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1.
Am J Transl Res ; 16(3): 781-793, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38586088

RESUMO

OBJECTIVE: The pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS-D) is related to damage to the intestinal mucosal barrier function. Based on the Mast cell (MC)/Tryptase/Protease-activated receptor-2 (PAR-2)/Myosin light chain kinase (MLCK) pathway, this study explored the effect of electroacupuncture (EA) on IBS-D rats and its possible mechanism of protecting the intestinal mucosal barrier. METHODS: The IBS-D rat model was established by mother-offspring separation, acetic acid enema, and chronic restraint stress. The efficacy of EA on IBS-D rats was evaluated by observing the rate of loose stool (LSP) and the minimum volume threshold of abdominal withdrawal reflex (AWR) in rats. Mast cells and the ultrastructure of intestinal mucosa were observed by H&E staining, toluidine blue staining, and transmission electron microscopy. The expression levels of Tryptase, PAR-2, MLCK, zonula occludens-1 (ZO-1), and Occludin in rats were detected by ELISA, qRT-PCR, and western blot. RESULTS: After 7 days of intervention, compared to the IBS-D group, the loose stool rates of rats in IBS-D + EA group and IBS-D + ketotifen group were decreased (P < 0.01), the minimum volume thresholds of AWR were improved (P < 0.01), the inflammation of colon tissue decreased, the number of MCs were decreased (P < 0.01), the expression of Tryptase, PAR-2, and MLCK were lowered (P < 0.01, P < 0.05), and the expression of ZO-1 and Occludin were enhanced (P < 0.01, P < 0.05). Compared to the EA group, there was no significant difference in each index between the ketotifen groups (P > 0.05). CONCLUSION: EA has a good therapeutic effect on IBS-D rats. Regulating the MCs/Tryptase/PAR-2/MLCK pathway may be a mechanism to protect the intestinal mucosal barrier.

2.
Angew Chem Int Ed Engl ; : e202406233, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38591161

RESUMO

The precise recognition and sensing of steroids, a type of vital biomolecules, hold immense practical value across various domains. In this study, we introduced corral[4]BINOLs (C[4]BINOLs), a pair of enantiomeric conjugated deep-cavity hosts, as novel synthetic receptors for binding steroids. Due to the strong hydrophobic effect of their deep nonpolar, chiral cavities, the two enantiomers of C[4]BINOLs demonstrated exceptionally high recognition affinities (up to 1012 M-1) for 16 important steroidal compounds as well as good enantioselectiviy (up to 15.5) in aqueous solutions, establishing them as the most potent known steroid receptors. Harnessing their ultrahigh affinity, remarkable enantioselectivity, and fluorescence emission properties, the two C[4]BINOL enantiomers were employed to compose a fluorescent sensor array which achieved discrimination and sensing of 16 structurally similar steroids at low concentrations.

3.
Environ Res ; 252(Pt 1): 118827, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38580006

RESUMO

BACKGROUND: PM2.5 is a harmful mixture of various chemical components that pose a challenge in determining their individual and combined health effects due to multicollinearity issues with traditional linear regression models. This study aimed to develop an analytical methodology combining traditional and novel machine learning models to evaluate PM2.5's combined effects on blood pressure (BP) and identify the most toxic components. METHODS: We measured late-pregnancy BP of 1138 women from the Heshan cohort while simultaneously analyzing 31 PM2.5 components. We utilized multiple linear regression modeling to establish the relationship between PM2.5 components and late-pregnancy BP and applied Random Forest (RF) and generalized Weighted Quantile Sum (gWQS) regression to identify the most toxic components contributing to elevated BP and to quantitatively evaluate the cumulative effect of the PM2.5 component mixtures. RESULTS: The results revealed that 16 PM2.5 components, such as EC, OC, Ti, Fe, Mn, Cu, Cd, Mg, K, Pb, Se, Na+, K+, Cl-, NO3-, and F-, contributed to elevated systolic blood pressure (SBP), while 26 components, including two carbon components (EC, OC), fourteen metallics (Ti, Fe, Mn, Cr, Mo, Co, Cu, Zn, Cd, Na, Mg, Al, K, Pb), one metalloid (Se), and nine water-soluble ions (Na+, K+, Mg2+, Ca2+, NH4+, Cl-, NO3-, SO42-, F-), contributed to elevated diastolic blood pressure (DBP). Mn and Cr were the most toxic components for elevated SBP and DBP, respectively, as analyzed by RF and gWQS models and verified against each other. Exposure to PM2.5 component mixtures increased SBP by 1.04 mmHg (95% CI: 0.33-1.76) and DBP by 1.13 mmHg (95% CI: 0.47-1.78). CONCLUSIONS: Our study highlights the effectiveness of combining traditional and novel models as an analytical strategy to quantify the health effects of PM2.5 constituent mixtures.

5.
Respir Med ; : 107611, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38570145

RESUMO

BACKGROUND: Benralizumab is indicated as add-on therapy in patients with uncontrolled, severe eosinophilic asthma; it has not yet been evaluated in a large Asian population with asthma in a clinical trial. OBJECTIVE: To evaluate the efficacy and safety of benralizumab in patients with severe asthma in Asia. METHODS: MIRACLE (NCT03186209) was a randomized, Phase 3 study in China, South Korea, and the Philippines. Patients aged 12-75 years with severe asthma receiving medium-to-high-dose inhaled corticosteroid/long-acting ß2-agonists, stratified (2:1) by baseline blood eosinophil count (bEOS) (≥300/µL; <300/µL), were randomized (1:1) to benralizumab 30 mg or placebo. Endpoints included annual asthma exacerbation rate (AAER; primary endpoint), change from baseline at Week 48 in pre-bronchodilator (BD) forced expiratory volume in 1 second (pre-BD FEV1) and total asthma symptom score (TASS). Safety was evaluated ≤ Week 56. RESULTS: Of 695 patients randomized, 473 had baseline bEOS ≥300/µL (benralizumab n = 236; placebo n = 237). In this population, benralizumab significantly reduced AAER by 74% (rate ratio 0.26 [95% CI 0.19, 0.36], p < 0.0001) and significantly improved pre-BD FEV1 (least squares difference [LSD] 0.25 L [95% CI 0.17, 0.34], p < 0.0001) and TASS (LSD -0.25 [-0.45, -0.05], p = 0.0126) versus placebo. In patients with baseline bEOS <300/µL, there were numerical improvements in AAER, pre-BD FEV1, and TASS with benralizumab versus placebo. The frequency of adverse events was similar for benralizumab (76%) and placebo (80%) in the overall population. CONCLUSIONS: MIRACLE data reinforces the efficacy and safety of benralizumab for severe eosinophilic asthma in an Asian population, consistent with the global Phase 3 results.

6.
Womens Health (Lond) ; 20: 17455057241242674, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38561970

RESUMO

BACKGROUND: Over the past two decades, there has been an increase of immigrants in Australia. Despite this, the availability of culturally responsive resources and services that cater to their needs remains insufficient. OBJECTIVE: The aim of this study was to explore the resources used and trusted by Mongolian- and Arabic-speaking migrant mothers in Australia for child health information and examine how they navigate and overcome challenges they encounter accessing this information. DESIGN: Semi-structured telephone interview. METHODS: A theory informed semi-structured 60-min telephone interview was conducted in Arabic and Mongolian with 20 Arabic- and 20 Mongolian-speaking migrant mothers of children younger than 2 years or currently pregnant and living in Australia. Data were analysed thematically using the framework method. RESULTS: The reliance on digital platforms such as google emerged as a common trend among both groups of mothers when seeking child health information. Notably, there were differences in resources selection, with Mongolian mothers showing a preference for Australian-based websites, while Arabic-speaking mothers tended to opt for culturally familiar resources. There were various barriers that hindered their access to health services and resources, including language barriers, cost, and limited knowledge or familiarity with their existence. Negative encounters with healthcare professionals contributed to a perception among many mothers that they were unhelpful. Both groups of mothers employed a cross-checking approach across multiple websites to verify trustworthiness of information. Acculturation was shown only among the Mongolian-speaking mothers who adapted their cultural practices in line with their country of residence. CONCLUSION: The findings of this study highlight the importance of addressing the needs of migrant mothers in accessing child health information. Health professionals, government agencies, and researchers have an opportunity to provide culturally responsive support by fostering a culturally inclusive approach to developing and promoting equitable access to services and resources, ultimately enhancing the wellbeing of migrant families.


Barriers and enablers to accessing child health resources and services: Findings from qualitative interviews with Arabic and Mongolian immigrant mothers in AustraliaMothers may experience barriers accessing resources and services related to child health behaviours after migration to Australia. Studies have found that parents actively seek health information and have a significant impact on their child's health behaviours, which can have long-term effects. Various factors influence parental decision-making regarding child health, including the socio-cultural environment, life experiences, and access to services and resources.This study reveals that both Arabic- and Mongolian-speaking migrant mothers heavily depend on online sources for accessing health information, primarily due to various barriers they face when accessing in person services, such as language constraints, financial limitations, and challenges in accessing healthcare services. This article also provides recommendations for future research and initiatives to be considered addressing the challenges faced by migrant mothers in accessing healthcare resources and services.


Assuntos
Saúde da Criança , Emigrantes e Imigrantes , Criança , Feminino , Gravidez , Humanos , Austrália , Pesquisa Qualitativa , Mães , Acesso aos Serviços de Saúde
7.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(3): 275-281, 2024 Mar 15.
Artigo em Chinês | MEDLINE | ID: mdl-38557380

RESUMO

OBJECTIVES: To investigate the nutritional status of children with cystic fibrosis (CF) and understand the correlation between malnutrition and clinical characteristics as well as lung function. METHODS: A retrospective analysis was performed on clinical data of CF children admitted from January 2016 to June 2023. Clinical characteristics of CF children with different nutritional statuses were compared, and the correlation between malnutrition and lung function was analyzed. RESULTS: A total of 52 CF children were included, comprising 25 boys (48%) and 27 girls (52%), aged between 7 months and 17 years. Respiratory symptoms were the predominant clinical manifestations (96%, 50/52). The prevalence of malnutrition was 65% (34/52), with moderate/severe malnutrition being the most common (65%, 22/34). The malnutrition group had a longer duration of illness, higher proportion of digestive system symptoms, and lower levels of serum albumin (P<0.05). Pulmonary function parameters, including forced expiratory volume in one second as a percentage of the predicted value, ratio of forced expiratory volume in one second to forced vital capacity, forced expiratory flow at 25% of forced vital capacity exhaled, forced expiratory flow at 50% of forced vital capacity exhaled, forced expiratory flow at 75% of forced vital capacity exhaled, and maximum mid-expiratory flow as a percentage of the predicted value, were lower in the malnutrition group compared to the normal nutrition group (P<0.05). Correlation analysis showed body mass index Z-score was positively correlated with the above six pulmonary function parameters (P<0.05). CONCLUSIONS: The prevalence of malnutrition is high in CF children and is associated with decreased lung function. CF children with higher body mass index have better lung function. Therefore, screening and evaluation of nutritional status as well as appropriate nutritional intervention should be emphasized in CF children.


Assuntos
Fibrose Cística , Desnutrição , Criança , Masculino , Feminino , Humanos , Lactente , Estado Nutricional , Estudos Retrospectivos , Fibrose Cística/complicações , Pulmão , Volume Expiratório Forçado , Desnutrição/etiologia , Desnutrição/complicações
8.
Orphanet J Rare Dis ; 19(1): 144, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38575988

RESUMO

BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient's cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.


Assuntos
Doença de Gaucher , Osteoporose , Humanos , Densidade Óssea/genética , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Inflamassomos , Osteoporose/genética , Osteoporose/tratamento farmacológico
9.
Nutr J ; 23(1): 41, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38594739

RESUMO

BACKGROUND: Gestational diabetes mellitus (GDM) is a common complication of pregnancy, with significant short-term and long-term implications for both mothers and their offspring. Previous studies have indicated the potential benefits of vitamin D in reducing the risk of GDM, yet little is known about this association in twin pregnancies. This study aimed to investigate maternal vitamin D status in the second trimester and examine its association with the risk of GDM in twin pregnancies. METHODS: We conducted a prospective cohort study based on data from the Chongqing Longitudinal Twin Study (LoTiS). Peripheral blood serum was collected from the mothers in the second trimester to measure 25(OH)D concentrations. GDM was diagnosed at 23-26 weeks of gestation using a 75-g 2-h oral glucose tolerance test. We used multivariable logistic regression analyses to examine the correlations between vitamin D status and the risk of GDM. RESULTS: Of the total participants, 93 (29.9%) women were diagnosed with GDM. The mean serum 25(OH)D concentration in the second trimester was 31.1 ± 11.2 ng/mL, and the rate of vitamin D insufficiency and deficiency were 23.5% and 18.7%, respectively. Compared to women with a 25(OH)D concentration < 30 ng/mL, those with a 25(OH)D concentration ≥ 30 ng/mL had a significantly lower risk of GDM (RR 0.61; 95% CI: 0.43, 0.86), especially those who were overweight before pregnancy (RR 0.32; 95% CI: 0.16, 0.64). The restricted cubic splines model showed an inverted J-shaped relationship between vitamin D concentrations and GDM risk. CONCLUSIONS: The risk of GDM was significantly reduced in twin pregnant women with vitamin D concentrations ≥ 30 ng/mL in the second trimester. TRIAL REGISTRATION: ChiCTR-OOC-16,008,203. Retrospectively registered on 1 April 2016.


Assuntos
Diabetes Gestacional , Deficiência de Vitamina D , Feminino , Gravidez , Humanos , Masculino , Vitamina D , Diabetes Gestacional/epidemiologia , Estudos de Coortes , Gravidez de Gêmeos , Estudos Prospectivos , Fatores de Risco , Vitaminas , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia
10.
Front Endocrinol (Lausanne) ; 15: 1333778, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38596222

RESUMO

There has been a major increase in Type 2 diabetes and obesity in many countries, and this will lead to a global public health crisis, which not only impacts on the quality of life of individuals well but also places a substantial burden on healthcare systems and economies. Obesity is linked to not only to type 2 diabetes but also cardiovascular diseases, musculoskeletal disorders, and certain cancers, also resulting in increased medical costs and diminished quality of life. A number of studies have linked changes in gut in obesity development. Dysbiosis, a deleterious change in gut microbiota composition, leads to altered intestinal permeability, associated with obesity and Type 2 diabetes. Many factors affect the homeostasis of gut microbiota, including diet, genetics, circadian rhythms, medication, probiotics, and antibiotics. In addition, bariatric surgery induces changes in gut microbiota that contributes to the metabolic benefits observed post-surgery. Current obesity management strategies encompass dietary interventions, exercise, pharmacotherapy, and bariatric surgery, with emerging treatments including microbiota-altering approaches showing promising efficacy. While pharmacotherapy has demonstrated significant advancements in recent years, bariatric surgery remains one of the most effective treatments for sustainable weight loss. However, access to this is generally limited to those living with severe obesity. This underscores the need for non-surgical interventions, particularly for adolescents and mildly obese patients. In this comprehensive review, we assess longitudinal alterations in gut microbiota composition and functionality resulting from the two currently most effective anti-obesity treatments: pharmacotherapy and bariatric surgery. Additionally, we highlight the functions of gut microbiota, focusing on specific bacteria, their metabolites, and strategies for modulating gut microbiota to prevent and treat obesity. This review aims to provide insights into the evolving landscape of obesity management and the potential of microbiota-based approaches in addressing this pressing global health challenge.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Humanos , Adolescente , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/complicações , Qualidade de Vida , Obesidade/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-38471493

RESUMO

INTRODUCTION: Upper urinary tract stones combined with parenchymal infiltrative renal pelvic cancer is challenging to detect on imaging, and to evaluate the differential diagnosis. CASE PRESENTATION: The symptoms and diagnoses in three cases of parenchymal infiltrative renal pelvic cancer and upper urinary tract stones that occurred between June 2019 and June 2022 were reviewed. Primary symptoms of lumbar discomfort and hemoturia were evident in all three patients. Preoperative Computed Tomography (CT) abdominal imaging revealed that all three cases had hydronephrosis along with renal stones, while the other two cases only had localized hypoenhancement of the renal parenchyma, which was only thought to be limited inflammatory changes in the renal cortex as a result of the combination of renal pelvis infection. After percutaneous nephrolithotomy or ureteroscopic lithotripsy, a combined renal pelvis tumor was discovered in all of these instances. Radical tumor surgery was later performed. One patient who had several tumor metastases passed away six months after surgery. A case with multiple metastases was discovered 15 months after surgery and survived with the help of the current chemotherapy. A case with a bladder tumor recurrence was discovered 16 months after surgery and had transurethral bladder tumor electrosurgery and routine bladder perfusion chemotherapy. CONCLUSION: Upper urinary tract stones and parenchymal infiltrative pyel carcinoma have atypical imaging, easily confused with infectious diseases. CT or Computed Tomography Urography (CTU) must be considered by urologists. Patients who have a CT with local renal parenchyma density should be suspected of having parenchymal invasive renal pelvis carcinoma; a needle biopsy ought to be performed; repeat biopsies may be performed if necessary. High-risk individuals need multiple, sufficient biopsies as needed and a comprehensive intraoperative assessment of the renal pelvic mucosa.

12.
Huan Jing Ke Xue ; 45(2): 854-861, 2024 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-38471924

RESUMO

The aggregation and sedimentation of micro/nano-plastics significantly affect their migration and distribution in the environment. This study investigated the effects of Na+ and natural organic matter (NOM) on the aggregation and sedimentation of polystyrene nano-plastics (PS-NPs) in the aqueous phase. Six types of water, such as seawater, lake water, and domestic sewage, were used to evaluate the above effects and other potential influencing factors. The results indicated that Na+ could facilitate the sedimentation of PS-NPs when it was less than 80 mmol·L-1, whereas it could promote the aggregation and suspension of PS-NPs when the concentration was greater than 80 mmol·L-1. NOM molecules affected the aggregation and sedimentation of PS-NPs by changing the ζ potential and relative density of particles via forming a multilayer adsorption structure with Na+ on the particle surface. It was observed that NOM greater than 10 mg·L-1 enhanced the dispersion and suspension of PS-NPs, which might have been attributed to the decrease in relative density of the particles as a large amount of NOM was absorbed onto the surface. Compared with synthetic waters, environmental waters enhanced the aggregation of PS-NPs, which may have been related to the amino acid, protein, and other organic macro-molecules in the water.

13.
Curr Drug Metab ; 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468514

RESUMO

BACKGROUND: Propofol is an intravenous agent for clinical anesthesia. As the influence of the hypobaric- hypoxic environment (Qinghai-Tibetan region, altitude: 2800-4300 m, PaO2: 15.1-12.4 kPa) on the metabolism of Propofol is complex, the research results on the metabolic characteristics of Propofol in high-altitude areas remain unclear. This study aimed to investigate the pharmacokinetic characteristics of Propofol in a high-altitude hypoxic environment using animal experiments. METHODS: Rats were randomly divided into three groups: high-altitude, medium-altitude, and plain groups. The time of disappearance and recovery of the rat righting reflex was recorded as the time of anesthesia induction and awakening, respectively. The plasma concentration of Propofol was determined by gas chromatography- mass spectrometry. A pharmacokinetic analysis software was used to analyze the blood-drug concentrations and obtain the pharmacokinetic parameters. RESULTS: We observed that when Propofol anesthetizes rats, the anesthesia induction time was shortened, and the recovery time was prolonged with increased altitude. Compared with the plain group, the clearance of Propofol decreased, whereas the half-life, area under the concentration-time curve, peak plasma concentration, and average residence time extension increased. CONCLUSION: The pharmacokinetic characteristics of Propofol are significantly altered in high-altitude hypoxic environments.

14.
bioRxiv ; 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38464148

RESUMO

Nuclear speckles, a type of membraneless nuclear organelle in higher eukaryotic cells, play a vital role in gene expression regulation. Using the reverse transcription-based RNA-binding protein binding sites sequencing (ARTR-seq) method, we study human transcripts associated with nuclear speckles. We identify three gene groups whose transcripts demonstrate different speckle localization properties and dynamics: stably enriched in nuclear speckles, transiently enriched in speckles at the pre-mRNA stage, and not enriched in speckles. Specifically, we find that stably-enriched transcripts contain inefficiently spliced introns. We show that nuclear speckles specifically facilitate splicing of speckle-enriched transcripts. We further reveal RNA sequence features contributing to transcript speckle localization, underscoring a tight interplay between genome organization, RNA cis-elements, and transcript speckle enrichment, and connecting transcript speckle localization with splicing efficiency. Finally, we show that speckles can act as hubs for the regulated retention of introns during cellular stress. Collectively, our data highlight a role of nuclear speckles in both co- and post-transcriptional splicing regulation.

15.
Fitoterapia ; 175: 105905, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38479616

RESUMO

Six new dimeric 2-(2-phenylethyl)chromones (1-6) were successfully isolated from the ethanol extract of agarwood of Aquilaria filaria from Philippines under HPLC-MS guidance. Compounds 1-6 are all dimers formed by linking 5,6,7,8-tetrahydro-2-(2-phenylethyl)chromone and flindersia 2-(2-phenylethyl)chromone via a single ether bond, and the linkage site (C5-O-C8'') of compound 2 is extremely rare. A variety of spectroscopic methods were used to ascertain their structures, including extensive 1D and 2D NMR spectroscopic analysis, HRESIMS, and comparison with literature. The in vitro tyrosinase inhibitory and anti-inflammatory activities of each isolate were assessed. Among these compounds, compound 2 had a tyrosinase inhibition effect with an IC50 value of 27.71 ± 2.60 µM, and compound 4 exhibited moderate inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells with an IC50 value of 35.40 ± 1.04 µM.

16.
RSC Adv ; 14(13): 9020-9031, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38500630

RESUMO

Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg2+ ions within the active site of integrase. Through optimization of compound 1, a series of indole-2-carboxylic acid derivatives were designed and synthesized, and compound 17a was proved to markedly inhibit the effect of integrase, with IC50 value of 3.11 µM. Binding mode analysis of 17a demonstrated that the introduced C6 halogenated benzene ring could effectively bind with the viral DNA (dC20) through π-π stacking interaction. These results indicated that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

17.
Acad Radiol ; 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38494348

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is an inflammatory cancer. We aimed to explore whether preoperative inflammation biomarkers compared to the gadoxetic acid disodium (Gd-EOB-DTPA) enhanced MRI can add complementary value for predicting HCC pathological grade, and to develop a dynamic nomogram to predict solitary HCC pathological grade. METHODS: 331 patients from the Institution A were divided chronologically into the training cohort (n = 231) and internal validation cohort (n = 100), and recurrence-free survival (RFS) was determined to follow up after surgery. 79 patients from the Institution B served as the external validation cohort. Overall, 410 patients were analyzed as the complete dataset cohort. Least absolute shrinkage and selection operator (LASSO) and multivariate Logistic regression were used to gradually filter features for model construction. The area under the receiver operating characteristic curve (AUC) and decision curve analysis were used to evaluate model's performance. RESULTS: Five models of the inflammation, imaging, inflammation+AFP, inflammation+imaging and nomogram were developed. Adding inflammation to imaging model can improve the AUC in training cohort (from 0.802 to 0.869), internal validation cohort (0.827 to 0.870), external validation cohort (0.740 to 0.802) and complete dataset cohort (0.739 to 0.788), and obtain more net benefit. The nomogram had excellent performance for predicting high-grade HCC in four cohorts (AUCs: 0.882 vs. 0.869 vs. 0.829 vs. 0.806) with a good calibration, and accessed at https://predict-solitaryhccgrade.shinyapps.io/DynNomapp/. Additionally, the nomogram obtained an AUC of 0.863 (95% CI 0.797-0.913) for predicting high-grade HCC in the HCC≤ 3 cm. Kaplan-Meier survival curves demonstrated that the nomogram owned excellent stratification for HCC grade (P < 0.0001). CONCLUSION: This easy-to-use dynamic online nomogram hold promise for use as a noninvasive tool in prediction HCC grade with high accuracy and robustness.

18.
Anal Bioanal Chem ; 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38491149

RESUMO

Deoxynivalenol (DON) is a mycotoxin that widely distributes in various foods and seriously threatens food safety. To minimize the consumers' dietary exposure to DON, there is an urgent demand for developing rapid and sensitive detection methods for DON in food. In this study, a bifunctional single-chain variable fragment (scFv) linked alkaline phosphatase (ALP) fusion protein was developed for rapid and sensitive detection of deoxynivalenol (DON). The scFv gene was chemically synthesized and cloned into the expression vector pET25b containing the ALP gene by homologous recombination. The prokaryotic expression, purification, and activity analysis of fusion proteins (scFv-ALP and ALP-scFv) were well characterized and performed. The interactions between scFv and DON were investigated by computer-assisted simulation, which included hydrogen bonds, hydrophobic interactions, and van der Waals forces. The scFv-ALP which showed better bifunctional activity was selected for developing a direct competitive enzyme-linked immunosorbent assay (dc-ELISA) for DON in cereals. The dc-ELISA takes 90 min for one test and exhibits a half inhibitory concentration (IC50) of 11.72 ng/mL, of which the IC50 was 3.08-fold lower than that of the scFv-based dc-ELISA. The developed method showed high selectivity for DON, and good accuracy was obtained from the spike experiments. Furthermore, the detection results of actual cereal samples analyzed by the method correlated well with that determined by high-performance liquid chromatography (R2=0.97165). These results indicated that the scFv-ALP is a promising bifunctional probe for developing the one-step colorimetric immunoassay, providing a new strategy for rapid and sensitive detection of DON in cereals.

19.
J Fungi (Basel) ; 10(3)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38535198

RESUMO

Xylariomycetidae comprises extremely diverse taxa that are widespread on decaying wood worldwide. An investigation of the diversity of microfungi on oil tree plantations in Sichuan Province was conducted during 2020-2021. Twelve saprobic taxa representing five species were identified as members of Amphisphaeriales and Xylariales through morphological comparisons. Phylogenetic analyses of combined ITS, LSU, rpb2, tub2 and tef1 sequence data indicated a distinct clade formed by three strains within Xylariomycetidae, unrelated to any currently recognized families. Thus, a novel anthostomella-like genus, Bicellulospora, is proposed and treated as Xylariales genera incertae sedis. Bicellulospora is characterized by dark brown to black, immersed, subglobose ascomata with a clypeus, cylindrical asci, and hyaline to yellowish brown, inequilaterally ellipsoidal ascospores with a large upper cell and a dwarf lower cell. Two new species of Amphisphaeria, namely A. oleae and A. verniciae, are introduced based on multi-gene phylogenetic analyses (ITS, LSU, rpb2 and tub2) coupled with morphological characteristics. Amphisphaeria micheliae and Endocalyx ptychospermatis are reported as new host records.

20.
Front Immunol ; 15: 1333967, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38482010

RESUMO

Introduction: The incidence of the autoimmune disease, type 1 diabetes (T1D), has been increasing worldwide and recent studies have shown that the gut microbiota are associated with modulating susceptibility to T1D. Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and is widely expressed on many cells, including dendritic cells (DCs), which are potent antigen-presenting cells (APCs). TLR5 modulates susceptibility to obesity and alters metabolism through gut microbiota; however, little is known about the role TLR5 plays in autoimmunity, especially in T1D. Methods: To fill this knowledge gap, we generated a TLR5-deficient non-obese diabetic (NOD) mouse, an animal model of human T1D, for study. Results: We found that TLR5-deficiency led to a reduction in CD11c+ DC development in utero, prior to microbial colonization, which was maintained into adulthood. This was associated with a bias in the DC populations expressing CD103, with or without CD8α co-expression, and hyper-secretion of different cytokines, both in vitro (after stimulation) and directly ex vivo. We also found that TLR5-deficient DCs were able to promote polyclonal and islet antigen-specific CD4+ T cell proliferation and proinflammatory cytokine secretion. Interestingly, only older TLR5-deficient NOD mice had a greater risk of developing spontaneous T1D compared to wild-type mice. Discussion: In summary, our data show that TLR5 modulates DC development and enhances cytokine secretion and diabetogenic CD4+ T cell responses. Further investigation into the role of TLR5 in DC development and autoimmune diabetes may give additional insights into the pathogenesis of Type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Animais , Humanos , Camundongos , Citocinas/metabolismo , Células Dendríticas , Suscetibilidade a Doenças/metabolismo , Camundongos Endogâmicos NOD , Receptor 5 Toll-Like/metabolismo
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