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Given the considerable potential of DOT1LR231Q inhibitors in lung cancer therapy and the problematic pharmacokinetics of nucleoside inhibitors, our group launched a development program of non-nucleoside DOT1LR231Q inhibitors to improve the pharmacokinetic properties. Herein, two series of non-nucleoside compounds bearing piperidine or 3-(aminomethyl)pyrrolidin-3-ol as "ribose mimics" were designed and evaluated through antiproliferation assay and western blot analysis. The optimal TB22 inhibited the proliferation of H460R231Q cells with an IC50 value of 2.85 µM, about 13-fold more potent than SGC0946. Notably, TB22 demonstrated significant in vivo efficacy (TGI = 60.57%) in H460R231Q cell-derived xenograft models and improved pharmacokinetic properties (t1/2 = 6.06 ± 2.94 h and CL = 55.18 ± 8.56 mL/kg/min). Moreover, a mechanism study validated that TB22 suppressed malignant phenotypes of lung cancer cells harboring R231Q mutation via the MAPK/ERK signaling pathway. This work provides a promising molecule for lung cancer therapy in favor of clinical patients.
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Antineoplásicos , Proliferação de Células , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Camundongos , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Camundongos Nus , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Histona-Lisina N-MetiltransferaseRESUMO
PURPOSE: Consumption of ultra-processed foods (UPF) has been associated with increased risks of various age-related diseases. However, the potential association between UPF consumption and age-related eye diseases (AREDs) remains unclear. We aim to assess the associations between consumption of UPF and risk of AREDs including age-related macular degeneration (AMD), cataract and glaucoma. METHODS: We included 156,232 individuals aged 50 or older, who were free from AREDs from UK biobank study. Dietary intake data were collected using 24-h dietary assessments. UPF is defined according to the NOVA classification, and all participants are divided into four quartiles based on the weight proportion (%) of UPF. During a median of 10 years of follow-up. Cox proportional hazards were used to estimate the association between the proportion of UPF in the diet and the subsequent risk of various AREDs. RESULTS: After adjusting for multiple variables, individuals in the highest quartiles for UPF consumption exhibited an increased risk of AMD (hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.01-1.63; p = 0.03), cataract (HR: 1.10; 95% CI: 1.01-1.20; p = 0.04), and glaucoma (HR: 1.27; 95% CI: 0.98-1.63; p = 0.06) compared to those in the lowest quartiles. Moreover, a 10% increase in the weight of UPF in diet was associated with an 8% higher risk of AMD (HR: 1.08; 95% CI: 1.01-1.15; p = 0.03), a 3% higher risk of cataract (HR: 1.03; 95% CI: 1.00-1.06; p = 0.04), and a 7% higher risk of glaucoma (HR: 1.07; 95% CI: 1.00-1.15; p = 0.05). CONCLUSION: Our results suggest that a higher proportion of UPF in the diet was significantly link with an elevated risk of AMD and cataract. While additional research is necessary to validate these findings in diverse populations and settings, these results offer initial evidence to endorse public health initiatives that encourage limiting consumption of UPF.
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Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer. Herein, a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q cell. The most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation, self-renewal, migration, and invasion of lung cancer cell lines at low micromolar concentrations. The cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS assays. In the H460R231Q OE cell-derived xenograft (CDX) model, 37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks (TGI = 54.38%), without obvious toxicities. A pharmacokinetic study revealed that 37 possessed tolerable properties (t 1/2 = 1.93 ± 0.91 h, F = 97.2%) after intraperitoneal administration in rats. Mechanism study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway. Moreover, analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the "Induced-fit" allosteric model in favor to the discovery of potent DOT1L candidates.
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The investigation was conducted to describe the status of coverage of HBV vaccination among the health care workers in Gansu province and to explore the associated factors of HBV vaccination in this study. A cross-sectional study was conducted among 1544 health care workers from 64 hospitals in Gansu province. A self-designed questionnaire was used to interview the health care workers about HBV vaccination coverage. A multivariate logistic regression model explored the associated factors with HBV vaccination. The vaccination coverage was 89.17% for health care workers, nurses (90.40%) had the highest rate, followed by administration staff (89.38%) and medical technicians (89.30%). The full-dose HBV vaccination coverage was 64.25% for health care workers, and administration staff (65.04%) had the highest rate, followed by nurses (65.00%). This study found that the associated factors with HBV vaccination and full-dose vaccination were the history of training and the detection of serological indicators. The coverage of HBV vaccination among health care workers in Gansu province was high, but full-dose HBV vaccination coverage was low. It is necessary to strengthen the HBV knowledge and training in HBV prevention and treatment among health care workers in Gansu Province.
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Pessoal de Saúde , Vacinas contra Hepatite B , Hepatite B , Cobertura Vacinal , Humanos , Cobertura Vacinal/estatística & dados numéricos , Estudos Transversais , Pessoal de Saúde/estatística & dados numéricos , Feminino , Masculino , Hepatite B/prevenção & controle , Adulto , Vacinas contra Hepatite B/administração & dosagem , Pessoa de Meia-Idade , Inquéritos e Questionários , China/epidemiologia , Adulto Jovem , Vacinação/estatística & dados numéricosRESUMO
OBJECTIVE: To investigate the relationship between the changes of C-reactive protein to Albumin Ratio (CAR) levels and Interval Debulking Surgery (IDS) outcome after Neoadjuvant Chemotherapy (NAC) in ovarian cancer patients. METHODS: A nested case-control study for 209 patients with ovarian cancer who received NAC-IDS therapy from the First Affiliated Hospital of Bengbu Medical College between 2015â2021 was conducted. Demographic data, laboratory indicators, and imaging examinations were collected. The outcome was regarded as optimal IDS in this study. Univariate and multivariate logistic regression analyses were performed to assess the relationship of CAR before NAC, CAR after NAC and ∆CAR with optimal IDS. The authors also performed the subgroup analysis based on menopausal state. RESULTS: The end time of follow-up was January 24, 2022. A total of 156 patients had been treated with optimal IDS, and 53 with suboptimal IDS. After adjusting age, body mass index, menopausal state, NAC drug, peritoneal perfusion and CAR before NAC, the result showed that CAR after NAC (Odds Ratio [OR = 3.48], 95% Confidence Interval [95% CI 1.28â9.48], p = 0.015) and ∆CAR (OR = 0.29, 95% CI 0.11â0.78, p = 0.015) were associated with optimal IDS, respectively. Additionally, the authors found a significant correlation between CAR after NAC and optimal IDS (OR = 3.16, 95% CI 1.07â9.35, p = 0.038), and ∆CAR and optimal IDS (OR = 0.32, 95% CI 0.11â0.94, p = 0.038) among ovarian cancer patients with menopause. CONCLUSION: CAR after NAC and ∆CAR were independent prognostic markers of optimal interval debulking surgery for ovarian cancer patients.
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Proteína C-Reativa , Procedimentos Cirúrgicos de Citorredução , Terapia Neoadjuvante , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/terapia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Proteína C-Reativa/análise , Estudos de Casos e Controles , Idoso , Resultado do Tratamento , Adulto , Albumina Sérica/análise , Quimioterapia AdjuvanteRESUMO
Finite element analysis can provide precise femoral strength assessment. However, its modeling procedures were complex and time-consuming. This study aimed to develop a model to evaluate femoral strength calculated by quantitative computed tomography-based finite element analysis (QCT/FEA) under stance loading configuration, offering an effective, simple, and explainable method. One hundred participants with hip QCT images were selected from the Hong Kong part of the Osteoporotic fractures in men cohort. Radiomics features were extracted from QCT images. Filter method, Pearson correlation analysis, and least absolute shrinkage and selection operator method were employed for feature selection and dimension reduction. The remaining features were utilized as inputs, and femoral strengths were calculated as the ground truth through QCT/FEA. Support vector regression was applied to develop a femoral strength prediction model. The influence of various numbers of input features on prediction performance was compared, and the femoral strength prediction model was established. Finally, Shapley additive explanation, accumulated local effects, and partial dependency plot methods were used to explain the model. The results indicated that the model performed best when six radiomics features were selected. The coefficient of determination (R2), the root mean square error, the normalized root mean square error, and the mean squared error on the testing set were 0.820, 1016.299 N, 10.645%, and 750.827 N, respectively. Additionally, these features all positively contributed to femoral strength prediction. In conclusion, this study provided a noninvasive, effective, and explainable method of femoral strength assessment, and it may have clinical application potential.
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Type 2 diabetes mellitus (T2DM) can lead to multiple complications. T2DM-related bone damage has been linked to abnormal bone turnover, but it cannot fully explain the mechanisms of T2DM bone disease. This study attempts to elucidate the underlying mechanisms of poor bone quality in T2DM. Hence, T2DM model was induced by a high-fat diet combined with a single streptozotocin injection in 7-week-old male SD rats. Osteoblasts derived from SD rats were cultured in high glucose to mimic hyperglycemia. Low bone turnover was observed in T2DM bone with elevated levels of advanced glycation end-products (AGEs) and receptor for AGEs (RAGE). Additionally, higher levels of oxidative stress and inflammatory factors were found in T2DM bone. AGEs content in bone was pairwise correlated with RAGE, hydrogen peroxide, and inflammatory factors. Serum levels of RAGE, oxidative stress, and inflammatory factors were higher in T2DM, while AGEs content tended to be lower. Besides, 35 differentially expressed metabolites were screened in T2DM serum. Osteoblasts exposed to high glucose displayed analogous abnormal changes in these biomarkers. Thus, low bone turnover in T2DM might be partially due to excess oxidative stress and inflammation induced by AGE-RAGE signaling. Furthermore, these biomarker levels in serum were mostly consistent with bone, demonstrating their possibility for predicting bone quality in T2DM.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Produtos Finais de Glicação Avançada , Inflamação , Estresse Oxidativo , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada , Animais , Produtos Finais de Glicação Avançada/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Ratos , Inflamação/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Diabetes Mellitus Experimental/metabolismo , Osteoblastos/metabolismo , Remodelação ÓsseaRESUMO
BACKGROUND: Repeated exposure to ultraviolet A (UVA) irradiation, which can penetrate the epidermis and reach the dermis, is one of the major causes of skin photoaging. Photoaged skin is characterized clinically by generalized wrinkling, a dry and loose appearance, and seborrheic keratoses, along with skin barrier dysfunction. Fucoxanthin, a xanthophyll carotenoid with a specific allenic bond and 5,6-monoepoxide in its structure, has been found to serve various functions as a food supplement. In the present study, the protective effects of orally administered fucoxanthin at relatively low concentrations (0.001% and 0.01%) against UVA induced photoaging were evaluated in vivo using hairless mice. RESULTS: Oral supplementation of 0.001% fucoxanthin was sufficient for its metabolites to accumulate in the skin, thereby inhibiting pathological changes induced by UVA irradiation, including impaired skin barrier function and accelerated wrinkle formation. Analysis of gene expression revealed that dietary fucoxanthin exerted antiphotoaging effects, possibly by modulating natural moisturizing factor (NMF) synthesis, desquamation, and ceramide composition in the epidermis, and by inhibiting the UVA induced degradation of collagen fibers and inflammation in the dermis. CONCLUSION: Taken together, our data indicate the potential application of dietary fucoxanthin as a novel ingredient in nutricosmetics for skin care against photoaging. © 2024 Society of Chemical Industry.
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RATIONALE: Nocardia infection is commonly regarded as an opportunistic pulmonary pathogen affecting debilitated or immunocompromised individuals. Brain abscesses caused by Nocardia farcinica are rare and pose a diagnostic challenge. Traditional diagnostic techniques for identifying Nocardia species, such as blood culture, microscopy, and pathology, have shown inadequate performance. In the reported case, we applied metagenomic next-generation sequencing (mNGS) to diagnose a case of brain abscess due to N. farcinica. PATIENT CONCERNS: A 66-year-old female developed a brain abscess after sustaining a hand injury. The patient exhibited a gradual change in personality and experienced tremors in her right upper limb for a duration of 1 month. DIAGNOSES: The pathogen responsible for the multiple brain abscesses was identified in the cerebrospinal fluid as N. farcinica through mNGS. INTERVENTIONS: Antibiotic treatment included trimethoprim-sulfamethoxazole, linezolid, amikacin, meropenem, and moxifloxacin. OUTCOMES: The patient's symptoms and signs improved significantly after administration of antibiotics to which the pathogen is known to be sensitive. After 5 months of follow-up, magnetic resonance imaging of the head showed that the abscess was basically cured. The patient lived a normal life with no adverse drug reactions. LESSONS: Nocardia brain infection is characterized by an insidious onset and lacks distinctive clinical and imaging features. mNGS was advantageous for the timely identification and management of Nocardia-associated brain abscess in the present case and obviated the need for invasive brain surgery. Expeditious and precise diagnosis coupled with prompt antibiotic therapy can significantly reduce the mortality rate associated with this condition.
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Antibacterianos , Abscesso Encefálico , Traumatismos da Mão , Nocardiose , Nocardia , Humanos , Feminino , Nocardiose/diagnóstico , Nocardiose/tratamento farmacológico , Abscesso Encefálico/microbiologia , Abscesso Encefálico/etiologia , Abscesso Encefálico/diagnóstico , Nocardia/isolamento & purificação , Idoso , Antibacterianos/uso terapêutico , Traumatismos da Mão/complicações , Imageamento por Ressonância Magnética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
In-depth research into the precise evaluation of enzymatic digestion efficiency and the selection of a suitable deuterium-labelled internal standard remains a gap in the accurate determination of ß2-agonists in animal-derived food by isotope dilution-liquid chromatography/tandem mass spectrometry (ID-LC-MS/MS). In this study, the enzymatic digestion conditions were optimized by monitoring the presence of ß2-agonist conjugates in positive samples, which proved to be reliable for ensuring complete enzymatic digestion. Comparative analysis of deuterium-labelled internal standards for salbutamol (SAL), ractopamine (RAC), and clenbuterol (CLB) revealed that CLB-D6 and SAL-D9 were less effective in compensating for matrix effects due to hydrogendeuterium exchange during MS fragment formation. Consequently, SAL-D3, RAC-D3 and CLB-D9 were chosen for the implementation of ID-LC-MS/MS. The developed method demonstrates high accuracy and precision, with the average recoveries ranging from 93.8% to 107.3% with RSD <6.1%, which can provide higher-order measurement results for ß2-agonists in pork.
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Albuterol , Clembuterol , Fenetilaminas , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Animais , Fenetilaminas/análise , Fenetilaminas/química , Clembuterol/análise , Suínos , Albuterol/análise , Albuterol/química , Cromatografia Líquida/métodos , Deutério/química , Deutério/análise , Técnicas de Diluição do Indicador , Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Alimentos/análiseRESUMO
Mixed germ cell tumors (mGCTs) involving both the ovaries and sellar region have been rarely reported; thus, they pose significant challenges in clinical management. Our report of a case of a 26-year-old female with left ovarian mGCTs (dysgerminoma + yolk sac tumor) who presented with postoperative headaches and blurred vision contributes new information to the literature on treating mGCTs, which can lead to standardized regimens and sequencing guidelines. A physical examination revealed right temporal hemianopia, and elevated levels of alpha-fetoprotein were detected in serum and cerebrospinal fluid. Magnetic resonance imaging (MRI) of the sellar region revealed a space-occupying lesion. Pathological examination of the tumor after endoscopic transnasal resection confirmed the diagnosis of mGCTs (germinomas + yolk sac tumor). The patient received adjuvant chemotherapy and radiotherapy at reduced dosages. During follow-up, tumor markers remained within normal limits, and there was no evidence of tumor recurrence on sellar region MRI. This case highlights the rarity of the simultaneous occurrence of ovarian and sellar region mGCTs and emphasizes the importance of accurate diagnosis and multidisciplinary management.
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A homozygous mutation of the DNAJC6 gene causes autosomal recessive familial type 19 of Parkinson's disease (PARK19). To test the hypothesis that PARK19 DNAJC6 mutations induce the neurodegeneration of dopaminergic cells by reducing the protein expression of functional DNAJC6 and causing DNAJC6 paucity, an in vitro PARK19 model was constructed by using shRNA-mediated gene silencing of endogenous DANJC6 in differentiated human SH-SY5Y dopaminergic neurons. shRNA targeting DNAJC6 induced the neurodegeneration of dopaminergic cells. DNAJC6 paucity reduced the level of cytosolic clathrin heavy chain and the number of lysosomes in dopaminergic neurons. A DNAJC6 paucity-induced reduction in the lysosomal number downregulated the protein level of lysosomal protease cathepsin D and impaired macroautophagy, resulting in the upregulation of pathologic α-synuclein or phospho-α-synucleinSer129 in the endoplasmic reticulum (ER) and mitochondria. The expression of α-synuclein shRNA or cathepsin D blocked the DNAJC6 deficiency-evoked degeneration of dopaminergic cells. An increase in ER α-synuclein or phospho-α-synucleinSer129 caused by DNAJC6 paucity activated ER stress, the unfolded protein response and ER stress-triggered apoptotic signaling. The lack of DNAJC6-induced upregulation of mitochondrial α-synuclein depolarized the mitochondrial membrane potential and elevated the mitochondrial level of superoxide. The DNAJC6 paucity-evoked ER stress-related apoptotic cascade, mitochondrial malfunction and oxidative stress induced the degeneration of dopaminergic neurons via activating mitochondrial pro-apoptotic signaling. In contrast with the neuroprotective function of WT DNAJC6, the PARK19 DNAJC6 mutants (Q789X or R927G) failed to attenuate the tunicamycin- or rotenone-induced upregulation of pathologic α-synuclein and stimulation of apoptotic signaling. Our data suggest that PARK19 mutation-induced DNAJC6 paucity causes the degeneration of dopaminergic neurons via downregulating protease cathepsin D and upregulating neurotoxic α-synuclein. Our results also indicate that PARK19 mutation (Q789X or R927G) impairs the DNAJC6-mediated neuroprotective function.
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Catepsina D , Neurônios Dopaminérgicos , Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico HSP40 , alfa-Sinucleína , Humanos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Apoptose/genética , Catepsina D/metabolismo , Catepsina D/genética , Linhagem Celular Tumoral , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação para Baixo , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP40/genética , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Regulação para CimaRESUMO
Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by developing peptide mimetics with nanomolar-range affinity for Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using computational methods. These peptides showed both specific targeting and deep penetration in vitro and in vivo. Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their in vivo half-life with fatty side chains for albumin binding. The antitumor candidate II-3 displayed exceptional affinity (KD = 1.72 × 10-9 M), internalization efficiency, anticancer potency (IC50 = 0.015 ± 0.002 µM), and pharmacokinetics (t1/2 = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.
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Peptídeos , Humanos , Animais , Peptídeos/química , Peptídeos/farmacologia , Camundongos , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Neoplasias/tratamento farmacológico , Feminino , Camundongos Endogâmicos BALB CRESUMO
A simple, rapid and novel method involving ultrahigh-performance liquid chromatography-electrospray ionization tandem triple quadrupole mass spectrometry (UHPLC-ESI-MS/MS) was developed to simultaneously detect erythromycin, its major metabolite and clarithromycin in chicken tissues (muscle, liver and kidney) and eggs (whole egg, albumen and yolk). Samples were extracted using acetonitrile-water (80:20, v/v), and a Cleanert MAS-Q cartridge was used to perform quick, easy, cheap, effective, rugged, and safe (QuEChERS) purification. The average recoveries were 87.78-104.22 %, and the corresponding intraday and interday relative standard deviations were less than 7.10 %. The decision limits and detection capabilities of the chicken tissues and eggs were 2.15-105.21 µg/kg and 2.26-110.42 µg/kg, respectively. For chicken tissues and eggs, the limits of detection and limits of quantification were 0.5 µg/kg and 2.0 µg/kg, respectively. The proposed method was successfully employed to analyse real samples, demonstrating its applicability.
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The issue of combined pollution in oligotrophic water has garnered increasing attention in recent years. To enhance the pollutant removal efficiency in oligotrophic water, the system containing Zoogloea sp. FY6 was constructed using polyester fiber wrapped sugarcane biochar and construction waste iron (PWSI), and the denitrification test of simulated water and actual oligotrophic water was carried out for 35 days. The experimental findings from the systems indicated that the removal efficiencies of nitrate (NO3--N), total nitrogen (TN), chemical oxygen demand (COD), and total phosphorus (TP) in simulated water were 88.61%, 85.23%, 94.28%, and 98.90%, respectively. The removal efficiencies of actual oligotrophic water were 83.06%, 81.39%, 81.66%, and 97.82%, respectively. Furthermore, the high-throughput sequencing data demonstrated that strain FY6 was successfully loaded onto the biological carrier. According to functional gene predictions derived from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, the introduction of PWSI enhanced intracellular iron cycling and nitrogen metabolism.
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Carvão Vegetal , Ferro , Nitrogênio , Fósforo , Poluentes Químicos da Água , Fósforo/análise , Nitrogênio/análise , Nitrogênio/metabolismo , Carvão Vegetal/química , Ferro/química , Poluentes Químicos da Água/análise , Eliminação de Resíduos Líquidos/métodosRESUMO
INTRODUCTION: Large prospective trials have demonstrated that finerenone could reduce the risk of cardiovascular death and progression of renal failure among patients with chronic kidney disease associated heart failure and/or type 2 diabetes mellitus (T2DM). The aim of this study was to explore the molecular mechanism of finerenone in the treatment of cardiorenal diseases through network pharmacology. METHODS: The STITH, SwissTargetPrediction, PharmMapper, DrugBank, and ChEMBL databases were used to screen the targets of finerenone. The disease-related targets were retrieved from the DisGeNET, GeneCards, CTD, OMIM, and MalaCards databases. The protein-protein interaction (PPI) network was conducted with STRING database and Cytoscape software. The clusterProfiler R package was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The interactions of key targets and finerenone were analyzed by molecular docking in Autodock software. Diabetes mellitus was induced by intraperitoneal injection of streptozotocin. Histopathology of myocardial and renal tissues was observed by hematoxylin-eosin (HE) staining, and detection of protein expressions was conducted using Western blotting. RESULTS: A total of 111 potential cardiorenal targets of finerenone were identified. The main mechanisms of action may be associated with lipids and atherosclerosis, fluid shear stress and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, and diabetic cardiomyopathy. The hub targets demonstrated by the PPI network were CASP3, ALB, MMP9, EGFR, ANXA5, IGF1, SRC, TNFRSF1A, IL2, and PPARG, and the docking results suggested that finerenone could bind to these targets with high affinities. HE staining revealed the cardiorenal protection of finerenone on diabetic mice. In addition, the protein expressions of CASP3 and EGFR were increased while ALB was decreased in myocardial and renal tissues in diabetic mice compared with control mice, which were reversed by finerenone. CONCLUSION: This study suggested that finerenone exerts cardiorenal benefits through multiple targets and pathways.
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Diabetes Mellitus Experimental , Simulação de Acoplamento Molecular , Naftiridinas , Farmacologia em Rede , Naftiridinas/farmacologia , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Mapas de Interação de Proteínas , Masculino , Receptores ErbB/metabolismo , Receptores ErbB/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológicoRESUMO
The present study aimed to conduct a comprehensive meta-analysis to assess the diagnostic value of fluorometric assays and tandem mass spectrometry (MS/MS) for hyperphenylalaninemia (HPA) and its subtypes. The PubMed, Embase and Cochrane Library databases were searched from inception to October 2023. The present study included studies that reported the newborn screening and genetic features of patients with HPA and excluded duplicate publications, studies without full text, studies with incomplete information, studies from which it was not possible to extract data, animal experiments, reviews and systematic reviews. STATA 15.1 was used to analyze the data. The pooled results revealed that 0.04% [95% confidence interval (CI): 0.019-0.069] of neonatal HPA fluorometric assays and MS/MS. The positive predictive value (PPV) of neonatal HPA screening using fluorometric assays and tandem mass spectrometry was 31.7% (95% CI: 19.6-45.2). Notably, the PPV of neonatal HPA screening using fluorometric assays was 8.3% (95% CI: 7.1-9.6), while the PPV of neonatal HPA screening using tandem mass spectrometry was 31.8% (95% CI: 16.4-49.4). Additionally, the pooled results showed that the incidence of tetrahydrobiopterin deficiency (BH4D) in HPA patients was 12.43% (95% CI: 3.28-25.75) and the incidence of phenylalanine hydroxylase deficiency (PAHD) in HPA patients was 88.65% (95% CI: 78.84-95.86). Newborn screening is an effective method for the early detection of HPA and MS/MS has a greater PPA than fluorometric assays for diagnosing HPA. In addition, in the screening of HPA, the proportion of HPA patients with PAHD was significantly higher than that of patients with BH4D.
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Saposhnikoviae Radix (SR) may enhance the pharmacodynamics of Huangqi Chifeng Tang (HQCFT) in the treatment of cerebral infarction according to our previous research, but the underlying mechanism is unknown. Herein, an in vivo pharmacokinetic assay in rats and in vitro MDCK-MDR1 cell assays were used to investigate the possible mechanism of SR, its main components, and its interactions with Astragali Radix (AR) and Paeoniae Radix (PR). An ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLCâMS/MS)-based analytical method for quantifying astragaloside IV (ASIV) and paeoniflorin (PAE) in microdialysis and transport samples was developed. The pharmacokinetic parameters of SR were determined using noncompartmental analyses CCK-8 assays were used to detect the cytotoxicity of ASIV, PAE, cimifugin (CIM), prim-o-glucosylcimifugin (POG) and their combinations. Moreover, drug transport was studied using MDCK-MDR1 cells. Western blotting was performed to measure the protein expression levels of P-GP and MRP1. Claudin-5, ZO-1, and F-actin expression was determined via immunohistochemical staining of MDCK-MDR1 cells. harmacokinetic studies revealed that, compared with those of Huangqi Chifeng Tang-Saposhnikoviae Radix (HQCFT-SR), the Tmax of ASIV increased by 11.11 %, and the MRT0-t and Tmax of PAE increased by 11.19 % and 20 %, respectively, in the HQCFT group. Transport studies revealed that when ASIV was coincubated with 28 µM CIM or POG, the apparent permeability coefficient (Papp) increased by 71.52 % and 50.33 %, respectively. Coincubation of PAE with 120 µM CIM or POG increased the Papp by 87.62 % and 60.95 %, respectively. Moreover, CIM and POG significantly downregulated P-gp and MRP1 (P < 0.05), inhibited the expression of Claudin-5, ZO-1, and F-actin (P < 0.05), and affected intercellular tight junctions (TJs). In conclusion, our study successfully established a selective, sensitive and reproducible UPLCâMS/MS analytical method to detect drugâdrug interactions between SR, AR and PR in vivo and in vitro, which is beneficial for enhancing the therapeutic efficacies of AR and PR. Moreover, this study provides a theoretical basis for further research on the use of SR as a drug carrier.
Assuntos
Medicamentos de Ervas Chinesas , Glucosídeos , Monoterpenos , Ratos Sprague-Dawley , Saponinas , Espectrometria de Massas em Tandem , Triterpenos , Animais , Glucosídeos/farmacocinética , Glucosídeos/análise , Glucosídeos/química , Glucosídeos/farmacologia , Saponinas/farmacocinética , Saponinas/farmacologia , Saponinas/química , Saponinas/análise , Monoterpenos/análise , Triterpenos/farmacologia , Triterpenos/farmacocinética , Triterpenos/química , Triterpenos/análise , Cães , Ratos , Células Madin Darby de Rim Canino , Espectrometria de Massas em Tandem/métodos , Masculino , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Apiaceae/química , Interações Ervas-Drogas , Interações Medicamentosas , Reprodutibilidade dos TestesRESUMO
Triclocarban (TCC), an emerging organic contaminant, poses a potential threat to human health with long-term exposure. Here, Rhodococcus rhodochrous BX2 and Pseudomonas sp. LY-1 were utilized to degrade TCC at environmental related concentrations for enhancing TCC biodegradation and investigating whether the toxicity of intermediate metabolites is lower than that of the parent compound. The results demonstrated that the bacterial consortium could degrade TCC by 82.0% within 7 days. The calculated 96 h LC50 for TCC, as well as its main degradation product 3,4-Dichloroaniline (DCA) were 0.134 mg/L and 1.318 mg/L respectively. Biodegradation also alleviated histopathological lesions induced by TCC in zebrafish liver and gut tissues. Liver transcriptome analysis revealed that biodegradation weakened differential expression of genes involved in disrupted immune regulation and lipid metabolism caused by TCC, verified through RT-qPCR analysis and measurement of related enzyme activities and protein contents. 16 S rRNA sequencing indicated that exposure to TCC led to gut microbial dysbiosis, which was efficiently improved through TCC biodegradation, resulting in decreased relative abundances of major pathogens. Overall, this study evaluated potential environmental risks associated with biodegradation of TCC and explored possible biodetoxification mechanisms, providing a theoretical foundation for efficient and harmless bioremediation of environmental pollutants.