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The main chemical compositions of 201 surface sediments and 53 deep sediment samples from Chaohu Lake, China, were analysed. Since the surface sediments (0-2 cm depth) in Chaohu Lake are modern sediments, this paper mainly focuses on the deep sediments (50-100 cm depth) in Chaohu Lake. Particle size analysis and magnetization determination of the CH3 and CH4 column sediment samples were carried out. The age determination data of the CH-1 column sediment samples are reported. A systematic study of the rocks and their chemical compositional characteristics in the Chaohu Lake Basin was also carried out. The results of this study show that four positive chemical weathering indicators and one negative chemical weathering indicator are applicable to the study of Chaohu Lake. The mean CIA of the Chaohu Lake sediments was less than 65, indicating that the Chaohu Lake Basin experienced weak chemical weathering and that the palaeoclimate was cold and dry. Vertical variations in the mean grain size and magnetization in the CH3 and CH4 columnar sediments reflect changes in the depositional environment and climate during deposition of the Chaohu Lake sediments. The age data from the CH-1 column sediment samples directly indicate deposition of the deep sediments in Chaohu Lake during the Little Ice Age in eastern China (AD 1380-1880). The Th/U, Sc/Th, Rb/Sr, Na2O/K2O, CaO/MgO and OC/N ratios of the Chaohu sediments reflect palaeoclimate characteristics and the chemical compositions of the source rocks in the Chaohu Lake basin. The correlations of the CIA, CIW, PIA, and CIX with the chemical compositional ratios provide information on the palaeoclimate and the distribution of the chemical compositions. The CIA, CIW, PIA, and CIX were not correlated with Cd, Pb, As, Hg, or P. In contrast, the CIA, CIW, PIA, and CIX were significantly positively correlated with Cr and N. The WIP was inconsistently correlated with the selected chemical components. Therefore, the study of the correlations of chemical weathering indicators with four heavy metals and two eutrophication-related elements is of little significance. The study of the chemical weathering characteristics of deep sediments of inland lakes should be combined with assessment of the geological characteristics of the lake basins, particularly the analysis of the chemical composition of the rocks in the lake basins.
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Tropical montane evergreen broad-leaved forests cover the majority of forest areas and have high carbon storage in Xishuangbanna, southwest China. However, stem radial growth dynamics and their correlations with climate factors have never been analyzed in this forest type. By combining bi-weekly microcoring and high-resolution dendrometer measurements, we monitored xylogenesis and stem radius variations of the deciduous species Betula alnoides and the evergreen species Schima wallichii. We analyzed the relationships between weekly climate variables prior to sampling and the enlarging zone width or wall thickening zone width, as well as weekly radial increments and climate factors during two consecutive years (2020-2021) showing contrasting hydrothermal conditions in the pre-monsoon season. In the year 2020, which was characterized by a warmer and drier pre-monsoon season, the onset of xylogenesis and radial increments of B. alnoides and S. wallichi were delayed by three months and one month, respectively, compared to the year 2021. In 2020, xylem formation and radial increments were significantly reduced for B. alnoides, but not for S. wallichill. The thickness of enlarging zone and wall thickening zone in S. wallichill were positively correlated with relative humidity, minimum and mean air temperature, but were negatively correlated with vapor pressure deficit during 2020-2021. The radial increments of both species showed significant positive correlations with precipitation and relative humidity, and negative correlations with vapor pressure deficit and maximum air temperature during two years. Our findings reveal that drier pre-monsoon conditions strongly delay growth initiation and reduce stem radial growth, providing deep insights to understand tree growth and carbon sequestration potential in tropical forests under a predicted increase in frequent drought events.
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BACKGROUND: To date, Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disease associated with clinical complications. Dietary fatty acids have been suggested to be involved in preventing or reversing the accumulation of hepatic fat. However, contradicting roles of monounsaturated fatty acids to the liver have been implicated in various human and murine models, mainly due to the insolubility nature of fatty acids. METHODS: High pressure homogenization methods were used to fabricate oleic acid embedded lipid nanoparticles (OALNs). The in vitro and in vivo models were used to validate the physiological effect of this OALNs via various cellular and molecular approaches including cell viability essay, fluorescent staining, electron microscope, RNAseq, qPCR, Western blots, and IHC staining. RESULTS: We successfully fabricated OALNs with enhanced stability and solubility. More importantly, lipid accumulation was successfully induced in hepatocytes via the application of OALNs in a dose-dependent manner. Overload of OALNs resulted in ROS accumulation and apoptosis of hepatocytes dose-dependently. With the help of transcriptome sequencing and traditional experimental approaches, we demonstrated that the lipotoxic effect induced by OALNs was exerted via the DDIT3/BCL2/BAX/Caspases signaling. Moreover, we also verified that OALNs induced steatosis and subsequent apoptosis in the liver of mice via the activation of DDIT3 in vivo. CONCLUSIONS: In all, our results established a potential pathogenic model of NAFLD for further studies and indicated the possible involvement of DDIT3 signaling in abnormal steatosis process of the liver.
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PAXLOVID™ (Co-packaging of Nirmatrelvir with Ritonavir) has been approved for the treatment of Coronavirus Disease 2019 (COVID-19). The goal of the experiment was to create an accurate and straightforward analytical method using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to simultaneously quantify nirmatrelvir and ritonavir in rat plasma, and to investigate the pharmacokinetic profiles of these drugs in rats. After protein precipitation using acetonitrile, nirmatrelvir, ritonavir, and the internal standard (IS) lopinavir were separated using ultra performance liquid chromatography (UPLC). This separation was achieved with a mobile phase composed of acetonitrile and an aqueous solution of 0.1% formic acid, using a reversed-phase column with a binary gradient elution. Using multiple reaction monitoring (MRM) technology, the analytes were detected in the positive electrospray ionization mode. Favorable linearity was observed in the calibration range of 2.0-10000 ng/mL for nirmatrelvir and 1.0-5000 ng/mL for ritonavir, respectively, within plasma samples. The lower limits of quantification (LLOQ) attained were 2.0 ng/mL for nirmatrelvir and 1.0 ng/mL for ritonavir, respectively. Both drugs demonstrated inter-day and intra-day precision below 15%, with accuracies ranging from -7.6% to 13.2%. Analytes were extracted with recoveries higher than 90.7% and without significant matrix effects. Likewise, the stability was found to meet the requirements of the analytical method under different conditions. This UPLC-MS/MS method, characterized by enabling accurate and precise quantification of nirmatrelvir and ritonavir in plasma, was effectively utilized for in vivo pharmacokinetic studies in rats.
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Tofacitinib can effectively improve the clinical symptoms of rheumatoid arthritis (RA) patients. In this current study, a recombinant human CYP2C19 and CYP3A4 system was operated to study the effects of recombinant variants on tofacitinib metabolism. Moreover, the interaction between tofacitinib and myricetin was analyzed in vitro. The levels of M9 (the main metabolite of tofacitinib) was detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The findings revealed that 11 variants showed significant changes in the levels of M9 compared to CYP3A4.1, while the other variants didn't reveal any remarkable significances. Compared with CYP2C19.1, 11 variants showed increases in the levels of M9, and 10 variants showed decreases. Additionally, it was demonstrated in vitro that the inhibition of tofacitinib by myricetin was a non-competitive type in rat liver microsomes (RLM) and human liver microsomes (HLM). However, the inhibitory mechanism was a competitive type in CYP3A4.18, and mixed type in CYP3A4.1 and .28, respectively. The data demonstrated that gene polymorphisms and myricetin had significant effects on the metabolism of tofacitinib, contributing to important clinical data for the precise use.
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Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Flavonoides , Microsomas Hepáticos , Piperidinas , Pirimidinas , Humanos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Flavonoides/farmacología , Flavonoides/metabolismo , Pirimidinas/farmacología , Pirimidinas/metabolismo , Animales , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Ratas , Piperidinas/farmacología , Piperidinas/farmacocinética , Piperidinas/metabolismo , Polimorfismo Genético , Pirroles/farmacología , Pirroles/metabolismoRESUMEN
Objective: Increasing breast meat production is one of the primary goals of the broiler industry. Over the past few decades, tremendous progress has been made in genetic selection and the identification of candidate genes for improving the breast muscle mass. However, the molecular network contributing to muscle production traits in chickens still needs to be further illuminated. Methods: A total of 150 1-day-old male 817 broilers were reared in a floor litter system. At the market age of 50 d, eighteen healthy 817 broilers were slaughtered and the left pectoralis major muscle sample from each bird was collected for RNA-seq sequencing. The birds were then plucked and eviscerated and the whole breast muscle was removed and weighed. Breast muscle yield was calculated as the ratio of the breast muscle weight to the eviscerated weight. To identify the co-expression networks and hub genes contributing to breast muscle yield in chickens, we performed weighted gene co-expression network analysis (WGCNA) based on the 18 transcriptome datasets of pectoralis major muscle from eighteen 817 broilers. Results: The WGCNA analysis classified all co-expressed genes in the pectoral muscle of 817 broilers into 44 modules. Among these modules, the turquoise and skyblue3 modules were found to be most significantly positively (r=0.78, p=1e-04) and negatively (r=-0.57, p=0.01) associated with breast meat yield, respectively. Further analysis identified several hub genes (e.g., DLX3, SH3RF2, TPM1, CAV3, MYF6, and CFL2) that involved in muscle structure and muscle development were identified as potential regulators of breast meat production. Conclusion: The present study has advanced our understanding of the molecular regulatory networks contributing to muscle growth and breast muscle production and will contribute to the molecular breeding of chickens in the future.
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BACKGROUND AND AIMS: Chronic kidney disease (CKD) causes low quality of life and alarming morbidity and mortality. The crucial to retard CKD progression is to diagnose early for timely treatment. IgA nephropathy (IgAN) is a typical CKD and the most common glomerulonephritis. Both CKD and IgAN lack accurate and sensitive blood biomarkers for early diagnosis. Here we report the potential of plasma biomarkers for early diagnosis of CKD and IgAN. MATERIALS AND METHODS: Plasma levels of metabolites derived from tryptophan were quantified with an LC-MS/MS-based metabolomics for two cohorts. Based on the predictive probability of each metabolite, multivariate models including logistic regression and random forest were used to establish the early diagnostic biomarkers for CKD and IgAN. RESULTS: The plasma melatonin diagnosed early CKD (stages â -â ¡) with an accuracy exceeding 95%, and a panel of melatonin and tryptophan achieved a remarkable 100% accuracy in diagnosing early CKD. Furthermore, indole-3-lactic acid had an excellent ability to distinguish IgAN among CKD patients. Based on the CKD screening and IgAN diagnosis primarily contributed by melatonin and indole-3-lactic acid, early IgAN could be diagnosed with an accuracy of over 85%. CONCLUSIONS: This study provides promising plasma biomarkers for early diagnosis of CKD and IgAN.
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Glomerulonefritis por IGA , Melatonina , Insuficiencia Renal Crónica , Humanos , Glomerulonefritis por IGA/diagnóstico , Estudios Transversales , Estudios Retrospectivos , Cromatografía Liquida , Calidad de Vida , Triptófano , Espectrometría de Masas en Tándem , Insuficiencia Renal Crónica/diagnóstico , Biomarcadores , Diagnóstico PrecozRESUMEN
The aim of this study was to investigate the potential drug-drug interactions (DDIs) between ticagrelor and other drugs as well as their underlying mechanisms. Rat liver microsome (RLM) reaction system was used to screen potential DDIs in vitro, and ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to detect the levels of ticagrelor and AR-C124910XX, the main metabolite of ticagrelor. A total of 68 drugs were screened, 11 of which inhibited the production of AR-C124910XX to 20% or less, especially two flavonoids (myricetin and quercetin). The half-maximal inhibitory concentration (IC50) of myricetin on ticagrelor was 11.51 ± 0.28 µM in RLM and 17.96 ± 0.54 µM in human liver microsome (HLM). The IC50 of quercetin in inhibiting ticagrelor in RLM and HLM was 16.92 ± 0.49 µM and 60.15 ± 0.43 µM, respectively. They all inhibited the metabolism of ticagrelor through a mixed mechanism. In addition, Sprague-Dawley (SD) rats were used to study the interactions of ticagrelor with selected drugs in vivo. We found that the main pharmacokinetic parameters including AUC (0-t), AUC (0-∞) and Cmax of ticagrelor were significantly increased when ticagrelor was combined with these two flavonoids. Our results suggested that myricetin and quercetin of flavonoids both had significant effects on the metabolism of ticagrelor, providing reference data for the clinical individualized medication of ticagrelor.
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Quercetina , Espectrometría de Masas en Tándem , Humanos , Ratas , Animales , Ticagrelor/farmacología , Ticagrelor/metabolismo , Quercetina/farmacología , Cromatografía Liquida/métodos , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem/métodos , Flavonoides/farmacología , Flavonoides/metabolismo , Microsomas Hepáticos/metabolismoRESUMEN
BACKGROUND: Tirabrutinib is an orally effective, approved, and highly selective second-generation Bruton's tyrosine kinase (BTK) inhibitor for the treatment of recurrent or refractory primary central nervous system lymphoma (PCNSL). OBJECTIVE: This study aimed to develop an ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) method for the determination of tirabrutinib concentration in rat plasma, where zanubrutinib was used as an internal standard (IS). This method was also applied to study whether tirabrutinib would interact with voriconazole, itraconazole, and fluconazole in rats, providing a reference value for clinical medication guidance. METHODS: In the current study, the organic solvent protein precipitation method was used to treat plasma samples, which is simple and reproducible. Tirabrutinib (m/z 455.32 â 320.21) and zanubrutinib (m/z 472.13 â 455.04) were separated on a Waters Acquity BEH C18 column (2.1 × 50 mm, 1.7 µm) and detected by multiple reaction monitoring (MRM) in positive ionization mode. RESULTS: The method showed good linearity in the range of 5-3000 ng/mL for tirabrutinib with the lower limit of quantification (LLOQ) of 5 ng/mL. The recovery and matrix effects were 85.7-91.0% and 102.0-113.3%, respectively. The accuracy, precision, stability, and carry-over effect were also acceptable. The method could also be used for determining the pharmacokinetic interaction of tirabrutinib in rats. The results showed AUC0â∞ of tirabrutinib to be increased by 139.3% and 83.9% in the presence of voriconazole and fluconazole, respectively, while itraconazole had little effect. CONCLUSION: It is necessary to monitor the concentration of tirabrutinib in patients when it is combined with voriconazole and fluconazole to achieve a better therapeutic effect and reduce the risk of adverse reaction. Further research should be conducted in the future.
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As a broad-spectrum antiviral, and especially as a popular drug for treating coronavirus disease 2019 (COVID-19) today, arbidol often involves drug-drug interactions (DDI) when treating critical patients. This study established a rapid and effective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to detect arbidol and its metabolite arbidol sulfoxide (M6-1) levels in vivo and in vitro. In this study, a 200 µL incubation system was used to study the inhibitory effect of the antitumor drug napabucasin on arbidol in vitro, with IC50 values of 2.25, 3.91, and 67.79 µM in rat liver microsomes (RLMs), human liver microsomes (HLMs), and CYP3A4.1, respectively. In addition, we found that the mechanism of inhibition was non-competitive inhibition in RLM and mixed inhibition in HLM. In pharmacokinetic experiments, it was observed that after gavage administration of 48 mg/kg napabucasin and 20 mg/kg arbidol, napabucasin inhibited the metabolism of arbidol in vivo and significantly changed the pharmacokinetic parameters of arbidol, such as AUC(0-t) and AUC(0-∞), in rats. We also found that napabucasin increased the AUC(0-t) and AUC(0-∞) of M6-1, the main metabolite of arbidol. This study provides a reference for the combined use of napabucasin and arbidol in clinical practice.
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The aim of this study was to investigate the impacts of 24 variants of recombinant human CYP3A4 and drug interactions on the metabolism of lurasidone. In vitro, enzymatic reaction incubation system of CYP3A4 was established to determine the kinetic parameters of lurasidone catalyzed by 24 CYP3A4 variants. Then, we constructed rat liver microsomes (RLM) and human liver microsomes (HLM) incubation system to screen potential anti-tumor drugs that could interact with lurasidone and studied its inhibitory mechanism. In vivo, Sprague-Dawley (SD) rats were applied to study the interaction between lurasidone and olmutinib. The concentrations of the analytes were detected by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). As the results, we found that compared with the wild-type CYP3A4, the relative intrinsic clearances vary from 355.77 % in CYP3A4.15 to 14.11 % in CYP3A4.12. A series of drugs were screened based on the incubation system, and compared to without olmutinib, the amount of ID-14283 (the metabolite of lurasidone) in RLM and HLM were reduced to 7.22 % and 7.59 %, and its IC50 were 18.83 ± 1.06 µM and 16.15 ± 0.81 µM, respectively. At the same time, it exerted inhibitory effects both through a mixed mechanism. When co-administration of lurasidone with olmutinib in rats, the AUC(0-t) and AUC(0-∞) of lurasidone were significantly increased by 73.52 % and 69.68 %, respectively, while CLz/F was observably decreased by 43.83 %. In conclusion, CYP3A4 genetic polymorphism and olmutinib can remarkably affect the metabolism of lurasidone.
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Citocromo P-450 CYP3A , Clorhidrato de Lurasidona , Animales , Humanos , Ratas , Cromatografía Liquida , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Clorhidrato de Lurasidona/farmacocinética , Microsomas Hepáticos , Polimorfismo Genético , Ratas Sprague-Dawley , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: As an active ingredient derived from Dioscorea zingiberensis C.H. Wright, deltonin has been reported to show anti-cancer effects in a variety of malignancies. AIM: To investigate the role and mechanism of action of deltonin in promoting gastric carcinoma (GC) cell apoptosis and chemosensitivity to cisplatin. METHODS: The GC cell lines AGS, HGC-27, and MKN-45 were treated with deltonin and then subjected to flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltetrazolium bromide assays for cell apoptosis and viability determination. Western blot analysis was conducted to examine alterations in the expression of apoptosis-related proteins (Bax, Bid, Bad, and Fas), DNA repair-associated proteins (Rad51 and MDM2), and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/AKT/mTOR) and p38-mitogen-activated protein kinase (MAPK) axis proteins. Additionally, the influence of deltonin on GC cell chemosensitivity to cisplatin was evaluated both in vitro and in vivo. RESULTS: Deltonin treatment weakened viability, enhanced apoptosis, and dampened DNA repair in GC cell lines in a dose-dependent pattern. Furthermore, deltonin mitigated PI3K, AKT, mTOR, and p38-MAPK phosphorylation. HS-173, an inhibitor of PI3K, attenuated GC cell viability and abolished deltonin inhibition of GC cell viability and PI3K/AKT/mTOR and p38-MAPK pathway activation. Deltonin also promoted the chemosensitivity of GC cells to cisplatin via repressing GC cell proliferation and growth and accelerating apoptosis. CONCLUSION: Deltonin can boost the chemosensitivity of GC cells to cisplatin via inactivating p38-MAPK and PI3K/AKT/mTOR signaling.
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Serum albumin, commonly recognized as a predominant major plasma protein, is ubiquitously distributed among vertebrates, demonstrating versatility and widespread accessibility. Numerous studies have discussed the composition and attributes of human and bovine serum albumin; nonetheless, few systematic and comprehensive summaries on human and bovine serum albumin exist. This paper reviews the applications of human and bovine serum albumin in biomedical engineering. First, we introduce the differences in the structure of human and bovine serum albumin. Next, we describe the extraction methods for human and bovine serum albumin (fractionation process separation, magnetic adsorption, reverse micellar (RM) extraction, and genetic engineering) and the advantages and disadvantages of recently developed extraction methods. The characteristics of different processing forms of human and bovine serum albumin are also discussed, concomitantly elucidating their intrinsic properties, functions, and applications in biomedicine. Notably, their pivotal functions as carriers for drugs and tissue-engineered scaffolds, as well as their contributions to cell reproduction and bioimaging, are critically examined. Finally, to provide guidance for researchers in their future work, this review summarizes the current state of human and bovine serum albumin research and outlines potential future research topics.
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Ingeniería Biomédica , Albúmina Sérica Bovina , Animales , Humanos , Albúmina Sérica Bovina/química , Albúmina Sérica , Fraccionamiento Químico , AdsorciónRESUMEN
Oprozomib, as a second-generation orally bioavailable protease inhibitor (PI), is undergoing clinical evaluation for the treatment of haematological malignancies. In relapsed refractory multiple myeloma (RRMM) patients, oprozomib has shown good efficacy as a single agent or combination therapy. In this experiment, our purpose was to validate a sensitive and rapid method for the determination of oprozomib concentration in rat plasma by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The samples were treated with acetonitrile as the precipitant and separated by gradient elution using a Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm). Using the selective reaction monitoring (SRM) method, the measurement was finished with the ion transitions of m/z 533.18 ⶠ199.01 for oprozomib and m/z 493.03 ⶠ112.03 for tepotinib (internal standard, IS), respectively. Meanwhile, acetonitrile and 0.1% formic acid aqueous solution were used as the mobile phase, and the flow rate was 0.3 mL/min. The lower limit of quantification (LLOQ) of the method was 1.0 ng/mL, and the linear relationship was good in the range of 1.0-100 ng/mL. In addition, the precision of four concentration levels was determined with the values of 3.1-7.3% and the accuracy was from -14.9% to 12.9%. Moreover, the recovery was determined to be from 85.1% to 96.1%, and the values of matrix effect were no more than 110.4%. The optimized UPLC-MS/MS method was also suitable for the pharmacokinetic study of rats after a single oral administration of 21 mg/kg oprozomib.
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Meat color is one of the most important economic traits in chickens. However, the gene network and regulatory mechanisms contributing to meat color traits in chickens remain largely unknown. In the present study, we performed weighted gene co-expression network analysis (WGCNA) based on RNA-Seq datasets of 16 pectoralis major muscle samples from two yellow-feather chicken breeds to identify the modules and hub genes related to meat color in chickens. A total of 18,821 genes were used to construct the weighted gene co-expression network, and 29 co-expression gene modules were identified. Among these modules, five modules including blue, brown, steel blue, paleturquoise and orange modules were found to be significantly correlated with meat color traits. Furthermore, several genes within the association module involved in the regulation of mitochondrial activity (e.g., ATP5L, UQCR10 and COX7C) and lipid oxidation (e.g., CAV3, RBP4A and APOH) were identified as hub genes that may play a crucial role in the regulation of meat color. These results provide valuable information to improve our understanding of gene expression and regulation in relation to meat color traits and contribute to future molecular breeding for improving meat color in chickens.
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As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The half-maximal inhibitory concentration (IC50) was 6.66 µM in human liver microsomes (HLM), while 0.62 µM in rat liver microsomes (RLM) and 2.90 µM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0-t), AUC(0-∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications.
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Leptospirosis is a recurring but neglected zoonotic disease caused by pathogenic Leptospira. The explicit underlying mechanism of necroptosis and its role in Leptospira infection have not yet been elucidated. Here we reported that leptospiral pathogen-associated molecular patterns, lipopolysaccharide, and glycolipoprotein activate the necroptotic RIPK1-RIPK3-MLKL cascade through the TLR4 signaling pathway in mouse macrophages. Using the murine acute leptospirosis model, we reveal that abolition of necroptosis exhibited significantly improved outcomes in acute phases, with enhanced eradication of Leptospira from liver, mild clinical symptoms, and decreased cytokine production. RIPK3 was also found to exert a necroptosis-independent function in CXCL1 production and neutrophil recruitment, with the consequence of improved Leptospira control. These findings improve our understanding of the mechanism of Leptospira-macrophage interactions, indicating potential therapeutic values by targeting necroptosis signaling pathways.
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Leptospira , Leptospirosis , Ratones , Animales , Lipopolisacáridos , Necroptosis , Leptospirosis/patología , Leptospira/metabolismo , Macrófagos/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con ReceptoresRESUMEN
CONTEXT: CYP2C19 is an important member of the human cytochrome P450 2C (CYP2C) family. Mavacamten is a novel treatment of patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) which was metabolized mainly by CYP2C19. OBJECTIVE: In this study, we firstly reported and validated a quantitative analysis method of mavacamten in rat plasma based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), which was applied to the drug-drug interaction (DDI) study between mavacamten and CYP2C19 inhibitors (fluvoxamine, fluoxetine and fluconazole) in rats. MATERIALS AND METHODS: Vericiguat was used as the internal standard (IS), and the analyte and IS were measured with electrospray ion (ESI) source in positive ion mode on a XEVO TQ-S triple quadrupole tandem mass spectrometer in multiple reaction monitoring (MRM) mode. RESULTS: In the scope of 1.0-100 ng/mL, this assay had excellent linearity. Both intra-day and inter-day accuracy of the analyte ranged from -2.4% to 9.1%, while the precision was ≤4.2%. Matrix effect, recovery, and stability were evaluated and validated to meet the requirements for the guidelines of bioanalytical assay. When compared with the control group, AUC0â∞ of mavacamten in fluconazole, fluoxetine and fluvoxamine were increased by 125.5%, 110.7% and 43.6%, respectively, which demonstrated that CYP2C19 inhibitors could inhibit mavacamten metabolism. CONCLUSIONS: The results showed that CYP2C19 inhibitors could significantly improve the bioavailability of mavacamten in rats, which indicated that we should pay more attention to the patient's condition to prevent the occurrence of side effects when used mavacamten in combination with CYP2C19 inhibitors.
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Inhibidores del Citocromo P-450 CYP2C19 , Espectrometría de Masas en Tándem , Ratas , Humanos , Animales , Cromatografía Liquida , Ratas Sprague-Dawley , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Citocromo P-450 CYP2C19 , Fluconazol/farmacología , Fluvoxamina/farmacología , Fluoxetina/farmacología , Reproducibilidad de los ResultadosRESUMEN
In this study, the effects of 17 CYP3A4 variants and drug-drug interactions (DDI) with its mechanism on alectinib metabolism were investigated. In vitro incubation systems of rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 variants were established. The formers were used to screen potential drugs that inhibited alectinib metabolism and study the underlying mechanism, and the latter was used to determine the dynamic characteristics of CYP3A4 variants. Alectinib and its main metabolite M4 were quantitatively determined by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results showed that compared with CYP3A4.1, only CYP3A4.29 showed higher catalytic activity, while the catalytic activity of CYP3A4.4, .7, .8, .12, .14, .16, .17, .18, .19, .20, .23, and .24 decreased significantly. Among them, the catalytic activity of CYP3A4.20 is the lowest, only 2.63% of that of CYP3A4.1. Based on the RLM incubation system in vitro, 81 drugs that may be combined with alectinib were screened, among which 18 drugs had an inhibition rate higher than 80%. In addition, nicardipine had an inhibition rate of 95.09% with a half-maximum inhibitory concentration (IC50) value of 3.54 ± 0.96 µM in RLM and 1.52 ± 0.038 µM in HLM, respectively. There was a mixture of non-competitive and anti-competitive inhibition of alectinib metabolism in both RLM and HLM. In vivo experiments of Sprague-Dawley (SD) rats, compared with the control group (30 mg/kg alectinib alone), the AUC(0-t), AUC(0-∞), Tmax and Cmax of alectinib administered in combination with 6 mg/kg nicardipine were significantly increased in the experimental group. In conclusion, the metabolism of alectinib was affected by polymorphisms of the CYP3A4 gene and nicardipine. This study provides reference data for clinical individualized administration of alectinib in the future.