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1.
J Biol Chem ; : 107493, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38925330

ABSTRACT

Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin analogues can delay the progression of DN, but the mechanism is not fully understood. In this study, we found that low molecular weight heparin (LMWH) therapy significantly upregulated some downstream proteins of the peroxisome proliferator-activated receptor (PPAR) signaling pathway by label-free quantification of the mouse kidney proteome. Through cell model verification, LMWH can protect the heparan sulfate (HS) of renal tubular epithelial cells from being degraded by heparanase that is highly expressed in a high-glucose environment, enhance the endocytic recruitment of fatty acid-binding protein 1 (FABP1), a coactivator of the PPAR pathway, and then regulate the activation level of intracellular PPAR. In addition, we have elucidated for the first time the molecular mechanism of HS and FABP1 interaction. These findings provide new insights into understanding the role of heparin in the pathogenesis of DN and developing corresponding treatments.

2.
J Magn Reson Imaging ; 59(1): 108-119, 2024 01.
Article in English | MEDLINE | ID: mdl-37078470

ABSTRACT

BACKGROUND: Vessels encapsulating tumor cluster (VETC) is a critical prognostic factor and therapeutic predictor of hepatocellular carcinoma (HCC). However, noninvasive evaluation of VETC remains challenging. PURPOSE: To develop and validate a deep learning radiomic (DLR) model of dynamic contrast-enhanced MRI (DCE-MRI) for the preoperative discrimination of VETC and prognosis of HCC. STUDY TYPE: Retrospective. POPULATION: A total of 221 patients with histologically confirmed HCC and stratified this cohort into training set (n = 154) and time-independent validation set (n = 67). FIELD STRENGTH/SEQUENCE: A 1.5 T and 3.0 T; DCE imaging with T1-weighted three-dimensional fast spoiled gradient echo. ASSESSMENT: Histological specimens were used to evaluate VETC status. VETC+ cases had a visible pattern (≥5% tumor area), while cases without any pattern were VETC-. The regions of intratumor and peritumor were segmented manually in the arterial, portal-venous and delayed phase (AP, PP, and DP, respectively) of DCE-MRI and reproducibility of segmentation was evaluated. Deep neural network and machine learning (ML) classifiers (logistic regression, decision tree, random forest, SVM, KNN, and Bayes) were used to develop nine DLR, 54 ML and clinical-radiological (CR) models based on AP, PP, and DP of DCE-MRI for evaluating VETC status and association with recurrence. STATISTICAL TESTS: The Fleiss kappa, intraclass correlation coefficient, receiver operating characteristic curve, area under the curve (AUC), Delong test and Kaplan-Meier survival analysis. P value <0.05 was considered as statistical significance. RESULTS: Pathological VETC+ were confirmed in 68 patients (training set: 46, validation set: 22). In the validation set, DLR model based on peritumor PP (peri-PP) phase had the best performance (AUC: 0.844) in comparison to CR (AUC: 0.591) and ML (AUC: 0.672) models. Significant differences in recurrence rates between peri-PP DLR model-predicted VETC+ and VETC- status were found. DATA CONCLUSIONS: The DLR model provides a noninvasive method to discriminate VETC status and prognosis of HCC patients preoperatively. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.


Subject(s)
Carcinoma, Hepatocellular , Deep Learning , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/diagnostic imaging , Bayes Theorem , Reproducibility of Results , Retrospective Studies , Liver Neoplasms/diagnostic imaging , Prognosis , Magnetic Resonance Imaging
3.
Liver Int ; 44(6): 1351-1362, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38436551

ABSTRACT

BACKGROUND AND AIMS: Accurate preoperative prediction of microvascular invasion (MVI) and recurrence-free survival (RFS) is vital for personalised hepatocellular carcinoma (HCC) management. We developed a multitask deep learning model to predict MVI and RFS using preoperative MRI scans. METHODS: Utilising a retrospective dataset of 725 HCC patients from seven institutions, we developed and validated a multitask deep learning model focused on predicting MVI and RFS. The model employs a transformer architecture to extract critical features from preoperative MRI scans. It was trained on a set of 234 patients and internally validated on a set of 58 patients. External validation was performed using three independent sets (n = 212, 111, 110). RESULTS: The multitask deep learning model yielded high MVI prediction accuracy, with AUC values of 0.918 for the training set and 0.800 for the internal test set. In external test sets, AUC values were 0.837, 0.815 and 0.800. Radiologists' sensitivity and inter-rater agreement for MVI prediction improved significantly when integrated with the model. For RFS, the model achieved C-index values of 0.763 in the training set and ranged between 0.628 and 0.728 in external test sets. Notably, PA-TACE improved RFS only in patients predicted to have high MVI risk and low survival scores (p < .001). CONCLUSIONS: Our deep learning model allows accurate MVI and survival prediction in HCC patients. Prospective studies are warranted to assess the clinical utility of this model in guiding personalised treatment in conjunction with clinical criteria.


Subject(s)
Carcinoma, Hepatocellular , Deep Learning , Liver Neoplasms , Magnetic Resonance Imaging , Neoplasm Invasiveness , Humans , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/mortality , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Liver Neoplasms/mortality , Magnetic Resonance Imaging/methods , Retrospective Studies , Female , Male , Middle Aged , Aged , Microvessels/diagnostic imaging , Microvessels/pathology , Disease-Free Survival , Neoplasm Recurrence, Local
4.
Inorg Chem ; 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38937860

ABSTRACT

S-block single atoms represent an ideal catalyst for the oxygen reduction reaction (ORR) as they can suppress the Fenton reaction. However, the symmetry of the s/p orbitals tends to generate either an excessively strong or weak interaction with intermediates. Herein, Ca single atoms coordinated with -S, -OP, and three N atoms (Ca/NPS-HC) were fabricated to modulate the adsorption of intermediates and promote the efficiency of s-block ORR catalysts. The experimental results from ORR demonstrated that the Ca/NPS-HC catalyst exhibited outstanding catalytic capability with a half-wave potential of 0.89 V, a kinetic current density of 56.6 mA cm-2 at 0.85 V, and a Tafel slope of 42 mV dec-1, outperforming commercial Pt/C. The detailed mechanistic studies revealed that the asymmetric coordination of Ca single atoms led to the symmetry-breaking of electron distribution in Ca single atoms, attenuating the s-p hybridization from the intermediate adsorption process, and thereby minimizing the energy barrier of the whole ORR.

5.
J Appl Microbiol ; 135(6)2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38849309

ABSTRACT

AIMS: To investigate alternative resistance mechanisms among seven ceftazidime-avibactam (CZA)-resistant carbapenem-resistant Klebsiella pneumoniae (CRKP) strains lacking common antimicrobial resistance genes (ARGs) using whole genome sequencing. METHODS AND RESULTS: ARG and virulence factors (VFs) were screened using the ARG database CARD and the VF database, respectively, and identified using genomic annotation data with BLAST+. Six strains were ST11 sequence types (STs), and one was ST2123. ST11 strains harbored more ARGs than the ST2123 strains. All seven strains carried multiple ARGs with efflux-mediated antibiotic resistance, including oqxA, oqxB, tet (A), qacEdltal, CRP, H-NS, Kpn-E, F, G, H, acrA, LptD, acrB, acrD, cpxA, mdtB, and mdtC. These efflux-mediated ARGs were identified in most strains and even all strains. Whole genome sequencing revealed that the ST11 strain carried multiple potential prophages, genomic islands, and integrative and conjugative elements, while the ST2123 strain carried an independent potential prophages and a genomic island. CONCLUSIONS: Whole genome sequencing analysis revealed that these seven CZA-resistant CRKP strains lacking common ARGs exhibited efflux-mediated antibiotic resistance-associated ARGs. The main mechanism by which CRKP resists CZA is antibiotic inactivation. Except for tet (A), no ARGs and validation experiments related to efflux were found. This study's results provide a new possibility for the resistance mechanism of CRKP to CZA, and we will verify this conclusion through experiments in the future.


Subject(s)
Anti-Bacterial Agents , Azabicyclo Compounds , Ceftazidime , Drug Combinations , Klebsiella pneumoniae , Microbial Sensitivity Tests , Whole Genome Sequencing , Ceftazidime/pharmacology , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/drug effects , Azabicyclo Compounds/pharmacology , Anti-Bacterial Agents/pharmacology , Genome, Bacterial , Drug Resistance, Multiple, Bacterial/genetics , Humans , Carbapenem-Resistant Enterobacteriaceae/genetics , Carbapenem-Resistant Enterobacteriaceae/drug effects , Klebsiella Infections/microbiology , Carbapenems/pharmacology , Virulence Factors/genetics
6.
Cancer Sci ; 114(5): 2014-2028, 2023 May.
Article in English | MEDLINE | ID: mdl-36715549

ABSTRACT

Increasing evidence indicates that angiogenesis plays a pivotal role in tumor progression. Formin-like 2 (FMNL2) is well-known for promoting metastasis; however, the molecular mechanisms by which FMNL2 promotes angiogenesis in colorectal cancer (CRC) remain unclear. Here, we found that FMNL2 promotes angiogenesis and metastasis of CRC in vitro and in vivo. The GDB/FH3 domain of FMNL2 directly interacts with epidermal growth factor-like protein 6 (EGFL6). Formin-like 2 promotes EGFL6 paracrine signaling by exosomes to regulate angiogenesis in CRC. Cytoskeleton associated protein 4 (CKAP4) is a downstream target of EGFL6 and is involved in CRC angiogenesis. Epidermal growth factor-like protein 6 binds to the N-terminus of CKAP4 to promote the migration of HUVECs by activating the ERK/MMP pathway. These findings suggest that FMNL2 promotes the migration of HUVECs and enhances angiogenesis and tumorigenesis in CRC by regulating the EGFL6/CKAP4/ERK axis. Therefore, the EGFL6/CKAP4/ERK axis could be a candidate therapeutic target for CRC treatment.


Subject(s)
Colorectal Neoplasms , Cytoskeleton , Humans , Calcium-Binding Proteins/genetics , Cell Adhesion Molecules/metabolism , Cell Line, Tumor , Colorectal Neoplasms/pathology , Cytoskeleton/metabolism , EGF Family of Proteins/metabolism , Formins/metabolism , Membrane Proteins/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism
7.
J Clin Immunol ; 43(6): 1302-1310, 2023 08.
Article in English | MEDLINE | ID: mdl-37093406

ABSTRACT

PURPOSE: To evaluate the role of circulating Epstein-Barr virus (EBV) DNA in lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). METHODS: We conducted a retrospective cohort study to explore the clinical and prognostic significance of EBV DNA in lymphoma-associated HLH. We included adult patients with combined diagnoses of lymphoma and HLH from January 2010 and November 2022 by retrieving the medical record system. RESULTS: A total of 281 patients with lymphoma-associated HLH were identified. Elevated whole-blood EBV DNA was observed in 54.4% (153/281) of patients, and the median copy number was significantly higher in the T/NK-cell malignancies (199,500, interquartile range, 30,000-1,390,000) than that in the B-cell non-Hodgkin lymphoma (5520, interquartile range, 1240-28,400, P < 0.001). The optimum cutoff for predicting survival was 16,100 copies/mL. Compared to the patients with EBV DNA ≤ 16,100 copies/mL, those with EBV DNA > 16,100 copies/mL were younger and had more T/NK-cell malignancies, lower levels of neutrophils and fibrinogen, and higher levels of hemoglobin, alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, and ß2-microglobulin. A higher load of EBV DNA (> 16,100 copies/mL), thrombocytopenia (< 100 × 109/L), neutropenia (< 1 × 109/L), hypofibrinogenemia (≤ 1.5 g/L), and elevated levels of creatinine (> 133 µmol/L) were independent adverse predictors of 60-day overall survival and overall survival. A prognostic index based on EBV DNA and the other four factors was established to categorize the patients into four groups with significantly different outcomes. CONCLUSION: Our study identified high EBV load as a risk factor for lymphoma-associated HLH and established a prognostic index to predict outcomes.


Subject(s)
Epstein-Barr Virus Infections , Lymphohistiocytosis, Hemophagocytic , Lymphoma , Adult , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/complications , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/diagnosis , Herpesvirus 4, Human , Prognosis , Retrospective Studies , Clinical Relevance , Lymphoma/complications , Lymphoma/diagnosis , DNA
8.
Small ; 19(40): e2303440, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37282780

ABSTRACT

Electrocatalytic hydrogen evolution reaction (HER) is a promising way to produce pure and clean hydrogen. However, the preparation of efficient and economical catalysts for pH-universal HER remains a challenging but rewarding task. Herein, ultrathin RuZn nanosheets (NSs) with moiré superlattices and abundant edges are synthesized. The RuZn NSs with unique structure exhibit superb HER performance with overpotentials of 11, 13, and 29 mV to achieve 10 mA cm-2 in 1 M KOH, 1 M PBS, and 0.5 M H2 SO4 , respectively, which is substantially lower than those of Ru NSs and RuZn NSs without moiré superlattices. Density functional theory investigations reveal that the charge transfer from Zn to Ru will lead the appropriate downshift of the d-band center of surface Ru atoms, thus accelerating hydrogen desorption from the Ru sites, lowering the dissociation energy barrier of water and greatly improving the HER performance. This work provides an effective design scheme for high-performance HER electrocatalysts over a wide pH range, and propose a general route to prepare Ru-based bimetallic nanosheets with moiré superlattices.

9.
J Med Virol ; 95(7): e28931, 2023 07.
Article in English | MEDLINE | ID: mdl-37448226

ABSTRACT

Monitoring variations in the virus genome to understand the SARS-CoV-2 evolution and spread of the virus is extremely important. Seven early SARS-CoV-2 isolates in China were cultured in vitro and were analyzed for their viral infectivity through viral growth assay, tissue culture infectious dose (TCID50 ) assay, spike protein quantification, and next generation sequencing analysis, and the resultant mutations in spike protein were used to generate the corresponding pseudoviruses for analysis of immune escape from vaccination and postinfection immunity. The results revealed that in vitro cultured SARS-CoV-2 virus had much higher mutation frequency (up to ~20 times) than that in infected patients, suggesting that SARS-CoV-2 diversify under favorable conditions. Monitoring viral mutations is not only helpful for better understanding of virus evolution and virulence change, but also the key to prevent virus transmission and disease progression. Compared with the D614G reference strain, a pseudovirus strain of SARS-CoV-2 was constructed with a high mutation rate site on the spike protein. We found some novel spike mutations during in vitro culture, such as E868Q, conferred further immune escape ability.


Subject(s)
COVID-19 , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Biological Assay , Mutation , Immunity
10.
J Med Virol ; 95(1): e28392, 2023 01.
Article in English | MEDLINE | ID: mdl-36484390

ABSTRACT

Reassortment can introduce one or more gene segments of influenza A viruses (IAVs) into another, resulting in novel subtypes. Since 2013, a new outbreak of human highly pathogenic avian influenza has emerged in the Yangtze River Delta (YRD) and South-Central regions of China. In this study, using Anhui province as an example, we discuss the possible impact of H7N9 IAVs on future influenza epidemics through a series of gene reassortment events. Sixty-one human H7N9 isolates were obtained from five outbreaks in Anhui province from 2013 to 2019. Bioinformatics analyses revealed that all of them were characterized by low pathogenicity and high human or mammalian tropism and had introduced novel avian influenza A virus (AIV) subtypes such as H7N2, H7N6, H9N9, H5N6, H6N6, and H10N6 through gene reassortment. In reassortment events, Anhui isolates may donate one or more segments of HA, NA, and the six internal protein-coding genes for the novel subtype AIVs. Our study revealed that H7N9, H9N2, and H5N1 can serve as stable and persistent gene pools for AIVs in the YRD and South-Central regions of China. Novel AIV subtypes might be generated continuously by reassortment. These AIVs may have obtained human-type receptor-binding abilities from their donors and prefer binding to them, which can cause human epidemics through accidental spillover infections. Facing the continual threat of emerging avian influenza, constant monitoring of AIVs should be conducted closely for agricultural and public health.


Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza A Virus, H7N9 Subtype , Influenza A Virus, H9N2 Subtype , Influenza in Birds , Influenza, Human , Animals , Humans , Influenza in Birds/epidemiology , Influenza A Virus, H7N9 Subtype/genetics , Influenza A Virus, H9N2 Subtype/genetics , Influenza A Virus, H5N1 Subtype/genetics , Influenza A Virus, H7N2 Subtype , Phylogeny , Reassortant Viruses/genetics , Influenza, Human/epidemiology , China/epidemiology , Mammals
11.
Reprod Biol Endocrinol ; 21(1): 57, 2023 Jun 20.
Article in English | MEDLINE | ID: mdl-37340405

ABSTRACT

BACKGROUND: Unexplained recurrent spontaneous abortion (URSA) is one of the most challenging conditions frustrates women of childbearing age profoundly. The gene expression patterns and biological characteristics of placental villus in patients with URSA remain largely unknown. The aim of our study was to identify potential lncRNAs as well as their action mechanisms in URSA. METHOD: The ceRNA microarray was used to identify the mRNA and lncRNA expression profiles of URSA patients and normal pregnancy. Functional enrichment analyses for differentially expressed mRNAs in URSA were performed. Protein-protein interaction analysis of differentially expressed mRNAs was performed to identify hub genes and key modules. Subsequently, the co-dysregulated ceRNA network of URSA was established, and the enrichment analyses for the mRNAs in the ceRNA network was implemented. qRT-PCR was performed to validated the expression of key ENST00000429019 and mRNAs in URSA. RESULTS: We found that URSA placental villus have distinct mRNA and lncRNA expression profiles through ceRNA microarray, with a total of 347 mRNAs and 361 lncRNAs differentially expressed compared with controls. The functional enrichment analysis revealed that ncRNA processing, DNA replication, cell cycle, apoptosis, cytokine-mediated signaling pathway, ECM-receptor interaction were the potentially disrupted pathways in URSA patients. Then we constructed a co-dysregulated ceRNA network and found differentially expressed mRNAs were regulated by a small fraction of hub lncRNAs. Finally, we found a key network of ENST00000429019 and three cell proliferation or apoptosis related key mRNAs (CDCA3, KIFC1, NCAPH), and validated their expression and regulation in tissue and cellular levels. CONCLUSIONS: This study identified a key ceRNA network, which might take part in URSA and correlate with cell proliferation and apoptosis. Optimistically, this study may deepen our apprehensions about the underlying molecular and biological causes of URSA and provide an important theoretical basis for future therapeutic strategies for patients with URSA.


Subject(s)
Abortion, Habitual , MicroRNAs , RNA, Long Noncoding , Humans , Female , Pregnancy , MicroRNAs/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Chorionic Villi/metabolism , Gene Regulatory Networks , Placenta/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Abortion, Habitual/genetics , Nuclear Proteins/genetics , Cell Cycle Proteins/genetics
12.
Langmuir ; 39(40): 14374-14383, 2023 Oct 10.
Article in English | MEDLINE | ID: mdl-37774103

ABSTRACT

Poly(bis(2-ethylhexyl) phosphoric) methacrylic anhydride-grafted carbon dots (CD-g-PEPMA) have been controllably synthesized and used as multifunctional lubricant additives of poly(ethylene glycol) (PEG200). The polymers on the surfaces of CD-g-PEPMA not only endow them with particularly excellent dispersion stability but also enhance their adsorbability on the steel surface and embedded stability between the rubbing surfaces. Hence, CD-g-PEPMA as an additive showed outstanding rust resistance and tribological performance. Among CD-g-PEPMA-X (X represents the polymerization time), CD-g-PEPMA-2 (X = 2 h) exhibited the best tribological performance. At the optimum c of 2.0 wt %, CD-g-PEPMA-2 reduced the coefficient of friction and wear volume of PEG200 by 60.1 and 74.0%, respectively. The striking friction-reducing and antiwear functions of CD-g-PEPMA as additives can be attributed to the synergistic lubrication effect of carbon cores and polymers. The rolling, polishing, and mending effects of carbon cores combined with the favorable adsorbability and reactivity of polymers on steel surfaces synergistically induced the formation of boundary lubrication films on wear track surfaces. The films are composed of tribochemical reaction products such as Fe2(CO3)3, Fe3C, and FePO4 embedded with carbon cores, tremendously reducing the friction and wear of the friction pair. The research results can provide substantial theoretical guidance and data support for designing and developing high-efficiency polymer-CD integrative multifunctional nanoadditives toward PEG.

13.
Org Biomol Chem ; 21(6): 1138-1142, 2023 Feb 08.
Article in English | MEDLINE | ID: mdl-36636962

ABSTRACT

Mechanistic studies reveal that the decarboxylative allylation of amino esters via dual photoredox and palladium catalysis occurs via oxidation giving π-allyl-Pd(II) species and carboxylate, which is oxidized by *Ir(III)-catalyst offering benzyl radicals. The alkylated product is formed via an SN2 pathway. Single-electron transfer between Pd(I)-species and Ir(II)-catalysis restores both catalysts.

14.
Cell Mol Biol (Noisy-le-grand) ; 69(15): 193-197, 2023 Dec 31.
Article in English | MEDLINE | ID: mdl-38279447

ABSTRACT

To provide a clinical reference for the management of lobar pneumonia (LP) by analyzing the association of interleukin-8 (IL-8) with the disease. A retrospective analysis was performed on 69 LP children (observation group, OG) and 60 healthy control children (control group, CG) who visited our hospital from January 2022 to November 2022. Fasting venous blood was drawn from the controls at admission to determine IL-8 levels. In addition, IL-8 concentrations in fasting venous blood and bronchoalveolar lavage fluid (BALF) were determined in LP patients in the observation group (OG) at admission and after treatment for comparative analysis with the control group (CG). The association of serum and BALF IL-8 levels in LP children, as well as the diagnostic value of IL-8 in LP, sputum emboli, and poor prognosis, were discussed.OG showed higher serum IL-8 levels than CG. Serum IL-8 had a diagnostic sensitivity of 80% and a specificity of 70% in diagnosing LP (P<0.05). Pearson correlation coefficients showed a positive correlation between IL-8 in serum and IL-8 in BALF in OG (P<0.05). In OG, IL-8 levels increased with LP progression and decreased after treatment (P<0.05). Similarly, IL-8 was increased in children with sputum emboli, and IL-8 in BALF was more effective in diagnosing sputum emboli formation (P<0.05). Finally, IL-8 also exhibited an excellent evaluation of poor prognosis in LP children after treatment (P<0.05).IL-8 is highly expressed in serum and BALF of LP children, which has excellent diagnostic effects on the occurrence of LP and the formation of sputum emboli.


Subject(s)
Interleukin-8 , Pneumonia , Child , Humans , Bronchoalveolar Lavage Fluid , Retrospective Studies , Sputum
15.
BMC Cardiovasc Disord ; 23(1): 22, 2023 01 16.
Article in English | MEDLINE | ID: mdl-36646995

ABSTRACT

BACKGROUND AND OBJECTIVE: The new non-invasive arterial stiffness indices, arterial pressure volume index (API) is explored as a novel marker of residual stress in the wall of the peripheral muscular arteries at zero-stress state in clinical settings. The present study aimed to study the association of API with cardiovascular disease (CVD) risk in China (China-PAR). METHODS: According to China-PAR score, participants were divided into three groups: low risk (< 5%), medium risk (5-9.9%), and high risk (≥ 10.0%). API ≥ 31 was defined as high API, and the incidences of high API were compared. Logistic regression models were used to analyze the risk factors of high API and high risk China-PAR categories. The association between China-PAR and API was analyzed by restrictive cubic spline. RESULTS: The study included 4311 participants. After adjustments for confounding factors, high API was independent factor associated with high risk China-PAR categories, and the probability of high API was 1.366 times higher than that in normal API subjects. While, the independent factors associated with high API were BMI, blood pressure and heart rate. Furthermore, API had a significant U-shaped association with China-PAR. CVD risk was lowest with API of 19 units, the fastest increase at 26 units and the flattest starting point at 59 units. CONCLUSION: API, an indicator of arterial stiffness and residual stress, had a U-shaped association with China-PAR score and might play an important role in predicting CVD risk in Chinese natural populations.


Subject(s)
Cardiovascular Diseases , Hypertension , Vascular Stiffness , Humans , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Arterial Pressure , Risk Factors , Hypertension/diagnosis , Hypertension/epidemiology , Blood Pressure/physiology , Heart Disease Risk Factors , China/epidemiology , Vascular Stiffness/physiology , Pulse Wave Analysis
16.
J Nat Prod ; 86(7): 1844-1854, 2023 07 28.
Article in English | MEDLINE | ID: mdl-37395092

ABSTRACT

Cancer is a major disease threatening human health worldwide, among which non-small-cell lung cancer (NSCLC) is the most deadly. Clinically, almost all anticancer drugs eventually fail to consistently benefit patients due to serious drug resistance. AKT is a key effector of the PI3K/AKT/mTOR pathway, which is closely related to the occurrence, development, and drug resistance of tumors. Herein, we first designed and synthesized 20 kinds of novel hybrid molecules targeting both tubulin and AKT based on a podophyllotoxin (PPT) skeleton through computer-aided drug design. By CCK8 assay, we screened the compound D1-1 (IC50 = 0.10 µM) with the strongest inhibitory activity against H1975 cells, and its activity was 100 times higher than PPT (IC50 = 12.56 µM) and 300 times higher than gefitinib (IC50 = 32.15 µM). Affinity analysis results showed that D1-1 not only retained the tubulin targeting of PPT but also showed strong AKT targeting. Subsequent pharmacological experiments showed that D1-1 significantly inhibited the proliferation and metastasis of H1975 cells and slightly induced their apoptosis by inhibiting both tubulin polymerization and the AKT pathway activation. Collectively, these data demonstrate that the novel hybrid molecule D1-1 may be an excellent lead compound for the treatment of human NSCLC as a dual inhibitor of tubulin and AKT.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Podophyllotoxin/pharmacology , Podophyllotoxin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Tubulin/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Lung Neoplasms/metabolism , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Phenylacetates/pharmacology , Cell Proliferation , Drug Screening Assays, Antitumor , Apoptosis
17.
Bioorg Chem ; 139: 106703, 2023 10.
Article in English | MEDLINE | ID: mdl-37399615

ABSTRACT

Warburg effect provides energy and material essential for tumor proliferation, the reverse of Warburg effect provides insights into the development of a novel anti-cancer strategy. Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only contribute to the Warburg effect through accelerating aerobic glycolysis, but also serve as druggable target for colorectal cancer (CRC). Considering that targeting PKM2 or PDK1 alone does not seem to be sufficient to remodel abnormal glucose metabolism and achieve significant antitumor activity, a series of novel benzenesulfonyl shikonin derivatives were designed to regulate PKM2 and PDK1 simultaneously. By means of molecular docking and antiproliferative screen, we found that compound Z10 could act as the combination of PKM2 activator and PDK1 inhibitor, thereby significantly inhibited glycolysis that reshaping tumor metabolism. Moreover, Z10 could inhibit proliferation, migration and induce apoptosis in CRC cell HCT-8. Finally, the in vivo anti-tumor activity of Z10 was evaluated in a colorectal cancer cell xenograft model in nude mice and the results demonstrated that Z10 induced tumor cell apoptosis and inhibited tumor cell proliferation with lower toxicity than shikonin. Our findings indicated that it is feasible to alter tumor energy metabolism through multi-target synergies, and the dual-target benzenesulfonyl shikonin derivative Z10 could be a potential anti-CRC agent.


Subject(s)
Colorectal Neoplasms , Pyruvate Kinase , Animals , Mice , Humans , Mice, Nude , Molecular Docking Simulation , Cell Proliferation , Pyruvate Kinase/pharmacology , Colorectal Neoplasms/drug therapy , Glucose/metabolism , Cell Line, Tumor
18.
BMC Surg ; 23(1): 377, 2023 Dec 12.
Article in English | MEDLINE | ID: mdl-38087216

ABSTRACT

BACKGROUND: To systematically assess the safety and effectiveness of titanium mesh grafting compared with bone grafting in the treatment of spinal tuberculosis. METHODS: Electronic databases, including PubMed, Embase, Web of Science, and Cochrane Library, were searched from their inception until April 2023. The outcome indicators for patients treated with titanium mesh grafting or bone grafting for spinal tuberculosis include surgical duration, intraoperative blood loss, graft fusion time, American Spinal Injury Association (ASIA) Spinal Cord Injury Grade E assessment, VAS score, lumbar pain score, post-graft kyphotic angle, and postoperative complications. The Newcastle-Ottawa Scale (NOS) and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach were used for quality assessment and evidence grading of clinical studies. Funnel plots and Begg's test were employed for bias assessment. RESULTS: A total of 8 studies were finally included, comprising 523 patients, with 267 cases of titanium mesh fixation and 256 cases of bone grafting. The meta-analysis showed no significant statistical differences in surgical duration (Weighted Mean Difference (WMD) = -7.20, 95% Confidence Interval (CI): -28.06 to 13.67, P = 0.499), intraoperative blood loss (WMD = 16.22, 95% CI: -40.62 to 73.06, P = 0.576), graft fusion time (WMD = 0.97, 95% CI: -0.88 to 2.81, P = 0.304), ASIA Spinal Cord Injury Grade E assessment (Relative Risk (RR) = 1.03, 95% CI: 0.97 to 1.09, P = 0.346), and overall complications (RR = 0.87, 95% CI: 0.49 to 1.55, P = 0.643). Differences in VAS score, ODI lumbar pain score, and post-graft kyphotic angle between the titanium mesh grafting group and the bone grafting group were not significant within the 95% CI range. The rate of postoperative implant subsidence was slightly lower in bone grafting than in titanium mesh grafting (RR = 9.30, 95% CI: 1.05 to 82.22, P = 0.045). CONCLUSIONS: Both bone grafting and titanium mesh grafting are effective and safe for the surgery, with no significant statistical differences in the results. Considering the limitations of the present study, large-scale randomized controlled trials are warranted to further verify the reliability of this finding.


Subject(s)
Kyphosis , Low Back Pain , Spinal Cord Injuries , Spinal Fusion , Tuberculosis, Spinal , Humans , Blood Loss, Surgical , Bone Transplantation/methods , Kyphosis/surgery , Lumbar Vertebrae/surgery , Reproducibility of Results , Retrospective Studies , Spinal Fusion/methods , Surgical Mesh , Thoracic Vertebrae/surgery , Titanium , Treatment Outcome , Tuberculosis, Spinal/surgery
19.
Angew Chem Int Ed Engl ; 62(13): e202218460, 2023 Mar 20.
Article in English | MEDLINE | ID: mdl-36749548

ABSTRACT

Developing highly efficient and stable photocatalysts for the CO2 reduction reaction (CO2 RR) remains a great challenge. We designed a Z-Scheme photocatalyst with N-Cu1 -S single-atom electron bridge (denoted as Cu-SAEB), which was used to mediate the CO2 RR. The production of CO and O2 over Cu-SAEB is as high as 236.0 and 120.1 µmol g-1 h-1 in the absence of sacrificial agents, respectively, outperforming most previously reported photocatalysts. Notably, the as-designed Cu-SAEB is highly stable throughout 30 reaction cycles, totaling 300 h, owing to the strengthened contact interface of Cu-SAEB, and mediated by the N-Cu1 -S atomic structure. Experimental and theoretical calculations indicated that the SAEB greatly promoted the Z-scheme interfacial charge-transport process, thus leading to great enhancement of the photocatalytic CO2 RR of Cu-SAEB. This work represents a promising platform for the development of highly efficient and stable photocatalysts that have potential in CO2 conversion applications.

20.
Ecol Lett ; 25(4): 754-765, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34957674

ABSTRACT

Nutrient enrichment can simultaneously increase and destabilise plant biomass production, with co-limitation by multiple nutrients potentially intensifying these effects. Here, we test how factorial additions of nitrogen (N), phosphorus (P) and potassium with essential nutrients (K+) affect the stability (mean/standard deviation) of aboveground biomass in 34 grasslands over 7 years. Destabilisation with fertilisation was prevalent but was driven by single nutrients, not synergistic nutrient interactions. On average, N-based treatments increased mean biomass production by 21-51% but increased its standard deviation by 40-68% and so consistently reduced stability. Adding P increased interannual variability and reduced stability without altering mean biomass, while K+ had no general effects. Declines in stability were largest in the most nutrient-limited grasslands, or where nutrients reduced species richness or intensified species synchrony. We show that nutrients can differentially impact the stability of biomass production, with N and P in particular disproportionately increasing its interannual variability.


Subject(s)
Ecosystem , Grassland , Biodiversity , Biomass , Eutrophication , Nitrogen , Nutrients
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