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1.
Accid Anal Prev ; 206: 107697, 2024 Jul 04.
Article de Anglais | MEDLINE | ID: mdl-38968864

RÉSUMÉ

Speeding, a risky act of driving a vehicle at a speed exceeding the posted limit, has consistently emerged as a leading contributor to traffic fatalities. Identifying the risk factors associated with injury severity in speeding-related crashes is essential for implementing countermeasures aimed at preventing severe injury incidents and achieving Vision Zero goals. With the wealth of traffic crash data collected by various agencies, researchers have a valuable opportunity to conduct data-driven studies and employ various modeling methods to gain insights into the correlated factors affecting injury severity in traffic crashes. Machine learning models, owing to their superior predictive power compared to statistical models, are increasingly being adopted by researchers. These models, in conjunction with interpretation techniques, can reveal potential relationships between crash injury severity and contributing factors. Traffic crashes are inherently tied to geographic locations, distributed across road networks influenced by diverse socioeconomic and geographical factors. Recognizing spatial heterogeneity in traffic safety is crucial for tailored safety measures to address speeding-related crashes, as a one-size-fits-all approach may not work effectively everywhere. However, most existing machine learning models are unable to incorporate the spatial dependency among observations, such as traffic crashes, which hinders their ability to uncover spatial heterogeneity in traffic safety. To address this gap, this study introduces the Geographically Weighted Neural Network (GWNN) model, a spatial machine-learning model that integrates neural network (NN) and geographically weighted modeling approaches to investigate spatial heterogeneity in speeding-related crashes. Unlike the traditional NN model, which trains a single set of model parameters for all observations, the GWNN trains a local NN model for each crash location using a spatially weighted subsample of nearby crashes, allowing for the quantification of corresponding local effects of features through calculating local marginal effects. To understand the spatial heterogeneity in speeding-related crashes, this study extracted two years (2020 and 2021) of speeding-related crash data from Alabama for the development of the GWNN local models. The modeling results show significant spatial variability among several factors contributing to injury severity in speeding-related crashes. These factors include driver condition, vehicle type, crash type, speed limit, weather, crash time and location, roadway alignment, and traffic volume. Based on the GWNN modeling results, this study identified three types of spatial variations in relationships between contributing factors and crash injury severity: consistent positive associations, consistent negative associations, and inverse associations (i.e., marginal effects can vary between positive and negative depending on the location). This study contributes by integrating advanced machine learning and spatial modeling approaches to uncover intricate spatial patterns and factors influencing injury severity in speeding-related crashes, thereby facilitating the development of targeted policy implementations and safety interventions.

2.
J Colloid Interface Sci ; 675: 488-495, 2024 Jul 08.
Article de Anglais | MEDLINE | ID: mdl-38986322

RÉSUMÉ

As a promising sustainable power source in intelligent electronics, Triboelectric Nanogenerators (TENGs) have garnered widespread interest, with various strategies explored to enhance their output performance. However, most optimization methods for triboelectric materials have focused solely on tuning chemical compositions or fabricating surface microstructures. Here, we have prepared amino-functionalized reduced graphene oxide (FRGO)/polyimide (PI) composite films (PI-FRGO) via in-situ polymerization, aimed at enhancing PI materials' nanotribological power generation performance. By varying the doping levels of amino groups and controlling the FRGO proportion during synthesis, we can explore the optimal FRGO/PI composite film ratio. At a p-Phenylenediamine: reduced Graphene Oxide (PPDA: RGO) ratio of 1:1 and an FRGO addition of 0.1 %, the output electrical performance peaks with a voltage of 58 V, a charge of 33 nC and a current of 12 µA, nearly 2 times that of a pure PI film. We have fabricated a TENG with an optimally formulated PI-FRGO composite to explore its application potential. Under a 10 MΩ external load resistance, the TENG can deliver a power density of 3.5 mW/m2 and can be powering small devices. This work presents new effective strategies to significantly enhance TENG output performance and promote their widespread application.

3.
Biomater Sci ; 2024 Jul 18.
Article de Anglais | MEDLINE | ID: mdl-39021349

RÉSUMÉ

Hydrogen therapy, leveraging its selective attenuation of hydroxyl radicals (˙OH) and ONOO-, has emerged as a pivotal pathophysiological modulator with antioxidant, anti-inflammatory, and antiapoptotic attributes. Hydrogen therapy has been extensively studied both preclinically and clinically, especially in diseases with an inflammatory nature. Despite the substantial progress, challenges persist in achieving high hydrogen concentrations in target lesions, especially in cancer treatment. A notable breakthrough lies in water/acid reactive materials, offering enhanced hydrogen generation and sustained release potential. However, limitations include hydrogen termination upon material depletion and reduced bioavailability at targeted lesions. To overcome these challenges, catalytic materials like photocatalytic and sonocatalytic materials have surfaced as promising solutions. With enhanced permeability and retention effects, these materials exhibit targeted delivery and sustained stimuli-reactive hydrogen release. The future of hydrogen therapy hinges on continuous exploration and modification of catalytic materials. Researchers are urged to prioritize improved catalytic efficiency, enhanced lesion targeting effects, and heightened biosafety and biocompatibility in future development.

4.
iScience ; 27(7): 110219, 2024 Jul 19.
Article de Anglais | MEDLINE | ID: mdl-39021795

RÉSUMÉ

The resected pⅢA-N2 non-small-cell lung cancer (NSCLC) patients who could benefit from postoperative radiotherapy (PORT) are not well-defined. The study explored the role of PORT on EGFR mutant and wild-type NSCLC patients. We retrospectively searched for resected pIIIA-N2 lung adenocarcinoma patients who underwent EGFR mutation testing. 80 patients with EGFR wild-type and 85 patients with EGFR mutation were included. 62 patients received PORT. In overall population, the median disease-free survival (DFS) was improved in PORT arm compared to non-PORT arm (22.9 vs. 16.1 months; p = 0.036), along with higher 2-year locoregional recurrence-free survival (LRFS) rate (88.3% vs. 69.3%; p = 0.004). In EGFR wild-type patients, PORT was associated with a longer median DFS (23.3 vs. 17.2 months; p = 0.044), and a higher 2-year LRFS rate (86.8% vs. 61.9%; p = 0.012). In EGFR mutant patients, PORT was not significantly correlated with improved survival outcomes. EGFR wild-type may a biomarker to identify the cohort that benefits from PORT.

5.
Int J Gen Med ; 17: 2877-2886, 2024.
Article de Anglais | MEDLINE | ID: mdl-38947567

RÉSUMÉ

Background: The aim of this study was to describe the demographic and clinical characteristics of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), analyse the risk factors associated with HBV-associated HCC, and to provide some references to the diagnosis and treatment of HCC. Methods: This study retrospectively enrolled 730 patients, including 390 patients with chronic hepatitis B (CHB) as controls, and 340 patients with CHB complicated with HCC as patients. Relevant information and medical records of these participants were collected, including age, sex, cigarette smoking, alcoholism, diabetes mellitus (DM), hypertension, coronary heart disease (CHD), cirrhosis, occupation, ascites, HBV-DNA load, the qualitative analysis of HBsAg, HBsAb, HBeAg, HBeAb, and HBcAb serological markers, and levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma-glutamyltransferase (GGT), TNM stage, tumor size and tumor number. The T test, Chi-square test, non-parametric rank-sum test, logistic regression analyses were used to explore the influencing factors and their degree of association with HCC in patients with HBV. Results: The proportion of smoking, alcoholism, married status, DM, hypertension, and the rate of HBV-DNA with a viral load of ≥500 copies/mL were significantly higher in the HCC group than in the controls (all p<0.05). Cirrhosis was more common among patients with CHB+HCC than in controls (p=0.013). The proportion of patients with HBsAg, HBeAb, and HBcAb positive was greater in CHB+HCC group than that in CHB group. Logistic regression analysis indicated that age ≥60 years (OR: 1.835, 95% CI: 1.020-3.302, p=0.043), HBeAb positive (OR: 9.105, 95% CI: 4.796-17.288, p<0.001), antiviral treatment with entecavir (OR: 2.209, 95% CI: 1.106-4.409, p=0.025), and GGT (OR: 1.004, 95% CI: 1.001-1.007, p=0.002) were risk factors for HCC in patients with CHB. Conclusion: Advanced age, HBeAb positive, antiviral treatment with entecavir, and GGT were independent risk factors for HCC in HBV patients.

6.
PeerJ ; 12: e17656, 2024.
Article de Anglais | MEDLINE | ID: mdl-38948216

RÉSUMÉ

Fusarium crown rot (FCR), caused by Fusarium spp., is a devastating disease in wheat growing areas. Previous studies have shown that FCR is caused by co-infection of F. graminearum, F. pseudograminearum, F. proliferatum and F. verticillioides in Hubei Province, China. In this study, a method was developed to simultaneously detected DNAs of F. graminearum, F. pseudograminearum, F. proliferatum and F. verticillioides that can efficiently differentiate them. Whole genome sequence comparison of these four Fusarium spp. was performed and a 20 bp sequence was designed as an universal upstream primer. Specific downstream primers of each pathogen was also designed, which resulted in a 206, 482, 680, and 963 bp amplicon for each pathogen, respectively. Multiplex PCR specifically identified F. graminearum, F. pseudograminearum, F. proliferatum and F. verticillioides but not from other 46 pathogens, and the detection limit of target pathogens is about 100 pg/µl. Moreover, we accurately determined the FCR pathogen species in wheat samples using the optimized multiplex PCR method. These results demonstrate that the multiplex PCR method established in this study can efficiently and rapidly identify F. graminearum, F. pseudograminearum, F. proliferatum, and F. verticillioides, which should provide technical support for timely and targeted prevention and control of FCR.


Sujet(s)
Fusarium , Réaction de polymérisation en chaine multiplex , Maladies des plantes , Triticum , Fusarium/génétique , Fusarium/isolement et purification , Triticum/microbiologie , Maladies des plantes/microbiologie , Réaction de polymérisation en chaine multiplex/méthodes , Chine , ADN fongique/génétique
7.
Orthop Surg ; 2024 Jul 01.
Article de Anglais | MEDLINE | ID: mdl-38946673

RÉSUMÉ

OBJECTIVE: Clinical concerns exist regarding the quality of bony consolidation in the context of the induced membrane technique. This study evaluates the clinical process of bone grafting in the second stage of induced membrane bone union in patients with tibial bone defects to infer the possibility of non-union and establish a reliable and effective evaluation method combined with computed tomography (CT) to assess fracture healing. METHODS: Patients with tibial bone defects who underwent the induced membrane technique at our hospital between February 2017 and February 2020 were retrospectively analyzed. The Hounsfield unit (HU) values of the patients were evaluated at different times during the second stage of bone grafting. Bone healing at the boundary value of the 120 HU output threshold (-1024 HU-3071 HU) was directionally selected, and the changes in the growth volume of union (new bone volume [selected according to HU value]/bone defect volume) were compared with analyzing individual class bone union. Method 1 involved X-rays revealing that at least three of the four cortices were continuous and at least 2 mm thick, with the patient being pain free. For Method 2, new bone volume (selected according to HU value/bone defect volume) at the stage was compared with analyzing individual class healing. Receiver operating characteristic curve analysis was used for Methods 1 and 2. RESULTS: A total of 42 patients with a segmental bone defect with a mean age of 40.5 years (40.5 ± 8.3 years) were included. The relationship between bone graft volume and time variation was analyzed by single factor repeated variable analysis (F = 6.477, p = 0.016). Further, curve regression analysis showed that the change in bone graft volume over time presented a logarithmic curve pattern (Y = 0.563 + 0.086 × ln(X), Ra2 = 0.608, p = 0.041). ROC curve analysis showed that Method 2 is superior to Method 1 (AUC: 86.3% vs. 68.3%, p < 0.05). CONCLUSION: The induced membrane technique could be used to treat traumatic long bone defects, with fewer complications and a higher healing rate. The proposed imaging grading of HU (new bone volume/bone defect volume) can be used as a reference for the quality of bony consolidation with the induced membrane technique.

8.
J Vis Exp ; (208)2024 Jun 14.
Article de Anglais | MEDLINE | ID: mdl-38949305

RÉSUMÉ

Conventional static cold storage (SCS) exacerbates ischemic injury in the DCD liver, leading to severe complications for transplant recipients. To address this issue, clinical application of MP technology for donor liver preservation is underway. Simultaneously, efforts are focused on the development of various MP instruments, validated through relevant animal model experiments. Effective large animal trials play a pivotal role in clinical applications. However, challenges persist in the ex vivo preservation of DCD livers and the transplantation procedure in pigs. These hurdles encompass addressing the prolonged preservation of donor livers, conducting viability tests, alleviating ischemic injuries, and shortening the anhepatic phase. The use of a variable temperature-controlled MP device facilitates the prolonged preservation of DCD livers through sequential Dual Hypothermic Oxygenated Machine Perfusion (DHOPE) and Normothermic Machine Perfusion (NMP) modes. This protocol enhances the porcine OLTx model by improving the quality of DCD livers, optimizing the anastomosis technique, and reducing the duration of the anhepatic phase.


Sujet(s)
Transplantation hépatique , Foie , Conservation d'organe , Perfusion , Animaux , Transplantation hépatique/méthodes , Conservation d'organe/méthodes , Suidae , Perfusion/méthodes , Foie/chirurgie
9.
Nutr Diabetes ; 14(1): 48, 2024 Jun 29.
Article de Anglais | MEDLINE | ID: mdl-38951151

RÉSUMÉ

BACKGROUND: This study aimed to assess whether the Haptoglobin (Hp) genotype influences the relationship between hemoglobin (Hb) levels and the development of gestational diabetes mellitus (GDM). Additionally, it sought to evaluate the interaction and joint association of Hb levels and Hp genotype with GDM risk. METHODS: This retrospective study involved 358 women with GDM and 1324 women with normal glucose tolerance (NGT). Peripheral blood leukocytes were collected from 360 individuals at 14-16 weeks' gestation for Hp genotyping. GDM was diagnosed between 24-28 weeks' gestation. Interactive moderating effect, joint analysis, and mediation analysis were performed to evaluate the crosslink of Hb levels and Hp genotype with GDM risk. RESULTS: Women who developed GDM had significantly higher Hb levels throughout pregnancy compared to those with NGT. Increase first-trimester Hb concentration was associated with a progressive rise in GDM incidence, glucose levels, glycosylated hemoglobin levels, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) values, cesarean delivery rates, and composite neonatal outcomes. Spline regression showed a significant linear association of GDM incidence with continuous first-trimester Hb level when the latter exceeded 122 g/L. Increased first-trimester Hb concentration was an independent risk factor for GDM development after adjusting for potential confounding factors in both the overall population and a matched case-control group. The Hp2-2 genotype was more prevalent among pregnant women with GDM when first-trimester Hb exceeded 122 g/L. Significant multiplicative and additive interactions were identified between Hb levels and Hp genotype for GDM risk, adjusted for age and pre-pregnancy BMI. The odds ratio (OR) for GDM development increased incrementally when stratified by Hb levels and Hp genotype. Moreover, first-trimester Hb level partially mediated the association between Hp genotype and GDM risk. CONCLUSION: Increased first-trimester Hb levels were closely associated with the development of GDM and adverse pregnancy outcomes, with this association moderated by the Hp2-2 genotype.


Sujet(s)
Diabète gestationnel , Génotype , Haptoglobines , Hémoglobines , Premier trimestre de grossesse , Humains , Femelle , Grossesse , Diabète gestationnel/génétique , Diabète gestationnel/sang , Diabète gestationnel/épidémiologie , Haptoglobines/génétique , Études rétrospectives , Adulte , Hémoglobines/analyse , Chine/épidémiologie , Facteurs de risque , Asiatiques/génétique , Hémoglobine glyquée/analyse , Glycémie/analyse , Glycémie/métabolisme , Insulinorésistance/génétique , Peuples d'Asie de l'Est
10.
J Neuroinflammation ; 21(1): 167, 2024 Jul 02.
Article de Anglais | MEDLINE | ID: mdl-38956605

RÉSUMÉ

BACKGROUND: Deposition of amyloid ß, which is produced by amyloidogenic cleavage of APP by ß- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be processed by α- and γ-secretase sequentially, to generate sAPPα, which has been shown to be neuroprotective by promoting neurite outgrowth and neuronal survival, etc. METHODS: The global expression profiles of miRNA in blood plasma samples taken from 11 AD patients as well as from 14 age and sex matched cognitively normal volunteers were analyzed using miRNA-seq. Then, overexpressed miR-140 and miR-122 both in vivo and in vitro, and knock-down of the endogenous expression of miR-140 and miR-122 in vitro. Used a combination of techniques, including molecular biology, immunohistochemistry, to detect the impact of miRNAs on AD pathology. RESULTS: In this study, we identified that two miRNAs, miR-140-3p and miR-122-5p, both targeting ADAM10, the main α-secretase in CNS, were upregulated in the blood plasma of AD patients. Overexpression of these two miRNAs in mouse brains induced cognitive decline in wild type C57BL/6J mice as well as exacerbated dyscognition in APP/PS1 mice. Although significant changes in APP and total Aß were not detected, significantly downregulated ADAM10 and its non-amyloidogenic product, sAPPα, were observed in the mouse brains overexpressing miR-140/miR-122. Immunohistology analysis revealed increased neurite dystrophy that correlated with the reduced microglial chemotaxis in the hippocampi of these mice, independent of the other two ADAM10 substrates (neuronal CX3CL1 and microglial TREM2) that were involved in regulating the microglial immunoactivity. Further in vitro analysis demonstrated that both the reduced neuritic outgrowth of mouse embryonic neuronal cells overexpressing miR-140/miR-122 and the reduced Aß phagocytosis in microglia cells co-cultured with HT22 cells overexpressing miR-140/miR-122 could be rescued by overexpressing the specific inhibitory sequence of miR-140/miR-122 TuD as well as by addition of sAPPα, rendering these miRNAs as potential therapeutic targets. CONCLUSIONS: Our results suggested that neuroprotective sAPPα was a key player in the neuropathological progression induced by dysregulated expression of miR-140 and miR-122. Targeting these miRNAs might serve as a promising therapeutic strategy in AD treatment.


Sujet(s)
Maladie d'Alzheimer , Chimiotaxie , Souris de lignée C57BL , microARN , Microglie , microARN/métabolisme , microARN/génétique , Animaux , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/anatomopathologie , Maladie d'Alzheimer/génétique , Souris , Humains , Microglie/métabolisme , Microglie/anatomopathologie , Mâle , Chimiotaxie/physiologie , Femelle , Protéine ADAM10/métabolisme , Protéine ADAM10/génétique , Amyloid precursor protein secretases/métabolisme , Amyloid precursor protein secretases/génétique , Souris transgéniques , Sujet âgé , Régulation de l'expression des gènes
11.
JCI Insight ; 2024 Jul 02.
Article de Anglais | MEDLINE | ID: mdl-38954484

RÉSUMÉ

Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodel system in this process remains largely unknown. Here we showed that BRD7, a component of the polybromo-associated BRG1-associated factor complex (PBAF), was required for naïve CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7-deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicated that the expression of BRD7 significantly turned to high from naïve CD8+ T cells to effector cells, bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and up-regulated its expression, leading to the maturation of effector T cells. Our research confirms BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.

12.
J Psychiatr Res ; 177: 1-10, 2024 Jun 26.
Article de Anglais | MEDLINE | ID: mdl-38964089

RÉSUMÉ

The variation in improvement among individuals with addiction after abstinence is a critical issue. Here, we aimed to identify robust multimodal markers associated with high response to 8-month abstinence in the individuals with heroin use disorder (HUD) and explore whether the identified markers could be generalized to the individuals with methamphetamine use disorder (MUD). According to the median of craving changes, 53 individuals with HUD with 8-month abstinence were divided into two groups: higher craving reduction and lower craving reduction. At baseline, clinical variables, cortical thickness and subcortical volume, fractional anisotropy (FA) of fibers and resting-state functional connectivity (RSFC) were extracted. Different strategies (single metric, multimodal neuroimaging fusion and multimodal neuroimaging-clinical data fusion) were used to identify reliable features for discriminating the individuals with HUD with higher craving reduction from those with lower reduction. The generalization ability of the identified features was validated in the 21 individuals with MUD. Multimodal neuroimaging-clinical fusion features with best performance was achieved an 87.1 ± 3.89% average accuracy in individuals with HUD, with a moderate accuracy of 66.7% when generalizing to individuals with MUD. The multimodal neuroimaging features, primarily converging in frontal regions (e.g., the left superior frontal (LSF) thickness, FA of the LSF-occipital tract, and RSFC of left middle frontal-right superior temporal lobe), collectively contributed to prediction alongside dosage and attention impulsiveness. In this study, we identified the validated multimodal frontal neuroimaging markers associated with higher response to long-term abstinence and revealed insights for the neural mechanisms of addiction abstinence, contributing to clinical strategies and treatment for addiction.

13.
Sci Rep ; 14(1): 16475, 2024 Jul 16.
Article de Anglais | MEDLINE | ID: mdl-39014082

RÉSUMÉ

Osteosarcoma (OS) is a heterogeneous malignant spindle cell tumor that is aggressive and has a poor prognosis. Although combining surgery and chemotherapy has significantly improved patient outcomes, the prognosis for OS patients with metastatic or recurrent OS has remained unsatisfactory. Therefore, it is imperative to gain a fresh perspective on OS development mechanisms and treatment strategies. After studying single-cell RNA sequencing (scRNA-seq) data in public databases, we identified seven OS subclonal types based on intra-tumor heterogeneity. Subsequently, we constructed a prognostic model based on pro-protein synthesis osteosarcoma (PPS-OS)-associated genes. Correlation analysis showed that the prognostic model performs extremely well in predicting OS patient prognosis. We also demonstrated that the independent risk factors for the prognosis of OS patients were tumor primary site, metastatic status, and risk score. Based on these factors, nomograms were constructed for predicting the 3- and 5-year survival rates. Afterward, the investigation of the tumor immune microenvironment (TIME) revealed the vital roles of γδ T-cell and B-cell activation. Drug sensitivity analysis and immune checkpoint analysis identified drugs that have potential application value in OS. Finally, the jumping translocation breakpoint (JTB) gene was selected for experimental validation. JTB silencing suppressed the proliferation, migration, and invasion of OS cells. Therefore, our research suggests that PPS-OS-related genes facilitate the malignant progression of OS and may be employed as prognostic indicators and therapeutic targets in OS.


Sujet(s)
Tumeurs osseuses , Ostéosarcome , Microenvironnement tumoral , Humains , Ostéosarcome/génétique , Ostéosarcome/thérapie , Ostéosarcome/métabolisme , Ostéosarcome/anatomopathologie , Ostéosarcome/mortalité , Ostéosarcome/traitement médicamenteux , Pronostic , Tumeurs osseuses/génétique , Tumeurs osseuses/thérapie , Tumeurs osseuses/anatomopathologie , Tumeurs osseuses/métabolisme , Tumeurs osseuses/mortalité , Tumeurs osseuses/traitement médicamenteux , Femelle , Mâle , Régulation de l'expression des gènes tumoraux , Nomogrammes , Lignée cellulaire tumorale , Marqueurs biologiques tumoraux/génétique , Marqueurs biologiques tumoraux/métabolisme , Prolifération cellulaire
14.
ACS Med Chem Lett ; 15(7): 1032-1040, 2024 Jul 11.
Article de Anglais | MEDLINE | ID: mdl-39015272

RÉSUMÉ

Heparanase (HPSE) is an enzyme that cleaves heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs). Overexpression of HPSE is associated with various types of cancer, inflammation, and immune disorders, making it a highly promising therapeutic target. Previously developed HPSE inhibitors that have advanced to clinical trials are polysaccharide-derived compounds or their mimetics; however, these molecules tend to suffer from poor bioavailability, side effects via targeting other saccharide binding proteins, and heterogeneity. Few small-molecule inhibitors have progressed to the preclinical or clinical stages, leaving a gap in HPSE drug discovery. In this study, a novel small molecule that can inhibit HPSE activity was discovered through high-throughput screening (HTS) using an ultrasensitive HPSE probe. Computational tools were employed to elucidate the mechanisms of inhibition. The essential structural features of the hit compound were summarized into a structure-activity relationship (SAR) theory, providing insights into the future design of HPSE small-molecule inhibitors.

15.
Front Pharmacol ; 15: 1351871, 2024.
Article de Anglais | MEDLINE | ID: mdl-39015370

RÉSUMÉ

Introduction: Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; Aconitum carmichaelii Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (Lycium barbarum L. [Solanaceae; Lycii fructus]), and Cinnamon (Neolitsea cassia (L.) Kosterm. [Lauraceae; Cinnamomi cortex]). It has been used to clinically treat nocturia caused by kidney-yang deficiency syndrome (KYDS) for over 30 years and warms kidney yang. However, the pharmacological mechanism and the safety of FQGBG in humans require further exploration and evaluation. Methods: We investigated the efficacy of FQGBG in reducing urination and improving immune organ damage in two kinds of KYDS model rats (hydrocortisone-induced model and natural aging model), and evaluated the safety of different oral FQGBG doses through pharmacokinetic (PK) parameters, metabonomics, and occurrence of adverse reactions in healthy Chinese participants in a randomized, double-blind, placebo-controlled, single ascending dose clinical trial. Forty-two participants were allocated to six cohorts with FQGBG doses of 12.5, 25, 50, 75, 100, and 125 g. The PKs of FQGBG in plasma were determined using a fully validated LC-MS/MS method. Results: FQGBG significantly and rapidly improved the symptoms of increased urination in both two KYDS model rats and significantly resisted the adrenal atrophy in hydrocortisone-induced KYDS model rats. No apparent increase in adverse events was observed with dose escalation. Major adverse drug reactions included toothache, thirst, heat sensation, gum pain, diarrhea, abdominal distension, T-wave changes, and elevated creatinine levels. The PK results showed a higher exposure level of benzoylhypaconine (BHA) than benzoylmesaconine (BMA) and a shorter half-life of BMA than BHA. Toxic diester alkaloids, aconitine, mesaconitine, and hypaconitine were below the lower quantitative limit. Drug-induced metabolite markers primarily included lysophosphatidylcholines, fatty acids, phenylalanine, and arginine metabolites; no safety-related metabolite changes were observed. Conclusion: Under the investigated dosing regimen, FQGBG was safe. The efficacy mechanism of FQGBG in treating nocturia caused by KYDS may be related to the improvement of the hypothalamus-pituitary-adrenal axis function and increased energy metabolism. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=26934, identifier ChiCTR1800015840.

16.
Front Med (Lausanne) ; 11: 1397900, 2024.
Article de Anglais | MEDLINE | ID: mdl-39015790

RÉSUMÉ

Background: Nonalcoholic fatty liver disease (NAFLD), also known as metabolic associated fatty liver disease (MAFLD), is a common liver condition characterized by excessive fat accumulation in the liver which is not caused by alcohol. The main causes of NAFLD are obesity and insulin resistance. Dachaihu decoction (DCHD), a classic formula in traditional Chinese medicine, has been proved to treat NAFLD by targeting different aspects of pathogenesis and is being progressively used in the treatment of NAFLD. DCHD is commonly applied in a modified form to treat the NAFLD. In light of this, it is imperative to conduct a systematic review and meta-analysis to assess the effectiveness and safety of DCHD in the management of NAFLD. There is a need for a systematic review and meta-analysis to assess the effectiveness and safety of modified DCHD in treating NAFLD. Objective: The objective of this meta-analysis was to systematically assess the clinical effectiveness and safety of DCHD in treating NAFLD. Methods: This meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Including seven databases, both Chinese and English databases were searched for relevant studies. The quality of included studies was carefully assessed using the bias risk assessment tool in the Cochrane Handbook. Eligible articles were the source of extracted data which was meta-analyzed by using Review Manager 5.4 and Stata 17.0. Results: A total of 10 studies containing 825 patients were included. Compared with conventional treatments, combined treatment could clearly improve the liver function of NAFLD patients, which could reduce the levels of ALT (MD = -7.69 U/L, 95% CI: -11.88 to -3.51, p < 0.001), AST (MD = -9.58 U/L, 95% CI: -12.84 to -6.33, p < 0.01), and it also had a certain impact on regulating lipid metabolism, which could reduce the levels of TC (MD = -0.85 mmol/L, 95% CI: -1.22 to 0.48, p < 0.01), TG (MD = -0.45 mmol/L, 95% CI: -0.64 to 0.21, p < 0.01). Adverse event showed that DCHD was relatively safe. Due to the inclusion of less than 10 trials in each group, it was not possible to conduct a thorough analysis of publication bias. Conclusion: According to the meta-analysis, in the treatment of the NAFLD, it is clear that the combination of DCHD was advantages over conventional treatment alone in improving liver function, regulating lipid metabolism. Additionally, DCHD demonstrates a relatively safe profile. Nevertheless, due to limitations in the quality and quantity of the studies incorporated, the effectiveness and safety of DCHD remain inconclusive. Consequently, further high-quality research is imperative to furnish more substantial evidence supporting the widespread clinical application of DCHD. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023397353, CRD42023397353.

17.
Plant Cell Environ ; 2024 Jul 05.
Article de Anglais | MEDLINE | ID: mdl-38965879

RÉSUMÉ

Thrips, Frankliniella intonsa, is a highly polyphagous pest with a worldwide distribution. F. intonsa-infested sunflower seeds show marked visual damage. The study findings revealed that significantly more F. intonsa infested confection sunflower compared to oilseed sunflower, via olfactometer bioassay studies, we found that compared with the flower and pollen of oilseed sunflowers, those of confection sunflowers attract F. intonsa. Considering this discrepancy in the preference of F. intonsa on oilseed and confection sunflowers, the volatiles of the flower and pollens of two sunflowers were analysed by gas chromatography-mass spectroscopy. The behavioural responses of F. intonsa were assessed for these compounds using Y-tube bioassays. Geranyl bromide, a unique volatile component of oilseed sunflowers, induced an assertive approach-avoidance behaviour in F. intonsa, whereas the unique component ethyl isovalerate in confection sunflowers attracted F. intonsa. F. intonsa adults demonstrated significant attraction to the blends of confection sunflowers. Furthermore, field verification revealed that intercropping confection and oilseed sunflowers could effectively control F. intonsa. The study provided insights into the chemical cues used by F. intonsa in locating hosts. Therefore, oilseed sunflowers can be used as repellent plants to prevent F. intonsa invasion.

19.
Antonie Van Leeuwenhoek ; 117(1): 98, 2024 Jul 09.
Article de Anglais | MEDLINE | ID: mdl-38981868

RÉSUMÉ

An aerobic, Gram-stain-negative bacterium, designated as SYSU D00382T, was sourced from soil of Gurbantunggut Desert, PR China. The strain was short-rod-shaped, oxidase-positive and catalase-negative, with yellow-colored, convex, round, and smooth colonies on TSA plate. Growth and proliferation occurred at 4-37 °C (optimal: 28-30 °C), pH 5.0-8.0 (optimal: pH 6.0-7.0) and NaCl concentration of 0-2.5% (optimal: 0-0.5%). The 16S rRNA gene based phylogenetic assessment showed that SYSU D00382T belonged to the genus Pedobacter, and was most closely related to Pedobacter ginsengisoli Gsoil 104T with similarity of 97.7%. The genomic DNA G+C content of SYSU D00382T was 46.4%. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between SYSU D00382T and P. ginsengisoli Gsoil 104T were 75.7% and 17.5%, respectively. The main polar lipid was phosphatidylethanolamine. The major fatty acids (> 5%) were iso-C15:0, iso-C17:0 3-OH, summed features 3 and 9. The sole respiratory quinone identified was MK-7. The phylogeny based on 16S rRNA gene and whole-genome sequences revealed that SYSU D00382T formed a robust lineage with P. ginsengisoli Gsoil 104T. Based on phenotypic, phylogenetic and genotypic data, a novel specie named Pedobacter deserti sp. nov. is proposed. The type strain is SYSU D00382T (= CGMCC 1.18627T = MCCC 1K04972T = KCTC 82279T).


Sujet(s)
Techniques de typage bactérien , Composition en bases nucléiques , ADN bactérien , Climat désertique , Acides gras , Pedobacter , Phylogenèse , ARN ribosomique 16S , Microbiologie du sol , Pedobacter/génétique , Pedobacter/classification , Pedobacter/isolement et purification , Pedobacter/physiologie , ARN ribosomique 16S/génétique , ADN bactérien/génétique , Acides gras/analyse , Chine , Hybridation d'acides nucléiques , Analyse de séquence d'ADN
20.
Transl Oncol ; 47: 102047, 2024 Jul 06.
Article de Anglais | MEDLINE | ID: mdl-38972174

RÉSUMÉ

Osteosarcoma, one of the most common primary malignancies in children and adolescents, has the primary characteristics of a poor prognosis and high rate of metastasis. This study used super-enhancer-related genes derived from two different cell lines to construct five novel super-enhancer-related gene prognostic models for patients with osteosarcoma. The training and testing datasets were used to confirm the prognostic models of the five super-enhancer-related genes, which resulted in an impartial predictive element for osteosarcoma. The immunotherapy and prediction of the response to anticancer drugs have shown that the risk signature of the five super-enhancer-related genes positively correlate with chemosensitivity. Furthermore, functional analysis of the risk signature genes revealed a significant relationship between gene groups and the malignant characteristics of tumours. TNF Receptor Superfamily Member 11b (TNFRSF11B) was selected for functional verification. Silencing of TNFRSF11B suppressed the proliferation, migration, and invasion of osteosarcoma cells in vitro and suppressed osteosarcoma growth in vivo. Moreover, transcriptome sequencing was performed on MG-63 cells to study the regulatory mechanism of TNFRSF11B in osteosarcoma cells, and it was discovered that TNFRSF11B is involved in the development of osteosarcoma via the phosphoinositide 3-kinase signalling pathway. Following the identification of TNFRSF11B as a key gene, we selected an inhibitor that specifically targeted this gene and performed molecular docking simulations. In addition, risedronic acid inhibited osteosarcoma growth at both cellular and molecular levels. In conclusion, the super-enhancer-related gene signature is a viable therapeutic tool for osteosarcoma prognosis and treatment.

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