food Sci 2020 Jul 24;85(7):2245-2254. Epub 2020 Jun 24.

College of Food Science, Northeast Agricultural University, Harbin, 150030, China.

Acrylamide (AA), classified as a probable carcinogen, can be neurotoxic, genotoxic, and can damage DNA. This study explored the ability of seabuckthorn berries juice (SBJ) to alleviate AA-induced toxic injury in rats. Twenty-four adult male Sprague-Dawley (SD) rats were randomly divided into four groups: control group, AA group (40 mg/kg), AA + SBJ (40 mg/kg AA and 5 mL/kg SBJ), and AA + vitamin C (VC) group (positive control group, 40 mg/kg AA and 100 mg/kg VC). At the end of the experiment, rats in AA group showed a marked decrease in the rate of weight gain, hind extremity abduction, and ataxia. Obvious anomalies were seen in plasma biochemical parameters (P < 0.05), and different degrees of injury were observed upon histological examination of five tissues (hippocampus, cerebellum, liver, small intestine, and kidney). Compared to the control group, levels of superoxide dismutase, catalase, and glutathione were significantly decreased, while malondialdehyde was elevated (P < 0.05). SBJ treatment reduced the abnormal of behavior, hematological index, antioxidant enzyme, and tissue damage caused by AA in rats. PRACTICAL APPLICATION: Seabuckthorn berries are wild berries rich in vitamin C and polyphenols, which have good antioxidant properties. In this experiment, SBJ has a significant alleviating effect on AA-induced oxidative damage in rats. Therefore, we speculate that SBJ may relieve the oxidative damage caused by diet or other forms of AA exposure in the general population. At the same time, this experiment also provides new ideas for alleviating AA-induced in vivo toxicity.
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http://dx.doi.org/10.1111/1750-3841.15313DOI Listing
July 2020

Semi-synthesis and biological evaluation of flavone hybrids as multifunctional agents for the potential treatment of Alzheimer's disease.

Bioorg Chem 2020 07 12;100:103917. Epub 2020 May 12.

Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. Electronic address:

7-O-galloyltricetiflavan (GTF), a natural flavonoid, is known to exert anti-oxidation and neuroprotective activity, which are related to the prevention of Alzheimer's disease (AD). In this study, three series of GTF hybrids have been designed, synthesized and evaluated as multifunctional agents for treatment AD. The biological assays indicated that most of them showed strong inhibitory effect on self-induced β-amyloid (Aβ) aggregation, and a significant ability to inhibit ChEs. Among them, compound A15 exhibited best inhibition of Aβ aggregation (78.81% at 20 μM), potent AChE inhibitory potencies (IC, 0.56 μM), and compound C4 presented the highest ability to inhibit BuChE (IC, 5.77 μM). Furthermore, kinetic, molecular modeling and molecular dynamics studies revealed that A15 and C4 could interact with the catalytic active site of AChE and BuChE, respectively. In addition, compounds A15 and C4 could cross the blood-brain barrier in vitro. More importantly, A15 and C4 also showed excellent neuroprotective activities against HO-induced human neuroblastoma SH-SY5Y cells damage and nearly no toxicity on SH-SY5Y cells. All of these outstanding in vitro results indicated A15 and C4 as the leading structure worthy of further investigation.
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http://dx.doi.org/10.1016/j.bioorg.2020.103917DOI Listing
July 2020

Integrin α4β7 in HIV-1 infection: A critical review.

J Leukoc Biol 2020 08 9;108(2):627-632. Epub 2020 Apr 9.

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Over the past decade, a series of observations linking α4β7, the principal gut-homing integrin, with various aspects of HIV-1 infection have generated considerable interest in the field of HIV-1 research. After the initial report that the major HIV-1 envelope glycoprotein, gp120, can bind to α4β7, intensive research efforts have been focused on the role of α4β7 as a key factor in HIV-1 pathogenesis and as a potential target for prevention and treatment. The interaction between α4β7 and its natural ligand, MAdCAM-1, directs infected CD4 T cells and HIV-1 virions carrying incorporated α4β7 to the gut mucosa, which may facilitate HIV-1 seeding and replication in the intestinal compartment during the early stages of infection. In addition, cells that express high levels of α4β7, such as Th17 cells, represent preferential targets for infection, and their frequency in the circulation was shown to correlate with susceptibility to HIV-1 infection and disease progression. A number of in vivo studies in nonhuman primates have investigated whether blockage of α4β7 may affect SIV transmission and pathogenesis. Administration of a primatized anti-α4β7 antibody that blocks MAdCAM-1 binding to α4β7 was reported to reduce SIV mucosal transmission in rhesus macaques. However, the mechanism responsible for such a protective effect is still undefined, and conflicting results have been reported on the effects of the same antibody, in combination with ART, during the early chronic phase of SIV infection. Thus, despite a series of tantalizing results accrued over the past decade, the jury is still out on the role of α4β7 in HIV-1 infection.
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http://dx.doi.org/10.1002/JLB.4MR0120-208RDOI Listing
August 2020

Real-world use of ACEI/ARB in diabetic hypertensive patients before the initial diagnosis of obstructive coronary artery disease: patient characteristics and long-term follow-up outcome.

J Transl Med 2020 04 1;18(1):150. Epub 2020 Apr 1.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Beijing, 100050, China.

Background: Current guidelines recommend angiotensin-converting-enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) as a first-line therapy in diabetic hypertensive patients and for secondary prevention in patients with obstructive coronary artery disease (OCAD). However, the effects of using ACEI/ARB before the initial diagnosis of OCAD on major adverse cardiac and cerebral event (MACCE) in diabetic hypertensive patients remain unclear. This study investigated whether using ACEI/ARB before the initial diagnosis of OCAD could be associated with improved clinical outcomes in diabetic hypertensive patients.

Methods: A total of 2501 patients with hypertension and diabetes, who were first diagnosed with OCAD by coronary angiography, were included in the analysis. Of the 2501 patients, 1300 did not used ACEI/ARB before the initial diagnosis of OCAD [the ACEI/ARB(-) group]; 1201 did [the ACEI/ARB(+) group]. Propensity score matching at 1:1 was performed to select 1050 patients from each group. Incidence of acute myocardial infarction (AMI), infarct size in patients with AMI, heart function, and subsequent MACCE during a median of 25.4-month follow-up were determined and compared between the 2 groups.

Results: Compared with the ACEI/ARB(-) group, the ACEI/ARB(+) group had significantly lower incidence of AMI (22.5% vs. 28.4%, p < 0.05), smaller infarct size in patients with AMI (pTNI: 5.7 vs. 6.8 ng/ml, p < 0.05; pCKMB: 21.7 vs. 28.7 ng/ml, p < 0.05), better heart function (LVEF: 60.0 vs. 58.5%, p < 0.05), and lower incidences of non-fatal stroke (2.4% vs. 4.6%, p < 0.05) and composite MACCE (23.1% vs. 29.7%, p < 0.05). No prior ACEI/ARB therapy was significantly and independently associated with non-fatal stroke and composite MACCE.

Conclusions: In diabetic hypertensive patients, treatment with ACEI/ARB before the initial diagnosis with OCAD was associated with decreased incidence of AMI, smaller infarct size, improved heart function, and lower incidences of non-fatal stroke and composite MACCE. Trial registration Retrospectively registered.
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http://dx.doi.org/10.1186/s12967-020-02314-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114815PMC
April 2020

Deep Convolutional Neural Network-Aided Detection of Portal Hypertension in Patients With Cirrhosis.

Clin Gastroenterol Hepatol 2020 12 21;18(13):2998-3007.e5. Epub 2020 Mar 21.

Department of Radiology, Ankara University School of Medicine, Ankara, Turkey.

Background & Aims: Noninvasive and accurate methods are needed to identify patients with clinically significant portal hypertension (CSPH). We investigated the ability of deep convolutional neural network (CNN) analysis of computed tomography (CT) or magnetic resonance (MR) to identify patients with CSPH.

Methods: We collected liver and spleen images from patients who underwent contrast-enhanced CT or MR analysis within 14 days of transjugular catheterization for hepatic venous pressure gradient measurement. The CT cohort comprised participants with cirrhosis in the CHESS1701 study, performed at 4 university hospitals in China from August 2016 through September 2017. The MR cohort comprised participants with cirrhosis in the CHESS1802 study, performed at 8 university hospitals in China and 1 in Turkey from December 2018 through April 2019. Patients with CSPH were identified as those with a hepatic venous pressure gradient of 10 mm Hg or higher. In total, we analyzed 10,014 liver images and 899 spleen images collected from 679 participants who underwent CT analysis, and 45,554 liver and spleen images from 271 participants who underwent MR analysis. For each cohort, participants were shuffled and then sampled randomly and equiprobably for 6 times into training, validation, and test data sets (ratio, 3:1:1). Therefore, a total of 6 deep CNN models for each cohort were developed for identification of CSPH.

Results: The CT-based CNN analysis identified patients with CSPH with an area under the receiver operating characteristic curve (AUC) value of 0.998 in the training set (95% CI, 0.996-1.000), an AUC of 0.912 in the validation set (95% CI, 0.854-0.971), and an AUC of 0.933 (95% CI, 0.883-0.984) in the test data sets. The MR-based CNN analysis identified patients with CSPH with an AUC of 1.000 in the training set (95% CI, 0.999-1.000), an AUC of 0.924 in the validation set (95% CI, 0.833-1.000), and an AUC of 0.940 in the test data set (95% CI, 0.880-0.999). When the model development procedures were repeated 6 times, AUC values for all CNN analyses were 0.888 or greater, with no significant differences between rounds (P > .05).

Conclusions: We developed a deep CNN to analyze CT or MR images of liver and spleen from patients with cirrhosis that identifies patients with CSPH with an AUC value of 0.9. This provides a noninvasive and rapid method for detection of CSPH (ClincialTrials.gov numbers: NCT03138915 and NCT03766880).
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http://dx.doi.org/10.1016/j.cgh.2020.03.034DOI Listing
December 2020

An Electrically Controlled Wavelength-Tunable Nanoribbon Laser.

ACS Nano 2020 Mar 18;14(3):3397-3404. Epub 2020 Feb 18.

Key Laboratory for Micro-Nano Physics and Technology of Hunan Province, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Materials Science and Engineering, Hunan University, Changsha 410082, Hunan, People's Republic of China.

Nanoscale laser sources with downscaled device footprint, high energy efficiency, and high operation speed are pivotal for a wide array of optoelectronic and nanophotonic applications ranging from on-chip interconnects, nanospectroscopy, and sensing to optical communication. The capability of on-demand lasing output with reversible and continuous wavelength tunability over a broad spectral range enables key functionalities in wavelength-division multiplexing and finely controlled light-matter interaction, which remains an important subject under intense research. In this study, we demonstrate an electrically controlled wavelength-tunable laser based on a CdS nanoribbon (NR) structure. Typical "S"-shaped characteristics of pump power dependence were observed for dominant lasing lines, with concomitant line width narrowing. By applying an increased bias voltage across the NR device, the lasing resonance exhibits a continuous tuning from 510 to 520 nm for a bias field in the range 0-15.4 kV/cm. Systematic bias-dependent absorption and time-resolved photoluminescence (PL) measurements were performed, revealing a red-shifted band edge of gain medium and prolonged PL lifetime with increased electric field over the device. Both current-induced thermal reduction of the band gap and the Franz-Keldysh effect were identified to account for the modification of the lasing profile, with the former factor playing the leading role. Furthermore, dynamical switching of NR lasing was successfully demonstrated, yielding a modulation ratio up to ∼21 dB. The electrically tuned wavelength-reversible CdS NR laser in this work, therefore, presents an important step toward color-selective coherent emitters for future chip-based nanophotonic and optoelectronic circuitry.
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http://dx.doi.org/10.1021/acsnano.9b09301DOI Listing
March 2020

Two predictive precision medicine tools for hepatocellular carcinoma.

Cancer Cell Int 2019 14;19:290. Epub 2019 Nov 14.

1Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Shunde, Guangdong China.

Background: Hepatocellular carcinoma (HCC) is a serious threat to public health due to its poor prognosis. The current study aimed to develop and validate a prognostic nomogram to predict the overall survival of HCC patients.

Methods: The model cohort consisted of 24,991 mRNA expression data points from 348 HCC patients. The least absolute shrinkage and selection operator method (LASSO) Cox regression model was used to evaluate the prognostic mRNA biomarkers for the overall survival of HCC patients.

Results: Using multivariate Cox proportional regression analyses, a prognostic nomogram (named Eight-mRNA prognostic nomogram) was constructed based on the expression data of N4BP3, -ADRA2B, E2F8, MAPT, PZP, HOXD9, COL15A1, and -NDST3. The C-index of the Eight-mRNA prognostic nomogram was 0.765 (95% CI 0.724-0.806) for the overall survival in the model cohort. The Harrell's concordance-index of the Eight-mRNA prognostic nomogram was 0.715 (95% CI 0.658-0.772) in the validation cohort. The survival curves demonstrated that the HCC patients in the high risk group had a significantly poorer overall survival than the patients in the low risk group.

Conclusion: In the current study, we have developed two convenient and efficient predictive precision medicine tools for hepatocellular carcinoma. These two predictive precision medicine tools are helpful for predicting the individual mortality risk probability and improving the personalized comprehensive treatments for HCC patients. The Smart Cancer Predictive System can be used by clicking the following URL: https://zhangzhiqiao2.shinyapps.io/Smart_cancer_predictive_system_HCC_2/. The Gene Survival Analysis Screen System is available at the following URL: https://zhangzhiqiao5.shinyapps.io/Gene_Survival_Analysis_A1001/.
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http://dx.doi.org/10.1186/s12935-019-1002-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854692PMC
November 2019

AGEs impair Kv channel-mediated vasodilation of coronary arteries by activating the NF-κB signaling pathway in ZDF rats.

Biomed Pharmacother 2019 Dec 17;120:109527. Epub 2019 Oct 17.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China; Department of Internal Medicine, Medical Health Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China; Beijing Key Laboratory of Metabolic Disorder-Related Cardiovascular Disease, Beijing 100069, PR China. Electronic address:

Excessive formation of advanced glycation end products (AGEs) impairs voltage-gated potassium (Kv) channels in rat coronary artery smooth muscle cells (CSMCs), resulting in weakened Kv-mediated coronary vasodilation. We hypothesized that induction of the nuclear factor-κB (NF-κB) signaling pathway by AGEs plays a significant role in the regulation of Kv channel-mediated vasodilation in Zucker diabetic fatty (ZDF) rats. Assays of mRNA transcripts, protein expression, and intracellular localization as well as patch-clamp experiments in cultured CSMCs revealed that AGEs significantly induced activation of the NF-κB signaling pathway, reduced Kv1.2/1.5 expression, and inhibited Kv currents. In addition, silencing of the receptor for AGEs (RAGE) or p65 with siRNA and treatment with alagrebrium (ALA) or pyrrolidine dithiocarbamate (PDTC) alleviated the AGE-induced impairment of Kv channels in CSMCs. Compared with Zucker lean (ZL) rats, the amount of AGEs, RAGE protein expression, and NF-κB activity in coronary arteries were higher in ZDF rats; whereas Kv1.2/1.5 expression was significantly lower in ZDF rats. Reduced Kv1.2/1.5 expression in coronary arteries and impaired Kv-mediated coronary relaxation tested by wire myography in ZDF rats were markedly improved by treatment with aminoguanidine (AG), ALA, or PDTC. These effects were accompanied by diminished NF-κB activity, inflammation, and oxidative stress. Taken together, these results indicate that an increased interaction between AGEs and RAGE in diabetic rats leads to impaired Kv channel-mediated coronary vasodilation. Moreover, activation of the NF-κB signaling pathway and a subsequent increase of inflammation and oxidative stress may play an important role in AGE-induced impairment of coronary vasodilation in diabetes.
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http://dx.doi.org/10.1016/j.biopha.2019.109527DOI Listing
December 2019

Identification of the perpetrator among identical twins using next-generation sequencing technology: A case report.

Forensic Sci Int Genet 2020 01 27;44:102167. Epub 2019 Sep 27.

Department of Biochemistry and Molecular Biology, Center for DNA Typing, Air Force Medical University, 169 Changle West Road, Xi'an, Shaanxi 710032, PR China. Electronic address:

Background: Monozygotic (MZ) twins, considered genetically identical, cannot be distinguished using regular short tandem repeats (STR) typing, thus presenting a challenge for forensic geneticists. In paternity testing, single nucleotide polymorphisms (SNPs) in nuclear DNA can help distinguish MZ twins. However, the unique features of the mitochondrial genome, such as high copy number, small genome size, and high substitution rate, make it a promising source for applications in forensic science.

Methods: Whole-genome sequencing (WGS) was performed on blood samples, and bioinformatic analysis was used to distinguish between MZ twins. Amplification refractory mutation system polymerase chain reaction (ARMS-PCR) was used to confirm the WGS results. This methodology was further applied to forensic samples from criminal cases. Amplicon sequencing was also performed to further exclude the innocent twin.

Results: The monozygosity of the twins was confirmed using STR typing. Only one potential somatic mutation, m.6903 T > C (2.6%), in the mitochondrial genome of one of the twins was verified when the sequence depth was set to 2000-fold, while no other distinguishing locus in the nuclear genome was identified. By dividing the number of C-reads by total reads, WGS data confirmed the amount of the minor component C to be 2.6%, which was further confirmed by ARMS-PCR. In addition, the heterogeneous locus was used to identify samples obtained from four criminal cases for forensic testing. Two heterogeneous loci in the sperm DNA of the other twin were identified by amplicon sequencing, and the amount of minor component T in m.6935C > T and m.6938C > T was estimated to be 17.91% and 18.79%, respectively.

Conclusion: The biological samples taken from the MZ twins were distinguished using a combination of WGS, allele-specific PCR, and deep-amplicon sequencing. Compared with nuclear DNA, mitochondrial DNA exhibited a higher potential for distinguishing between the MZ twins. The distinguishing feature of the mitochondrial DNA was the heterogeneous SNPs that occurred in only one twin. One SNP was further verified in the samples from the criminal cases and helped identify the perpetrator in case 1 and case 2. Furthermore, two heterogeneous SNPs found by amplicon sequencing helped to exclude the innocent twin in all four cases. Our findings demonstrated that a combination of deep sequencing and molecular analysis can be an effective way to distinguish between identical twins and can be used to analyze samples from criminal cases.
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http://dx.doi.org/10.1016/j.fsigen.2019.102167DOI Listing
January 2020

Monitoring a Heatsink Temperature Field Using Raman-Based Distributed Temperature Sensor in a Vacuum and -173 °C Environment.

Sensors (Basel) 2019 Sep 26;19(19). Epub 2019 Sep 26.

School of Instrumentation and Optoelectronic Engineering, Beihang University, Beijing 100191, China.

A heatsink is a large experimental device which is used to simulate the outer space environment. In this paper, a Raman-based distributed temperature sensor was used for real-time and continuous heatsink temperature monitoring, and a special Raman-based distributed temperature sensing method and system have been proposed. This method takes advantage of three calibration parameters ( Δ α , γ , C ) to calculate the temperature. These three parameters are related to the attenuation of the optical fiber, the Raman translation, and the difference of optoelectronic conversion, respectively. Optical time domain reflectometry was used to calculate the location. A series of heatsink temperature measurement experiments were performed in a vacuum and -173 °C environment. When the temperature dropped to -100 °C, the parameter Δ α was found to vary. A method was proposed to recalculate Δ α and modify the traditional Raman fiber temperature equation. The results of the experiments confirmed the validity of this modified Raman fiber temperature equation. Based on this modified equation, the temperature field in the heatsink was calculated. The Raman-based distributed temperature sensor has potential applications in temperature measurement and judging the occurrence of faults in space exploration.
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http://dx.doi.org/10.3390/s19194186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806063PMC
September 2019

Predictive Value of the Acute-to-Chronic Glycemic Ratio for In-Hospital Outcomes in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

Angiology 2020 Jan 25;71(1):38-47. Epub 2019 Sep 25.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

This study investigated whether a novel index of stress hyperglycemia might have a better prognostic value compared to admission glycemia alone in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). The acute-to-chronic glycemic ratio was expressed as admission blood glucose (ABG) devided by the estimated average glucose (eAG), and eAG was derived from the glycated hemoglobin (HbA1c). A total of 1300 consecutive patients with STEMI treated with PCI were included. Baseline data and outcomes were analyzed. The study end point was a composite of in-hospital all-cause death, cardiogenic shock, and acute pulmonary edema. Accuracy was defined with area under the curve (AUC) by a receiver-operating characteristic (ROC) curve analysis. After multivariate adjustment, both ABG/eAG and ABG were closely associated with an increased risk of the composite end point in nondiabetic patients. However, only ABG/eAG (odds ratio = 2.45, 95% confidence interval: 1.24-4.82, = .010), instead of ABG, was associated with the outcomes in diabetic patients. Compared to ABG, ABG/eAG had an equivalent predictive value in nondiabetic patients but a superior discriminatory ability in diabetic patients (AUC improved from 0.52-0.63, < .001). Taken together, ABG/eAG provides more significant in-hospital prognostic information than ABG in diabetic patients with STEMI after PCI.
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http://dx.doi.org/10.1177/0003319719875632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886151PMC
January 2020

Pioglitazone downregulates Twist-1 expression in the kidney and protects renal function of Zucker diabetic fatty rats.

Biomed Pharmacother 2019 Oct 23;118:109346. Epub 2019 Aug 23.

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China; Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular Disease, Beijing 100069, PR China. Electronic address:

Aims: Renal interstitial fibrosis and glomerulosclerosis are the characteristic presentation of diabetic nephropathy progression. Twist-1 overexpression contributes to renal fibrosis. Previous studies have demonstrated that pioglitazone (PIO), a PPAR-γ agonists, can ameliorate renal fibrosis and protect renal function. However, whether PIO attenuates renal fibrosis and delays diabetic nephropathy progression by regulating Twist-1 expression remains unclear.

Methods: Male Zucker diabetic fatty (ZDF) rats were randomly divided into 3 groups: (1) ZDF group, (2) ZDF + PIO group treated with PIO for 10 weeks, (3) ZDF + PIO + GW9662 group treated with GW9662 (a PPAR-γ antagonist) and PIO for 10 weeks. Age-matched Zucker lean rats (ZL group) were used as a control group. Urinary albumin/creatinine ratio (UACR) and renal blood flow were measured. Renal histopathology and Twist-1 expression were determined by immunohistochemistry. The protein and mRNA levels of Twist-1 and PPAR-γ were analyzed by Western blot and qRT-PCR.

Results: PIO considerably reduced UACR and improved renal blood flow. This was associated with amelioration of glomerulosclerosis and tubulointerstitial fibrosis evidenced by the expression decrease of collagen I, aquaporin 1, α-SMA, transforming growth factor β1 and nephrin, although glycaemia remained high. Moreover, Twist-1 protein and mRNA expression in kidney of ZDF rats were significantly increased compared with ZL rats and PIO significantly decreased Twist-1 levels.

Conclusions: This study shows that PIO can downregulate Twist-1 expression in the kidney, inhibit renal fibrosis and protect renal function in ZDF rats. These PIO-mediated effects are independent of glycemic control.
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http://dx.doi.org/10.1016/j.biopha.2019.109346DOI Listing
October 2019

Predictive value of the combination of age, creatinine, and ejection fraction score and diabetes in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.

Coron Artery Dis 2020 03;31(2):109-117

Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University.

Background: This study investigated whether the age, creatinine, and ejection fraction (ACEF) score [age (years) /ejection fraction (%) +1 (if creatinine>176μmol/L)] could predict 1-year outcomes following ST-segment elevation myocardial infarction after percutaneous coronary intervention, and whether accuracy could be improved by establishing novel ACEF-derived risk models.

Methods: A total of 1146 patients were included. The study endpoint was 1-year major adverse cardio-cerebrovascular events, including all-cause death, nonfatal myocardial infarction, unplanned revascularization, and nonfatal stroke. Accuracy was defined with area under the curve by receiver-operating characteristic curve analysis.

Results: The incidence of 1-year major adverse cardio-cerebrovascular event increased with the rising age, creatinine, and ejection fraction score tertiles (4.8%, 8.4%, and 15.2%, P < 0.001 for all). Higher ACEF score was significantly associated with an increased risk of the endpoint in overall (odds ratio = 3.75, 95% confidence interval, 2.44-5.77, P < 0.001) and in subgroups (all P < 0.05). The accuracy of the ACEF score was equivalent to the other complex risk scores. The combination of ACEF, and diabetes (ACEF-diabetes score) yielded a superior discriminatory ability than the original ACEF score (increase in C-statistic from 0.67 to 0.71, P = 0.048; continuous net reclassification improvement = 51.9%, 95% confidence interval, 33.4-70.5%, P < 0.001; integrated discrimination improvement = 0.020, 95% confidence interval, 0.011-0.030, P < 0.001).

Conclusions: The simplified ACEF score performed well in predicting 1-year outcomes in ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention. The novel ACEF-diabetes score provided a better predictive value and thus may help stratify high-risk patients and potentially facilitate decision making.
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http://dx.doi.org/10.1097/MCA.0000000000000791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004452PMC
March 2020

[Detection and analysis of an ATP2A2 mutation in a family with Darier-White disease].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Aug;36(8):794-797

Department of Biochemistry and Molecular Biology, Center for DNA Typing, the Fourth Military Medical University, Xi' an, Shaanxi 710032, China.

Objective: To explore the molecular basis for a pedigree affected with Darier-White disease.

Methods: Genomic DNA was isolated from 3 patients and 1 unaffected member from the pedigree, as well as 80 healthy controls. Targeted sequence capture and next-generation sequencing were used to screen mutations of skin disease-related genes. Candidate mutations were verified by Sanger sequencing, and co-segregation analysis was carried out to confirm the pathogenicity of mutation. Conservation analysis and protein structure and function were also predicted with Bioinformatic tools.

Results: A heterozygous mutation c.2246G>T (p.G749V) was identified in exon 15 of ATP2A2 gene in all 3 patients from the pedigree, but not in the unaffected member or 80 healthy controls. The corresponding amino acid was highly conserved, and mutation of which can lead to structural and functional changes of the protein.

Conclusion: The c.2246G>T missense mutation of the ATP2A2 gene probably underlies the Darier-White disease in this pedigree by causing damages to the structure and function of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2).
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.08.010DOI Listing
August 2019

Synthesis and Structure-Activity Relationship Correlations of Gnidimacrin Derivatives as Potent HIV-1 Inhibitors and HIV Latency Reversing Agents.

J Med Chem 2019 08 25;62(15):6958-6971. Epub 2019 Jul 25.

Natural Products Research Laboratories, UNC Eshelman School of Pharmacy , University of North Carolina , Chapel Hill , North Carolina 27599 , United States.

Currently, due to the HIV latency mechanism, the search continues for effective drugs to combat this issue and provide a cure for AIDS. Gnidimacrin activates latent HIV-1 replication and inhibits HIV-1 infection at picomolar concentrations. This natural diterpene was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells. Therefore, gnidimacrin is an excellent lead compound, and its anti-HIV potential merits further investigation. Twenty-nine modified gnidimacrin derivatives were synthesized and evaluated in assays for HIV replication and latency activation to establish which molecular structures must be maintained and which can tolerate changes that may be needed for better pharmacological properties. The results indicated that hydroxyl substituents at C-5 and C-20 are essential, while derivatives modified at 3-OH with aromatic esters retain anti-HIV replication and latent activation activities. The half-lives of the potent GM derivatives are over 20 h, which implies that they are stable in the plasm even though they contain ester linkages. The established structure-activity relationship should be useful in the development of gnidimacrin or structurally related compounds as clinical trial candidates.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442216PMC
August 2019

The competitive endogenous RNA regulatory network reveals potential prognostic biomarkers for overall survival in hepatocellular carcinoma.

Cancer Sci 2019 Sep 7;110(9):2905-2923. Epub 2019 Aug 7.

Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Shunde, China.

The aim of the present study is to construct a competitive endogenous RNA (ceRNA) regulatory network by using differentially expressed long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in patients with hepatocellular carcinoma (HCC), and to construct a prognostic model for predicting overall survival (OS) of HCC patients. Differentially expressed lncRNAs, miRNAs, and mRNAs were explored between HCC tissues and normal liver tissues. A prognostic model was built for predicting OS of HCC patients and receiver operating characteristic curves were used to evaluate the performance of the prognostic model. There were 455 differentially expressed lncRNAs, 181 differentially expressed miRNAs, and 5035 differentially expressed mRNAs. A ceRNA regulatory network was constructed based on 43 lncRNAs, 37 miRNAs, and 105 mRNAs. Eight mRNA biomarkers (H2AFX, SQSTM1, ITM2A, PFKP, TPD52L1, ACSL4, STRN3, and CPEB3) were identified as independent risk factors by multivariate Cox regression and were used to develop a prognostic model for OS. The C-indexes in the model group were 0.776 (95% confidence interval [CI], 0.730-0.822), 0.745 (95% CI, 0.699-0.791), and 0.789 (95% CI, 0.743-0.835) for 1-, 3-, and 5-year OS, respectively. The current study revealed potential molecular biological regulation pathways and prognostic biomarkers by the ceRNA regulatory network. A prognostic model based on prognostic mRNAs in the ceRNA network might be helpful to predict the individual mortality risk for HCC patients. The individual mortality risk calculator can be used by visiting the following URL: https://zhangzhiqiao.shinyapps.io/Smart_cancer_predictive_system_HCC/.
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http://dx.doi.org/10.1111/cas.14138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726690PMC
September 2019
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