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1.
Hum Mol Genet ; 33(14): 1215-1228, 2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38652261

ABSTRACT

Immunotherapy has revolutionized the treatment of tumors, but there are still a large number of patients who do not benefit from immunotherapy. Pericytes play an important role in remodeling the immune microenvironment. However, how pericytes affect the prognosis and treatment resistance of tumors is still unknown. This study jointly analyzed single-cell RNA sequencing (scRNA-seq) data and bulk RNA sequencing data of multiple cancers to reveal pericyte function in the colorectal cancer microenvironment. Analyzing over 800 000 cells, it was found that colorectal cancer had more pericyte enrichment in tumor tissues than other cancers. We then combined the TCGA database with multiple public datasets and enrolled more than 1000 samples, finding that pericyte may be closely related to poor prognosis due to the higher epithelial-mesenchymal transition (EMT) and hypoxic characteristics. At the same time, patients with more pericytes have higher immune checkpoint molecule expressions and lower immune cell infiltration. Finally, the contributions of pericyte in poor treatment response have been demonstrated in multiple immunotherapy datasets (n = 453). All of these observations suggest that pericyte can be used as a potential biomarker to predict patient disease progression and immunotherapy response.


Subject(s)
Biomarkers, Tumor , Colorectal Neoplasms , Immunotherapy , Pericytes , Single-Cell Analysis , Tumor Microenvironment , Humans , Pericytes/immunology , Pericytes/metabolism , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Single-Cell Analysis/methods , Prognosis , Immunotherapy/methods , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Biomarkers, Tumor/genetics , Sequence Analysis, RNA/methods , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic
2.
Acta Pharmacol Sin ; 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39020084

ABSTRACT

Ferroptosis is an iron-dependent programmed cell death process that involves lipid oxidation via the Fenton reaction to produce lipid peroxides, causing disruption of the lipid bilayer, which is essential for cellular survival. Ferroptosis has been implicated in the occurrence and treatment response of various types of cancer, and targeting ferroptosis has emerged as a promising strategy for cancer therapy. However, cancer cells can escape cellular ferroptosis by activating or remodeling various signaling pathways, including oxidative stress pathways, thereby limiting the efficacy of ferroptosis-activating targeted therapy. The key anti-oxidative transcription factor, nuclear factor E2 related factor 2 (Nrf2 or NFE2L2), plays a dominant role in defense machinery by reprogramming the iron, intermediate, and glutathione peroxidase 4 (GPX4)-related network and the antioxidant system to attenuate ferroptosis. In this review, we summarize the recent advances in the regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy and explore the prospect of combining Nrf2 inhibitors and ferroptosis inducers as a promising cancer treatment strategy.

3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(2): 171-176, 2023 Feb 10.
Article in Zh | MEDLINE | ID: mdl-36709935

ABSTRACT

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a child with acute form of tyrosinemia type I (TYRSN1). METHODS: A child with TYRSN1 who presented at the Gansu Provincial Maternal and Child Health Care Hospital in October 2020 was selected as the subject. The child was subjected to tandem mass spectrometry (MS-MS) and urine gas chromatography-mass spectrometry (GC-MS) for the detection of inherited metabolic disorders, in addition with whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing. RESULTS: The child's clinical features included abdominal distension, hepatomegaly, anemia and tendency of bleeding. By mass spectrometry analysis, her serum and urine tyrosine and succinylacetone levels have both exceeded the normal ranges. WES and Sanger sequencing revealed that she has harbored c.1062+5G>A and c.943T>C (p.Cys315Arg) compound heterozygous variants of the FAH gene, which were inherited from her father and mother, respectively. Among these, the c.943T>C was unreported previously. CONCLUSION: Considering her clinical phenotype and result of genetic testing, the child was diagnosed with TYRSN1 (acute type). The compound heterozygous variants of the FAH gene probably underlay the disease in this child. Above finding has further expanded the spectrum of FAH gene variants, and provided a basis for accurate treatment, genetic counseling and prenatal diagnosis for her family.


Subject(s)
Tyrosinemias , Female , Humans , Gas Chromatography-Mass Spectrometry , Genetic Testing , Mutation , Phenotype , Prenatal Diagnosis , Tyrosinemias/diagnosis , Tyrosinemias/genetics , Child
4.
Cell Commun Signal ; 20(1): 39, 2022 03 28.
Article in English | MEDLINE | ID: mdl-35346236

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify new insights in HCC to develop novel strategies for HCC management. METHODS: The role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, xenograft model, DEN (Diethylnitrosamine) induced mice liver cancer model with WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, western blotting, comet assay, and Immunofluorescence. RESULTS: High expression of WIP1 is associated with the poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation. Besides, WIP1 knockout retarded DEN induced mice hepato-carcinogenesis. Mechanically, WIP1 inhibition induced DNA damage by increasing H2AX phosphorylation (γH2AX). Therefore, suppression of WIP1 and PARP induced synthetic lethality in HCC in vitro and in vivo by augmenting DNA damage. CONCLUSION: WIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair alone or in combination with PARP inhibition might be a reasonable strategy for HCC management. Video abstract.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Mice , Phosphoprotein Phosphatases/genetics , Phosphoprotein Phosphatases/metabolism , Poly(ADP-ribose) Polymerase Inhibitors , Protein Phosphatase 2C/genetics , Protein Phosphatase 2C/metabolism , Synthetic Lethal Mutations
5.
Chemistry ; 27(21): 6529-6537, 2021 Apr 12.
Article in English | MEDLINE | ID: mdl-33521989

ABSTRACT

Through a dual-ligand synthetic approach, five isoreticular primitive cubic (pcu)-type pillared-layer metal-organic frameworks (MOFs), [Zn2 (dicarboxylate)2 (NI-bpy-44)]⋅x DMF⋅y H2 O, in which dicarboxylate=1,4-bdc (1), Br-1,4-bdc (2), NH2 -1,4-bdc (3), 2,6-ndc (4), and bpdc (5), have been engineered. MOFs 1-5 feature twofold degrees of interpenetration and have open pores of 27.0, 33.6, 36.8, 52.5, and 62.1 %, respectively. Nitrogen adsorption isotherms of activated MOFs 1'-5' at 77 K all displayed type I adsorption behavior, suggesting their microporous nature. Although 1' and 3'-5' exhibited type I adsorption isotherms of CO2 at 195 K, MOF 2' showed a two-step gate-opening sorption isotherm of CO2 . Furthermore, MOF 3' also had a significant influence of amine functions on CO2 uptake at high temperature due to the CO2 -framework interactions. MOFs 1-5 revealed solvent-dependent fluorescence properties; their strong blue-light emissions in aqueous suspensions were efficiently quenched by trace amounts of nitrobenzene (NB), with limits of detection of 4.54, 5.73, 1.88, 2.30, and 2.26 µm, respectively, and Stern-Volmer quenching constants (Ksv ) of 2.93×103 , 1.79×103 , 3.78×103 , 4.04×103 , and 3.21×103 m-1 , respectively. Of particular note, the NB-included framework, NB@3, provided direct evidence of the binding sites, which showed strong host-guest π-π and hydrogen-bonding interactions beneficial for donor-acceptor electron transfer and resulting in fluorescence quenching.

6.
Anal Bioanal Chem ; 413(12): 3329-3337, 2021 May.
Article in English | MEDLINE | ID: mdl-33712917

ABSTRACT

A new biosensing method is presented to detect gene mutation by integrating the MutS protein from bacteria with a fiber optic particle plasmon resonance (FOPPR) sensing system. In this method, the MutS protein is conjugated with gold nanoparticles (AuNPs) deposited on an optical fiber core surface. The target double-stranded DNA containing an A and C mismatched base pair in a sample can be captured by the MutS protein, causing increased absorption of green light launching into the fiber and hence a decrease in transmitted light intensity through the fiber. As the signal change is enhanced through consecutive total internal reflections along the fiber, the limit of detection for an AC mismatch heteroduplex DNA can be as low as 0.49 nM. Because a microfluidic chip is used to contain the optical fiber, the narrow channel width allows an analysis time as short as 15 min. Furthermore, the label-free and real-time nature of the FOPPR sensing system enables determination of binding affinity and kinetics between MutS and single-base mismatched DNA. The method has been validated using a heterozygous PCR sample from a patient to determine the allelic fraction. The obtained allelic fraction of 0.474 reasonably agrees with the expected allelic fraction of 0.5. Therefore, the MutS-functionalized FOPPR sensor may potentially provide a convenient quantitative tool to detect single nucleotide polymorphisms in biological samples with a short analysis time at the point-of-care sites.


Subject(s)
Biosensing Techniques/instrumentation , MutS Proteins/chemistry , Optical Fibers , Polymorphism, Single Nucleotide , Surface Plasmon Resonance/instrumentation , DNA, Single-Stranded/genetics , DNA, Single-Stranded/standards , Gold/chemistry , Humans , Limit of Detection , Metal Nanoparticles/chemistry , Point Mutation , Reference Standards , beta-Thalassemia/genetics
7.
Environ Sci Technol ; 54(4): 2510-2519, 2020 02 18.
Article in English | MEDLINE | ID: mdl-31922401

ABSTRACT

To investigate the effect of nonthermal plasma (NTP) on the microstructure and oxidation characteristics of particulate matter (PM) from diesel engines at different oxidation stages, a self-designed NTP reactor was used to conduct a time-varying oxidation test on PM samples. The oxidized PM samples were analyzed via thermogravimetric analysis and Raman spectroscopy. The results indicated that the effect of NTP could allow the elemental carbon (EC) to more easily start ignition. The oxidation activity of the EC decreased when the action time of the NTP was less than 5 min. Conversely, when the NTP action time was more than 5 min, the EC oxidation activity gradually increased. When the NTP was active for more than 10 min, it rapidly reacted with the EC, and the oxidation priority of the volatile fraction was higher than that of the EC. During the oxidation process, there are many forms of carbon structures in the particles and they have a mutual transmission relationship. The variation trend of the graphitization degree was consistent with that of the thermogravimetric results, indicating that the degree of graphitization directly affected the PM oxidation activity.


Subject(s)
Air Pollutants , Particulate Matter , Carbon , Oxidation-Reduction , Particle Size , Vehicle Emissions
8.
J Struct Biol ; 205(3): 44-52, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30742895

ABSTRACT

The 2-carboxy-6-hydroxyoctahydroindole (Choi) moiety is a hallmark of aeruginosins, a class of cyanobacterial derived bioactive linear tetrapeptides that possess antithrombotic activity. The biosynthetic pathway of Choi has yet to be resolved. AerE is a cupin superfamily enzyme that was shown to be involved in the biosynthesis of Choi, but its exact role remains unclear. This study reports the functional characterization and structural analyses of AerE. Enzymatic observation reveals that AerE can dramatically accelerate 1,3-allylic isomerization of the non-aromatic decarboxylation product of prephenate, dihydro-4-hydroxyphenylpyruvate (H2HPP). This olefin isomerization reaction can occur non-enzymatically and is the second step of the biosynthetic pathway from prephenate to Choi. The results of comparative structural analysis and substrate analogue binding geometry analysis combined with the results of mutational studies suggest that AerE employs an induced fit strategy to bind and stabilize the substrate in a particular conformation that is possibly favorable for 1,3-allylic isomerization of H2HPP through coordinate bonds, hydrogen bonds, π-π conjugation interaction and hydrophobic interactions. All of these interactions are critical for the catalytic efficiency.


Subject(s)
Bacterial Proteins/chemistry , Indoles/chemistry , Isomerases/chemistry , Microcystis/chemistry , Oligopeptides/chemistry , Amino Acid Sequence , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Binding Sites , Cloning, Molecular , Crystallography, X-Ray , Cyclohexanecarboxylic Acids/chemistry , Cyclohexanecarboxylic Acids/metabolism , Cyclohexenes/chemistry , Cyclohexenes/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/metabolism , Gene Expression , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Indoles/metabolism , Isomerases/genetics , Isomerases/metabolism , Kinetics , Microcystis/enzymology , Models, Molecular , Oligopeptides/genetics , Oligopeptides/metabolism , Phenylpyruvic Acids/chemistry , Phenylpyruvic Acids/metabolism , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Substrate Specificity
9.
Protein Expr Purif ; 154: 112-117, 2019 02.
Article in English | MEDLINE | ID: mdl-30240633

ABSTRACT

Carboxyl-terminal repeat domain (CTD) of the largest subunit Rpb1 of RNA polymerace II is essential for transcription regulation. Heptapeptide repeat of CTD of Rpb1 is phosphorylated by carboxyl-terminal repeat domain kinase (CTDK-I), composed of CTK1, CTK2 and CTK3, in order to regulate transcription and transcription associated processes. The yeast specific protein CTK3 binds to cyclin CTK2 to form a heterodimer serving as a regulational factor to control CTK1 activity by binding to CTK1. Structural information of CTK2-CTK3 complex is yet to be elucidated. Here, we report the co-expression of CTK2-CTK3 complex from Saccharomyces cerevisiae with N-terminal His6-tag in CTK3 in Escherichia coli (E. coli), purification of the complex by four chromatographic steps and crystallization of the complex as well as the diffraction data collection and processing. This study provides some essential information and a guide for structural and functional study of CTK2-CTK3 complex and CTDK-I in the future.


Subject(s)
Protein Kinases , Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Crystallography, X-Ray , Protein Kinases/biosynthesis , Protein Kinases/chemistry , Protein Kinases/genetics , Protein Kinases/isolation & purification , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/biosynthesis , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/isolation & purification
10.
Int J Mol Sci ; 20(3)2019 Feb 10.
Article in English | MEDLINE | ID: mdl-30744182

ABSTRACT

The prion protein (PrPSc) has drawn widespread attention due to its pathological potential to cause prion diseases. Herein, we successfully synthesized Fe3C@C by carbonizing Fe3O4-lignin clusters, which were prepared through a facile hydrogen bonding interaction between ≡Fe-OH and hydroxyl groups of lignin. Our in-depth investigation confirmed that the composites were Fe3C@C core/shell particles. We constructed a novel sandwich surface plasmon resonance (SPR) detection assay for sensitive PrPSc detection, utilizing bare gold surface and aptamer-modified Fe3C@C (Fe3C@C-aptamer). Due to the highly specific affinity of Fe3C@C-aptamer towards PrPSc, the sandwich type SPR sensor exhibited excellent analytical performance towards the discrimination and quantitation of PrPSc. A good linear relationship was obtained between the SPR responses and the logarithm of PrPSc concentrations over a range of 0.1⁻200 ng/mL. The detection sensitivity for PrPSc was improved by ~10 fold compared with the SPR direct detection format. The required detection time was only 20 min. The specificity of the present biosensor was also confirmed by PrPC and other reagents as controls. This proposed approach could also be used to isolate and detect other highly pathogenic biomolecules with similar structural characteristics by altering the corresponding aptamer in the Fe3C@C conjugates.


Subject(s)
Biosensing Techniques , Ferric Compounds , Lignin , Prion Proteins , Surface Plasmon Resonance , Aptamers, Peptide , Ferric Compounds/chemistry , Lignin/chemistry , Prion Proteins/chemistry , Pyrolysis , SELEX Aptamer Technique , Spectrum Analysis , Surface Plasmon Resonance/methods
11.
Opt Express ; 25(25): 32206-32213, 2017 Dec 11.
Article in English | MEDLINE | ID: mdl-29245884

ABSTRACT

Zinc gallate (ZnGa2O4; ZGO) thin films were employed as the p-type transparent contact layer in deep-ultraviolet AlGaN-based light-emitting diodes (LEDs) to increase light output power. The transmittance of 200-nm-thick ZGO in deep-ultraviolet wavelength (280 nm) was as high as 92.3%. Two different ohmic contact structures, a dot-LED (D-LED; ZGO/dot-ITO/LED) and whole-LED (W-LED; ZGO/ITO/LED), exhibited improved light output power and current spreading compared to a conventional ITO-LED (C-LED). At an injection current of 20 mA, the D-LED and W-LED exhibited 33.7% and 12.3% enhancements in light output power, respectively, compared to the C-LED. The enhanced light output power of the D-LED can be attributed to an improvement in current spreading and enhanced light-extracting efficiency achieved by introducing ZGO/dot-ITO.

12.
BMC Musculoskelet Disord ; 18(1): 150, 2017 04 08.
Article in English | MEDLINE | ID: mdl-28388886

ABSTRACT

BACKGROUND: The purpose was retrospectively to investigate functional and clinical outcomes after anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) reconstruction using a single allograft. METHODS: Patients with severe chronic lateral instability of the ankle underwent surgery after conservative treatment failed. Ultrasounds of the ankle were performed, and if the AFTL and CFL were completely torn without enough soft tissue for repair, the ligaments were reconstructed using allograft tendon. Outcomes were assessed by clinical examination, stress radiography, ultrasound, the American Orthopaedic Foot and Ankle Society score (AOFAS), and Karlsson Ankle Functional score (KAFS) before surgery and at final follow-up. RESULTS: Nineteen patients, ten men and nine women with mean age of 27.9 years (range, 19-41 years), underwent reconstruction. Mean follow-up was 30 months (range, 24-40 months). At final follow-up, all patients had returned to activity without instability, pain, or limited range of motion. On stress radiography, mean talar tilt angle decreased from 17.32° ± 3.58° before surgery to 4.16° ± 1.12° at follow-up (p < 0.001). Mean anterior drawer test (ADT) distance decreased from 9.79 ± 1.01 mm before surgery to 3.97 ± 0.99 mm at follow-up (p < 0.05). Mean AOFAS improved from 64.00 ± 18.43 to 90.32 ± 5.17 points (p < 0.001), and mean KAFS improved from 50.84 ± 16.73 to 90.89 ± 5.08 points (p < 0.001). Ultrasound showed the reconstructed ligaments maintained good continuity and excellent tension. No case of infection and immunological rejection was reported. CONCLUSION: This novel reconstruction technique takes into account the anatomical specialty of AFTL and CFL. This case series showed increased stability of the ankle in clinical and functional outcomes. TRIAL REGISTRATION: The trial registration number (TRN) and date of registration: ChiCTR-ORC-17010796 , Mar 6th 2017. Retrospectively registered.


Subject(s)
Ankle Joint/surgery , Arthroplasty/methods , Joint Instability/surgery , Lateral Ligament, Ankle/surgery , Tendons/transplantation , Adult , Allografts , Chronic Disease , Female , Humans , Male , Retrospective Studies , Young Adult
14.
Opt Express ; 23(12): 15452-8, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-26193525

ABSTRACT

A composite AlSi alloy substrate was fabricated to eliminate thermal expansion coefficient mismatch in high-power vertical light-emitting diodes (VLEDs). At 2000-mA injection current, the light output power performance of LED/sapphire, VLED/Si, and VLED/AlSi are 1458, 2465, and 2499 mW and the wall-plug efficiencies are 13.66%, 26.39%, and 28.02%, respectively. The enhanced performance is attributable to the lower tensile stress and series resistance in VLED/AlSi than in LED/sapphire. The surface temperature of LED/AlSi is almost identical to and lower than that of LED/Si and LED/sapphire, respectively. Raman spectroscopy confirms that the residual strain in GaN film bonding on the composite AlSi is lower than that on bulk sapphire.

15.
Int J Gen Med ; 17: 2701-2709, 2024.
Article in English | MEDLINE | ID: mdl-38895048

ABSTRACT

Background: In Asia, Hanta virus (HTNV) results in severe hemorrhagic fever with renal syndrome (HFRS). The efficacy of sivelestat in treating children with HTNV-induced HFRS remains unclear. Methods: An ambispective cohort study was performed on children diagnosed with HFRS and hospitalized at the Children's Hospital Affiliated to Xi'an Jiaotong University from August 2018 to 2023. Patients who received neutrophil elastin-inhibitor infusion between August 2019 and August 2023 were assigned to the sivelestat group, while patients who did not were assigned to the control group. The independent sample t test was used for inter-group analysis. The Chi-square test and Fisher's exact probability test were used for categorical variables. Spearman correlation test was used to evaluate the correlation between two sets of continuous variables. Kaplan-Meier survival curve and Log -Rank test was used to evaluate the difference in cumulative probability of survival between the two groups. Results: No significant differences were observed between the two groups in gender, age, contact history, body mass index, HFRS severity, clinical indexes at admission. Compared to the control group, the sivelestat group exhibited a significant decrease in the interleukin-8 level at 48 h (28.5±3 vs 34.5±3.5) and 72 h (21.3±4.5 vs 31.5±5.6) (P<0.05), as well as the ICAM-1 level at 48 h (553±122 vs 784±187) and 72 h (452±130 vs 623±85) (P<0.05). The concentration of VCAM-1 in the sivelestat group exhibited a consistent downward trend. Moreover, the level of VCAM-1 was significantly lower than that in the control group at 24 h (1760±289 vs 2180±445), 48 h (1450±441 vs 1890±267), and 72 h (1149±338 vs 1500±396) (P<0.05). Kaplan-Meier curve analysis revealed a statistically significant difference in the cumulative probability of survival between two groups (P = 0.041). In the secondary outcomes, the sivelestat group demonstrated a decrease in the utilization rate of mechanical ventilation and continuous renal replacement therapy (CRRT). Conclusion: Sivelestat may suppress neutrophil-mediated inflammatory response to reduce endothelial and organ damage, and improve clinical outcomes in children with severe hemorrhagic fever and renal syndrome.

16.
Theranostics ; 14(10): 4090-4106, 2024.
Article in English | MEDLINE | ID: mdl-38994016

ABSTRACT

Purpose: Due to intrinsic defensive response, ferroptosis-activating targeted therapy fails to achieve satisfactory clinical benefits. Though p62-Keap1-Nrf2 axis is activated to form a negative feedback loop during ferroptosis induction, how p62 is activated remains largely unknown. Methods: MTS assay was applied to measure cell growth. Lipid ROS was detected with C11-BODIPY reagent by flow cytometer. Quantitative real-time PCR (qPCR) and western blotting were performed to determine mRNA and protein level. Immunofluorescence (IF) was performed to examine the distribution of proteins. Fluorescence recovery after photobleaching (FRAP) was adopted to evaluate p62 phase separation. Immunoprecipitation (IP), co-IP and Proximal ligation assay (PLA) were performed to detected protein posttranslational modifications and protein-protein interactions. Tumor xenograft model was employed to inspect in vivo growth of pancreatic cancer cells. Results: Upon ferroptosis induction, Nuclear Factor E2 Related Factor 2 (Nrf2) protein and its downstream genes such as HMOX1 and NQO1 were upregulated. Knockdown of p62 significantly reversed Nrf2 upregulation and Keap1 decrease after ferroptosis induction. Knockdown of either p62 or Nrf2 remarkably sensitized ferroptosis induction. Due to augmented p62 phase separation, formation of p62 bodies were increased to recruit Keap1 after ferroptosis induction. Protein arginine methyltransferase 6 (PRMT6) mediated asymmetric dimethylarginine (ADMA) of p62 to increase its oligomerization, promoting p62 phase separation and p62 body formation. Knockdown of p62 or PRMT6 notably sensitized pancreatic cancer cells to ferroptosis both in vitro and in vivo through suppressing Nrf2 signaling. Conclusion: During ferroptosis induction, PRMT6 mediated p62 ADMA to promote its phase separation, sequestering Keap1 to activate Nrf2 signaling and inhibit ferroptosis. Therefore, targeting PRMT6-mediated p62 ADMA could be a new option to sensitize ferroptosis for cancer treatment.


Subject(s)
Arginine , Ferroptosis , Kelch-Like ECH-Associated Protein 1 , NF-E2-Related Factor 2 , Protein-Arginine N-Methyltransferases , Protein-Arginine N-Methyltransferases/metabolism , Protein-Arginine N-Methyltransferases/genetics , Humans , Animals , Arginine/metabolism , Arginine/analogs & derivatives , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Mice , Cell Line, Tumor , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Feedback, Physiological , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Sequestosome-1 Protein/metabolism , Sequestosome-1 Protein/genetics , Mice, Nude , Signal Transduction , Phase Separation , RNA-Binding Proteins
17.
Biosens Bioelectron ; 247: 115917, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38101186

ABSTRACT

Streptococcus agalactiae (Group B Streptococcus, GBS) has been the leading cause of infections in newborns. Rapid and accurate diagnosis of GBS in pregnant women is a deterministic strategy to prevent newborn infection. Conventional detection methods based on nucleic acid amplification assay have been applied in GBS diagnosis in central laboratories, with demonstrated high sensitivity. However, their heavy dependence on instrumentation and trained technicians forms remarkable obstacles to GBS detection in wide scenarios, including self-testing, and bedside-/community-screening. Furthermore, the structures of GBS bring about extra challenges to the nucleic acid extraction and purification. Novel GBS diagnosis platforms integrating sample processing, amplification, and read-out, are highly desired in clinical. Here, we report a portable, integrated microfluidics that enables rapid extraction of DNA from sampling swabs (<10 min), power-free DNA amplification (<30 min), and simple read-out in GBS detection. The platform works without an external pump, achieving rapid and highly efficient DNA extraction from clinical samples, with a significantly reduced time from 6 h to less than 50 min. Systematic clinical tests based on 47 patient samples validated the high performance of the platform, highlighted with a low limit of detection (LOD, 103 copies/ml), high sensitivity (100%), and specificity (100%). Head-to-head comparisons showed that the device improved the LOD by an order of magnitude than the traditional PCR method, showing a simple yet powerful POCT platform for home-/community-based testing towards GBS (and other pathogens) prevention in remote areas.


Subject(s)
Biosensing Techniques , Nucleic Acids , Streptococcal Infections , Infant, Newborn , Pregnancy , Female , Humans , Streptococcus agalactiae/genetics , Microfluidics , DNA , Streptococcal Infections/diagnosis , Sensitivity and Specificity
18.
J Clin Anesth ; 86: 111079, 2023 06.
Article in English | MEDLINE | ID: mdl-36796213

ABSTRACT

STUDY OBJECTIVE: The main objective was to devise an endotracheal intubation formula based on pediatric patients' strongly correlated growth parameters. The secondary objective was to compare the accuracy of the new formula to the age-based formula from Advanced Pediatric Life Support Course (APLS formula) and the middle finger length-based formula (MFL-based formula). DESIGN: A prospective, observational study. SETTING: Operation. PATIENTS: 111 subjects age 4-12 years old undergoing elective surgeries with general orotracheal anesthesia. INTERVENTIONS AND MEASUREMENTS: Growth parameters, including age, gender, height, weight, BMI, middle finger length, nasal-tragus length, and sternum length, were measured before surgeries. Tracheal length and the optimal endotracheal intubation depth (D) were measured and calculated by Disposcope. Regression analysis were used to establish a new formula for predicting the intubation depth. A self-controlled paired design was used to compare the accuracy of the intubation depth between the new formula, APLS formula, and MFL-based formula. MAIN RESULTS: Height (R = 0.897, P < 0.001) was strongly correlated to tracheal length and the endotracheal intubation depth in pediatric patients. New formulae basing on height were established, including new formula 1: D (cm) = 4 + 0.1 × Height (cm) and new formula 2: D (cm) = 3 + 0.1 × Height (cm). Via Bland-Altman analysis, the mean differences for new formula 1, new formula 2, APLS formula and MFL-based formula were - 0.354 cm (95% LOA, -1.289 to 1.998 cm), 1.354 cm (95% LOA, -0.289 to 2.998 cm), 1.154 cm (95% LOA, -1.002 to 3.311 cm), -0.619 cm (95% LOA, -2.960 to 1.723 cm), respectively. The rate of optimal intubation for new formula 1 (84.69%) was higher than for new formula 2 (55.86%), APLS formula (61.26%), and MFL-based formula. (69.37%). CONCLUSIONS: The prediction accuracy for intubation depth of the new formula 1 was higher than the other formulae. The new formula based on height: D (cm) = 4 + 0.1 × Height (cm) was preferable to APLS formula and MFL-based formula with a high incidence of appropriate endotracheal tube position.


Subject(s)
Intubation, Intratracheal , Trachea , Child , Humans , Child, Preschool , Prospective Studies , Anesthesia, General , Nose
19.
Curr Mol Med ; 2023 Jul 10.
Article in English | MEDLINE | ID: mdl-37431903

ABSTRACT

Sepsis is a fatal organ dysfunction caused by the host's uncontrolled response to infection, with high morbidity and mortality. Early diagnosis and intervention are the most effective methods to reduce the mortality due to sepsis. However, there is still a lack of definite biomarkers or intervention targets for the diagnosis, evaluation, prognosis, and treatment of sepsis. Long non-coding RNAs (lncRNAs) are a type of non-coding transcript with a length ranging from 200 to 100,000 nucleotides. LncRNAs mainly locate in the cytoplasm and nucleus and participate in various signaling pathways related to inflammatory reactions and organ dysfunction. Recent studies have reported that lncRNAs are involved in regulating the pathophysiological process of sepsis. Some classical lncRNAs have been confirmed as promising biomarkers to evaluate the severity and prognosis of sepsis. This review summarizes the mechanical studies on lncRNAs in sepsis-induced acute lung, kidney, myocardial, and liver injuries, analyzes the role of lncRNAs in the pathogenesis of sepsis, and explores the possibility of lncRNAs as potential biomarkers and intervention targets for sepsis-induced multiple organ dysfunction.

20.
Diagnostics (Basel) ; 13(4)2023 Feb 20.
Article in English | MEDLINE | ID: mdl-36832300

ABSTRACT

This study aimed to assess cardiovascular risk factors in the offspring of preeclampsia (PE) pregnancies. PubMed, Web of Science, Ovid, and other foreign language databases, as well as SinoMed, China National Knowledge Infrastructure, Wanfang, and China Science and Technology Journal Databases, were searched. The case-control studies on cardiovascular risk factors in the offspring of PE pregnancies from 1 January 2010 to 31 December 2019 were collected. A random-effects model or a fixed-effects model was used, and RevMan 5.3 software was used for meta-analysis to determine the OR value and 95%CI of each cardiovascular risk factor. A total of 16 documents were included in this research, all of which were case-control studies, with a total of 4046 cases in the experimental group and 31,505 in the control group. The meta-analysis that was conducted demonstrated that SBP [MD = 1.51, 95%CI (1.15, 1.88)] and DBP [MD = 1.90, 95%CI (1.69, 2.10)] values in the PE pregnancy offspring group presented an elevation relative to the non-PE pregnancy offspring group. The total cholesterol value in the PE pregnancy offspring group presented an elevation relative to the non-PE pregnancy offspring group [MD = 0.11, 95%CI (0.08, 0.13)]. The low-density lipoprotein cholesterol value in the PE pregnancy offspring group was comparable to that in the non-PE pregnancy offspring group [MD = 0.01, 95%CI (-0.02, 0.05)]. The high-density lipoprotein cholesterol value in the PE pregnancy offspring group presented an elevation relative to the non-PE pregnancy offspring group [MD = 0.02, 95%CI (0.01, 0.03)]. The non-HDL cholesterol value in the PE pregnancy offspring group presented an elevation relative to the non-PE pregnancy offspring group [MD = 0.16, 95%CI (0.13, 0.19)]. The triglycerides [MD = -0.02, 95%CI (-0.03, -0.01)] and glucose [MD = -0.08, 95%CI (-0.09, -0.07)] values in the PE pregnancy offspring group presented a depletion relative to the non-PE pregnancy group. The insulin value in the PE pregnancy offspring group presented a depletion relative to the non-PE pregnancy offspring group [MD = -0.21, 95%CI (-0.32, -0.09)]. The BMI value in the PE pregnancy offspring group presented an elevation relative to the non-PE pregnancy offspring group [MD = 0.42, 95%CI (0.27, 0.57)]. In conclusion, dyslipidemia, elevated blood pressure, and increased BMI occur postpartum with PE, all of which are risk factors for cardiovascular diseases.

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