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1.
J Am Chem Soc ; 146(19): 13588-13597, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38695646

RESUMO

Membrane channel proteins (MCPs) play key roles in matter transport through cell membranes and act as major targets for vaccines and drugs. For emerging ionic liquid (IL) drugs, a rational understanding of how ILs affect the structure and transport function of MCP is crucial to their design. In this work, GPU-accelerated microsecond-long molecular dynamics simulations were employed to investigate the modulating mechanism of ILs on MCP. Interestingly, ILs prefer to insert into the lipid bilayer and channel of aquaporin-2 (AQP2) but adsorb on the entrance of voltage-gated sodium channels (Nav). Molecular trajectory and free energy analysis reflect that ILs have a minimal impact on the structure of MCPs but significantly influence MCP functions. It demonstrates that ILs can decrease the overall energy barrier for water through AQP2 by 1.88 kcal/mol, whereas that for Na+ through Nav is increased by 1.70 kcal/mol. Consequently, the permeation rates of water and Na+ can be enhanced and reduced by at least 1 order of magnitude, respectively. Furthermore, an abnormal IL gating mechanism was proposed by combining the hydrophobic nature of MCP and confined water/ion coordination effects. More importantly, we performed experiments to confirm the influence of ILs on AQP2 in human cells and found that treatment with ILs significantly accelerated the changes in cell volume in response to altered external osmotic pressure. Overall, these quantitative results will not only deepen the understanding of IL-cell interactions but may also shed light on the rational design of drugs and disease diagnosis.


Assuntos
Líquidos Iônicos , Simulação de Dinâmica Molecular , Líquidos Iônicos/química , Líquidos Iônicos/farmacologia , Humanos , Aquaporina 2/metabolismo , Aquaporina 2/química , Água/química , Bicamadas Lipídicas/química , Bicamadas Lipídicas/metabolismo , Sódio/química , Sódio/metabolismo
2.
Int J Mol Sci ; 25(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38732216

RESUMO

Aspartate ß-hydroxylase (ASPH) is a protein associated with malignancy in a wide range of tumors. We hypothesize that inhibition of ASPH activity could have anti-tumor properties in patients with head and neck cancer. In this study, we screened tumor tissues of 155 head and neck squamous cell carcinoma (HNSCC) patients for the expression of ASPH using immunohistochemistry. We used an ASPH inhibitor, MO-I-1151, known to inhibit the catalytic activity of ASPH in the endoplasmic reticulum, to show its inhibitory effect on the migration of SCC35 head and neck cancer cells in cell monolayers and in matrix-embedded spheroid co-cultures with primary cancer-associated fibroblast (CAF) CAF 61137 of head and neck origin. We also studied a combined effect of MO-I-1151 and HfFucCS, an inhibitor of invasion-blocking heparan 6-O-endosulfatase activity. We found ASPH was upregulated in HNSCC tumors compared to the adjacent normal tissues. ASPH was uniformly high in expression, irrespective of tumor stage. High expression of ASPH in tumors led us to consider it as a therapeutic target in cell line models. ASPH inhibitor MO-I-1151 had significant effects on reducing migration and invasion of head and neck cancer cells, both in monolayers and matrix-embedded spheroids. The combination of the two enzyme inhibitors showed an additive effect on restricting invasion in the HNSCC cell monolayers and in the CAF-containing co-culture spheroids. We identify ASPH as an abundant protein in HNSCC tumors. Targeting ASPH with inhibitor MO-I-1151 effectively reduces CAF-mediated cellular invasion in cancer cell models. We propose that the additive effect of MO-I-1151 with HfFucCS, an inhibitor of heparan 6-O-endosulfatases, on HNSCC cells could improve interventions and needs to be further explored.


Assuntos
Movimento Celular , Neoplasias de Cabeça e Pescoço , Invasividade Neoplásica , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Feminino , Pessoa de Meia-Idade , Oxigenases de Função Mista/metabolismo , Masculino , Técnicas de Cocultura , Idoso , Proteínas de Ligação ao Cálcio , Proteínas de Membrana , Proteínas Musculares
3.
Chem Biodivers ; : e202302059, 2024 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-38736027

RESUMO

This study extracted and purified a polysaccharide from Rehmanniae radix praeparata (RGP) with an average molecular weight. The structural characteristics of RGP and its iron(III) complex, RGP-Fe(III), were examined for their antioxidant properties and potential in treating iron deficiency anemia (IDA). Analysis revealed that RGP comprised Man, Rha, Gal, and Xyl, with a sugar residue skeleton featuring 1→3; 1→2, 3; and 1→2, 3, 4 linkages, among others. RGP-Fe(III) had a molecular weight of 4.39×104 Da. Notably, RGP-Fe(III) exhibited superior antioxidant activity compared to RGP alone. In IDA rat models, treatment with RGP-Fe(III) led to increased weight gain, restoration of key blood parameters including hemoglobin, red blood cells, and mean hemoglobin content, elevated serum iron levels, and decreased total iron-binding capacity. Histological examination revealed no observable toxic effects of RGP-Fe(III) on the liver and spleen. These findings suggest the potential of RGP-Fe(III) as a therapeutic agent for managing IDA and highlight its promising antioxidant properties.

4.
Front Nutr ; 11: 1395362, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38751742

RESUMO

Background: The association between Body Mass Index (BMI), frailty index (FI), and dietary supplement in cancer survivors has been a subject of growing interest. This study investigates the relationship of BMI and FI with mortality in American cancer survivors and explores the impact of dietary supplement usage on different BMI and FI groups. Methods: Three thousand nine hundred and thirty-two cancer patients from the National Health and Nutrition Examination Survey (NHANES) database were included in the analyses. BMI, FI, and supplement usage were obtained through the NHANES structured survey and the 49-item FI tool. Weighted logistic and Cox proportional hazards models, Kaplan-Meier survival analyses, and propensity score matching (PSM) were used to elucidate the relationships between BMI, FI, dietary supplement, and mortality outcomes. Results: The study found significant associations between higher BMI and increased frailty (Odds ratio [OR] = 1.04, 95% confidence interval [95% CI], 1.02-1.06). BMI < 25 kg/m2 and FI > 0.2 are associated with an increased mortality rate. Dietary supplement use can reduce all-cause and cancer mortality in cancer patients with BMI < 25 kg/m2 (Hazard ratio [HR] = 0.63, 95% CI, 0.47-0.84; HR = 0.48, 95% CI, 0.29-0.80) or FI ≤ 0.2 (HR = 0.77, 95% CI, 0.60-0.99; HR = 0.59, 95% CI, 0.39-0.89). In cancer patients with BMI < 25 kg/m2 and FI ≤ 0.2, dietary supplement users had lower all-cause and cancer mortality (HR = 0.49, 95% CI, 0.30-0.79; HR = 0.25, 95% CI, 0.10-0.60). Conclusion: The study revealed a negative correlation between BMI and the FI among the cancer patient cohort as well as their complex impact on mortality and highlighted the role of dietary supplement in cancer prognosis, indicating benefits for non-frail patients with BMI < 25 kg/m2.

5.
Cell Stem Cell ; 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38759653

RESUMO

ß0/ß0 thalassemia is the most severe type of transfusion-dependent ß-thalassemia (TDT) and is still a challenge facing lentiviral gene therapy. Here, we report the interim analysis of a single-center, single-arm pilot trial (NCT05015920) evaluating the safety and efficacy of a ß-globin expression-optimized and insulator-engineered lentivirus-modified cell product (BD211) in ß0/ß0 TDT. Two female children were enrolled, infused with BD211, and followed up for an average of 25.5 months. Engraftment of genetically modified hematopoietic stem and progenitor cells was successful and sustained in both patients. No unexpected safety issues occurred during conditioning or after infusion. Both patients achieved transfusion independence for over 22 months. The treatment extended the lifespan of red blood cells by over 42 days. Single-cell DNA/RNA-sequencing analysis of the dynamic changes of gene-modified cells, transgene expression, and oncogene activation showed no notable adverse effects. Optimized lentiviral gene therapy may safely and effectively treat all ß-thalassemia.

6.
Eur Radiol ; 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750169

RESUMO

OBJECTIVES: To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. METHODS: This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015-2021). SER is defined as (SIlt - SIpre)/(SIea - SIpre), where SIpre, SIea, and SIlt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan-Meier curves. RESULTS: The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets (n = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma (r = 0.29-0.74, all p < 0.001) and epithelium (r = -0.23 to -0.71, all p < 0.001) across a wide post-injection time window (range, 25-300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17-2.91), p = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25-2.41), p = 0.001). CONCLUSION: SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. CLINICAL RELEVANCE STATEMENT: The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. KEY POINTS: Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio (SER)-predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio (SER)-predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC.

9.
Ecotoxicol Environ Saf ; 276: 116281, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38581907

RESUMO

Bromophenols (BPs) are prominent environmental pollutants extensively utilized in aquaculture, pharmaceuticals, and chemical manufacturing. This study aims to identify UDP- glucuronosyltransferases (UGTs) isoforms involved in the metabolic elimination of BPs. Mono-glucuronides of BPs were detected in human liver microsomes (HLMs) incubated with the co-factor uridine-diphosphate glucuronic acid (UDPGA). The glucuronidation metabolism reactions catalyzed by HLMs followed Michaelis-Menten or substrate inhibition kinetics. Recombinant enzymes and inhibition experiments with chemical reagents were employed to phenotype the principal UGT isoforms participating in BP glucuronidation. UGT1A6 emerged as the major enzyme in the glucuronidation of 4-Bromophenol (4-BP), while UGT1A1, UGT1A6, and UGT1A8 were identified as the most essential isoforms for metabolizing 2,4-dibromophenol (2,4-DBP). UGT1A1, UGT1A8, and UGT2B4 were deemed the most critical isoforms in the catalysis of 2,4,6-tribromophenol (2,4,6-TBP) glucuronidation. Species differences were investigated using the liver microsomes of pig (PLM), rat (RLM), monkey (MyLM), and dog (DLM). Additionally, 2,4,6-TBP effects on the expression of UGT1A1 and UGT2B7 in HepG2 cells were evaluated. The results demonstrated potential induction of UGT1A1 and UGT2B7 upon exposure to 2,4,6-TBP at a concentration of 50 µM. Collectively, these findings contribute to elucidating the metabolic elimination and toxicity of BPs.


Assuntos
Glucuronídeos , Glucuronosiltransferase , Microssomos Hepáticos , Fenóis , Glucuronosiltransferase/metabolismo , Humanos , Animais , Fenóis/toxicidade , Fenóis/metabolismo , Glucuronídeos/metabolismo , Poluentes Ambientais/toxicidade , Poluentes Ambientais/metabolismo , Cães , Ratos , Isoenzimas/metabolismo , Especificidade da Espécie
10.
Biotechnol J ; 19(4): e2300710, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38581096

RESUMO

Reconstruction and optimization of biosynthetic pathways can help to overproduce target chemicals in microbial cell factories based on genetic engineering. However, the perturbation of biosynthetic pathways on cellular metabolism is not well investigated and profiling the engineered microbes remains challenging. The rapid development of omics tools has the potential to characterize the engineered microbial cell factory. Here, we performed label-free quantitative proteomic analysis and metabolomic analysis of engineered sabinene overproducing Saccharomyces cerevisiae strains. Combined metabolic analysis andproteomic analysis of targeted mevalonate (MVA) pathway showed that co-ordination of cytosolic and mitochondrial pathways had balanced metabolism, and genome integration of biosynthetic genes had higher sabinene production with less MVA enzymes. Furthermore, comparative proteomic analysis showed that compartmentalized mitochondria pathway had perturbation on central cellular metabolism. This study provided an omics analysis example for characterizing engineered cell factory, which can guide future regulation of the cellular metabolism and maintaining optimal protein expression levels for the synthesis of target products.


Assuntos
Monoterpenos Bicíclicos , Engenharia Metabólica , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Proteômica , Mitocôndrias/genética , Mitocôndrias/metabolismo
11.
J Mater Chem B ; 12(17): 4262-4269, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38602378

RESUMO

Mass spectrometry (MS)-based proteomics can identify and quantify the differential abundance of expressed proteins in parallel, and bottom-up proteomic approaches are even approaching comprehensive coverage of the complex eukaryotic proteome. Protein-nanoparticle (NP) interactions have been extensively studied owing to their importance in biological applications and nanotoxicology. However, the proteome-level effects of NPs on cells have received little attention, although changes in protein abundance can reflect the direct effects of nanocarriers on protein expression. Herein, we investigated the effect of PLGA-based NPs on protein expression in HepG2 cells using a label-free quantitative proteomics approach with data independent acquisition (DIA). The percentage of two-fold change in the protein expression of cells treated with PLGA-based NPs was less than 10.15% during a 6 hour observation period. Among the changed proteins, we found that dynamic proteins involved in cell division, localization, and transport are more likely to be more susceptible to PLGA-based NPs.


Assuntos
Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteômica , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Nanopartículas/química , Proteômica/métodos , Células Hep G2 , Tamanho da Partícula
12.
Int J Mol Sci ; 25(7)2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38612898

RESUMO

The NAC (NAM, ATAF1/2, CUC2) family of transcription factors (TFs) is a vital transcription factor family of plants. It controls multiple parts of plant development, tissue formation, and abiotic stress response. We cloned the FvNAC29 gene from Fragaria vesca (a diploid strawberry) for this research. There is a conserved NAM structural domain in the FvNAC29 protein. The highest homology between FvNAC29 and PaNAC1 was found by phylogenetic tree analysis. Subcellular localization revealed that FvNAC29 is localized onto the nucleus. Compared to other tissues, the expression level of FvNAC29 was higher in young leaves and roots. In addition, Arabidopsis plants overexpressing FvNAC29 had higher cold and high-salinity tolerance than the wild type (WT) and unloaded line with empty vector (UL). The proline and chlorophyll contents of transgenic Arabidopsis plants, along with the activities of the antioxidant enzymes like catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) under 200 mM NaCl treatment or -8 °C treatment, were higher than those activities of the control. Meanwhile, malondialdehyde (MDA) and the reactive oxygen species (ROS) content were higher in the WT and UL lines. FvNAC29 improves transgenic plant resistance to cold and salt stress by regulating the expression levels of AtRD29a, AtCCA1, AtP5CS1, and AtSnRK2.4. It also improves the potential to tolerate cold stress by positively regulating the expression levels of AtCBF1, AtCBF4, AtCOR15a, and AtCOR47. These findings suggest that FvNAC29 may be related to the processes and the molecular mechanisms of F. vesca response to high-salinity stress and LT stress, providing a comprehensive understanding of the NAC TFs.


Assuntos
Arabidopsis , Fragaria , Arabidopsis/genética , Fragaria/genética , Filogenia , Peroxidases , Antioxidantes
13.
Precis Chem ; 2(3): 103-111, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38550915

RESUMO

Electrochemical glycerol oxidation (EGO) emerges as a promising route to valorize glycerol, an underutilized byproduct from biodiesel production, into value-added chemicals. This study employed three types of gold (Au) nanocrystals with controlled shapes to elucidate the facet-dependent electrocatalytic behavior in EGO. Octahedral, rhombic dodecahedral, and cubic Au nanocrystals with {111}, {110}, and {100} facets, respectively, were precisely synthesized with uniform size and shape. Rhombic dodecahedra exhibited the lowest onset potential for EGO due to facile AuOH formation, while octahedra showed enhanced electrochemical activity for glycerol oxidation and resistance to poisoning. In-situ FTIR analysis revealed that Au {111} surfaces selectively favored C2 products, whereas Au {100} surfaces promoted C3 product formation, highlighting the significant effect of facet orientation on EGO performance and informing catalyst design.

14.
Nat Protoc ; 19(5): 1557-1589, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38429518

RESUMO

Mono-dimensional fiber-based electronics can effectively address the growing demand for improved wearable electronic devices because of their exceptional flexibility and stretchability. For practical applications, functional fiber electronic devices need to be integrated into more powerful and versatile systems to execute complex tasks that cannot be completed by single-fiber devices. Existing techniques, such as printing and sintering, reduce the flexibility and cause low connection strength of fiber-based electronic devices because of the high curvature of the fiber. Here, we outline a twisting fabrication process for fiber electrodes, which can be woven into functional threads and integrated within textiles. The design of the twisted thread structure for fiber devices ensures stable interfacing and good flexibility, while the textile structure features easily accessible, interlaced points for efficient circuit connections. Electronic textiles can be customized to act as displays, health monitors and power sources. We detail three main fabrication sections, including the fabrication of the fiber electrodes, their twisting into electronic threads and their assembly into functional textile-based devices. The procedures require ~10 d and are easily reproducible by researchers with expertise in fabricating energy and electronic devices.


Assuntos
Eletrodos , Desenho de Equipamento , Têxteis , Dispositivos Eletrônicos Vestíveis , Eletrônica/instrumentação
15.
Adv Sci (Weinh) ; 11(18): e2306950, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38441365

RESUMO

Intracellular proteome aggregation is a ubiquitous disease hallmark with its composition associated with pathogenicity. Herein, this work reports on a cell-permeable photosensitizer (P8, Rose Bengal derivative) for selective photo induced proximity labeling and crosslinking of cellular aggregated proteome. Rose Bengal is identified out of common photosensitizer scaffolds for its unique intrinsic binding affinity to various protein aggregates driven by the hydrophobic effect. Further acetylation permeabilizes Rose Bengal to selectively image, label, and crosslink aggregated proteome in live stressed cells. A combination of photo-chemical, tandem mass spectrometry, and protein biochemistry characterizations reveals the complexity in photosensitizing pathways (both Type I & II), modification sites and labeling mechanisms. The diverse labeling sites and reaction types result in highly effective enrichment and identification of aggregated proteome. Finally, aggregated proteomics and interaction analyses thereby reveal extensive entangling of proteostasis network components mediated by HSP70 chaperone (HSPA1B) and active participation of autophagy pathway in combating proteasome inhibition. Overall, this work exemplifies the first photo induced proximity labeling and crosslinking method (namely AggID) to profile intracellular aggregated proteome and analyze its interactions.


Assuntos
Fármacos Fotossensibilizantes , Proteoma , Fármacos Fotossensibilizantes/metabolismo , Proteoma/metabolismo , Humanos , Rosa Bengala/metabolismo , Reagentes de Ligações Cruzadas/metabolismo , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos , Agregados Proteicos
16.
Am Heart J ; 272: 69-85, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38490563

RESUMO

BACKGROUND: We aimed to develop and validate a model to predict 1-year mortality risk among patients hospitalized for acute heart failure (AHF), build a risk score and interpret its application in clinical decision making. METHODS: By using data from China Patient-Centred Evaluative Assessment of Cardiac Events Prospective Heart Failure Study, which prospectively enrolled patients hospitalized for AHF in 52 hospitals across 20 provinces, we used multivariate Cox proportional hazard model to develop and validate a model to predict 1-year mortality. RESULTS: There were 4,875 patients included in the study, 857 (17.58%) of them died within 1-year following discharge of index hospitalization. A total of 13 predictors were selected to establish the prediction model, including age, medical history of chronic obstructive pulmonary disease and hypertension, systolic blood pressure, Kansas City Cardiomyopathy Questionnaire-12 score, angiotensin converting enzyme inhibitor or angiotensin receptor blocker at discharge, discharge symptom, N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T, serum creatine, albumin, blood urea nitrogen, and highly sensitive C-reactive protein. The model showed a high performance on discrimination (C-index was 0.759 [95% confidence interval: 0.739, 0.778] in development cohort and 0.761 [95% confidence interval: 0.731, 0.791] in validation cohort), accuracy, calibration, and outperformed than several existed risk scores. A point-based risk score was built to stratify low- (0-12), intermediate- (13-16), and high-risk group (≥17) among patients. CONCLUSIONS: A prediction model using readily available predictors was developed and internal validated to predict 1-year mortality risk among patients hospitalized for AHF. It may serve as a useful tool for individual risk stratification and informing decision making to improve clinical care.


Assuntos
Insuficiência Cardíaca , Hospitalização , Humanos , Insuficiência Cardíaca/mortalidade , Masculino , Feminino , China/epidemiologia , Idoso , Medição de Risco/métodos , Doença Aguda , Hospitalização/estatística & dados numéricos , Estudos Prospectivos , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Modelos de Riscos Proporcionais , Peptídeo Natriurético Encefálico/sangue , Troponina T/sangue , Proteína C-Reativa/análise , Fragmentos de Peptídeos/sangue
17.
Acta Diabetol ; 61(6): 735-743, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38436703

RESUMO

AIMS: To examine any potential links between remnant cholesterol (RC) and comorbid chronic kidney disease (CKD) in individuals with prediabetes and type 2 diabetes mellitus (T2DM). METHODS: We used data from 2709 American people aged > 20 years from the National Health and Nutrition Examination Survey (NHANES) during 2011-2018. Subjects were categorized according to whether they had comorbid CKD. Logistic regression models and smoothed curve fitting methods were employed to assess the association of RC with comorbid CKD in patients with prediabetes and T2DM. RESULTS: The 2709 participants included 1473 patients with T2DM and 1236 with prediabetes [impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)], of whom 744 (27.46%) had comorbid CKD. In multivariate-adjusted analysis, both RC and triglycerides (TG) were significantly associated with an increased risk of comorbid CKD, and a 1 mmol/L elevation of RC increased the risk by 38.1% [OR (95% CI) 1.636 (1.242, 2.156)], which was higher than the risk associated with a 1 mmol/L increase in TG [1.255 (1.106, 1.424)]. Additionally, those in the highest quartile of RC had a 43.6% higher risk of concomitant renal damage than those in the lowest quartile. RC was linearly and positively associated with the incidence of comorbid CKD in this population. CONCLUSIONS: RC is an independent risk factor for comorbid CKD in patients with prediabetes and T2DM. This finding provides a novel insight into the management and early detection of renal disease in patients with impaired glucose metabolism.


Assuntos
Colesterol , Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/sangue , Estado Pré-Diabético/epidemiologia , Masculino , Feminino , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/etiologia , Pessoa de Meia-Idade , Estudos Transversais , Fatores de Risco , Adulto , Estados Unidos/epidemiologia , Colesterol/sangue , Idoso , Inquéritos Nutricionais , Triglicerídeos/sangue
18.
Bioresour Technol ; 399: 130596, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38493939

RESUMO

Cembratriene-ol (CBT-ol), a plant-derived macrocyclic diterpene with notable insecticidal activity, has attracted considerable attention with respect to the development of sustainable and green biopesticides. Currently, CBT-ol production is limited by an inefficient and costly plant extraction strategy. Herein, CBT-ol production was enhanced by redesigning the CBT-ol biosynthetic pathway in Candida tropicalis, with subsequent truncation of CBT-ol synthase further increasing CBT-ol production. Moreover, bottlenecks in the CBT-ol biosynthetic pathway were eliminated by adjusting the gene dosage of the rate-limiting enzymes. Ultimately, the resulting strain C. tropicalis CPPt-03D produced 129.17 mg/L CBT-ol in shaking flasks (a 144-fold increase relative to that of the initial strain C01-CD) with CBT-ol production reaching 1,425.76 mg/L in a 5-L bioreactor, representing the highest CBT-ol titer reported to date. These findings provide a green process and promising platform for the industrial production of CBT-ol and lays the foundation for organic farming.


Assuntos
Vias Biossintéticas , Diterpenos , Vias Biossintéticas/genética , Engenharia Metabólica/métodos , Diterpenos/metabolismo , Plantas/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-38449345

RESUMO

OBJECTIVE: We aim to examine the association between long-term cumulative health status and subsequent mortality among patients with acute heart failure (HF). METHODS: Based on a national prospective cohort study of patients hospitalized for HF, we measured health status by Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 at 4 time points, i.e. admission, 1-,6- and 12-month after discharge. Cumulative health status was interpreted by cumulative KCCQ-12 score and cumulative times of good health status. Outcomes included subsequent all-cause and cardiovascular mortality. Multivariable Cox proportional hazard models were performed to examine the association between cumulative health status and subsequent mortality. RESULTS: Totally, 2328 patients (36.7% women and median age 66 [IQR: 56-75] years) were included, the median follow-up was 4.34 (IQR: 3.93-4.96) years. Compared with Quartile 4, the lowest Quartile 1 had the highest HR for all-cause mortality (2.96; 95% CI: 2.26-3.87), followed by Quartile 2 (1.79; 95% CI: 1.37-2.34) and Quartile 3 (1.62; 95% CI: 1.23-2.12). Patients with 0-time of good health status had the highest risk of all-cause mortality (HR: 2.41, 95% CI: 1.69-3.46) compared with patients with 4-times of good health status. Similar associations persisted for cardiovascular mortality. CONCLUSIONS: A greater burden of cumulative health status indicated worse survival among patients hospitalized for HF. Repeated KCCQ measurements could be helpful to monitor long-term health status and identify patients vulnerable to death. Clinical Trial Registration: www.clinicaltrials.gov (NCT02878811).

20.
Sci Rep ; 14(1): 7014, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38528051

RESUMO

The seismic deterioration effects of anchor cables and slope structural planes are often neglected in the dynamic stability analysis of anchored rocky slopes to the extent that the stability of slopes is overestimated. In this paper, a dynamic calculation method for anchored rocky slopes considering the seismic deterioration effect is established, and a stability evaluation method for anchored rocky slopes based on the Gaussian mixture model is proposed. The seismic deterioration effect on the stability of anchored rocky slopes is quantitatively analyzed with an engineering example, and the relationship between seismic intensity and the failure probability of slopes is clarified. The results show that compared with the calculation method without considering the seismic deterioration effect, the minimum safety factor and post-earthquake safety factor obtained by the proposed method in this paper are smaller. The number of seismic deteriorations of the slope is used as the number of components of the Gaussian mixture model to construct the failure probability model of the slope, which can accurately predict the failure probability of anchored rocky slopes. The research results significantly improve the accuracy of the stability calculation of anchored rocky slopes, which can be used to guide the seismic design and safety assessment of anchored rocky slopes.

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