RESUMEN
BACKGROUND: Cytochrome P450 (CYP) 46A1, also known as cholesterol 24S-hydroxylase, is essential for maintaining the homeostasis of cholesterol in the brain and serves as a therapeutic target of neurodegenerative disorders and excitatory neurotoxicity. N-methyl-d-aspartate receptor (NMDAR) is a prototypical receptor for the excitatory neurotransmitter glutamate and can be specifically regulated by 24S-hydroxycholesterol (24S-HC). Glycyrrhiza is one of the most widely used herbs with broad clinical applications. It has several pharmacological activities, such as clearing heat and detoxifying, moistening the lung and relieving cough, analgesic, neuroprotective outcomes, and regulating a variety of drug activities. Glycyrrhiza is a commonly used herb for the treatment of epileptic encephalopathy. However, whether glycyrrhiza can interfere with the activity of CYP46A1 remains unknown. OBJECTIVE: This study aimed to investigate the regulating effects of glycyrrhiza polysaccharides (GP) on CYP46A1-mediated cholesterol conversion, as well as in the modulation of related proteins. MATERIALS AND METHODS: The effects of glycyrrhiza polysaccharide (GP) on the activity of CYP46A1 were investigated in vivo and in vitro. Moreover, the potential regulatory effects of GP on the expressions of CYP46A1, HMG-CoA reductase (HMGCR), and NMDAR were also detected. RESULTS: The in vitro results demonstrated that glycyrrhiza polysaccharide (GP), as the main water-soluble active component of glycyrrhiza, remarkably inhibited the activity of CYP46A1 in a non-competitive mode with a Ki value of 0.7003 mg/ml. Furthermore, the in vivo experiments verified that GP markedly decreased the contents of 24S-HC in rat plasma and brain tissues as compared to the control. More importantly, the protein expressions of CYP46A1, GluN2A, GluN2B, and HMG-CoA reductase (HMGCR) in rat brains were all downregulated, whereas the mRNA expressions of CYP46A1 and HMGCR were not significantly changed after treatment with GP. CONCLUSION: GP exhibits a significant inhibitory effect on CYP46A1 activity in vitro and in vivo, and the protein expressions of CYP46A1, HMGCR, and NMDAR are also inhibited by GP, which are of considerable clinical significance for GP's potential therapeutic role in treating neurological diseases.
RESUMEN
Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.
Asunto(s)
Senescencia Celular , Neoplasias Hepáticas , Acortamiento del Telómero , Proteína 2 de Unión a Repeticiones Teloméricas , Proteína 2 de Unión a Repeticiones Teloméricas/metabolismo , Proteína 2 de Unión a Repeticiones Teloméricas/antagonistas & inhibidores , Proteína 2 de Unión a Repeticiones Teloméricas/genética , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Animales , Acortamiento del Telómero/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Ratones , Ratones Desnudos , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Masculino , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Wear is a common issue in the operation of emulsion pumps. When it becomes severe, it can lead to machine downtime and economic losses. This paper aims to investigate the wear phenomenon on the slideway of emulsion pumps using Archard's wear model and the finite element method. The fretting friction and wear experiment was used to calibrate the parameters of the numerical model. Based on the established numerical model, a parametric analysis is conducted on the slideway experiencing the most severe wear. It is observed that the wear amount initially increases and then decreases as the crankshaft speed increases. Furthermore, a smaller clearance between the slide and the slider results in a reduced wear amount on the slideway. This study presents an effective numerical simulation method for studying the wear of emulsion pumps.
RESUMEN
Emulsion pump station is widely used to provide power for full-mechanized coal mining face equipment. With the development of the mining technique of longwall face and the extensive use of large mining height and high working resistance of the hydraulic support, the fluid supply pressure is more unstable and the pressure impact is increasingly intensified. The intelligent control of the emulsion pump station is the key to the development of the stable fluid supply technology at the working face. This paper develops a new on-line adaptive learning technique to improve the response speed of pumping station based on the optimal control algorithm of adaptive dynamic programming (ADP). The state space model of the working face fluid supply system in the process of no-load column lifting of hydraulic support is first established using the flow relationship, and the effectiveness of the proposed control algorithm is then verified by simulation validation. Moreover, combined with a certain fluid supply system of a fully mechanized caving face in Shandong Energy Xinwen Group XinJulong Co., Ltd, a technical scheme of adaptive stable fluid supply is verified in engineering practice. The results indicate that the fluid supply system using the proposed control algorithm has a favorable tracking effect on the ideal trajectory, and the tracking error can converge to near zero. The output pressure of the fluid supply system using the stable fluid supply technology is more stable, and the practical effect is good, which meets the demand of stable fluid supply in the mining face.
RESUMEN
Aberrant FGFR4 signaling has been implicated in the development of several cancers, making FGFR4 a promising target for cancer therapy. Several FGFR4-selective inhibitors have been developed, yet none of them have been approved. Herein, we report a novel series of 1,6-naphthyridine-2-one derivatives as potent and selective inhibitors targeting FGFR4 kinase. Preliminary structure-activity relationship analysis was conducted. The screening cascades revealed that 19g was the preferred compound among the prepared series. 19g demonstrated excellent kinase selectivity and substantial cytotoxic effect against all tested colorectal cancer cell lines. 19g induced significant tumor inhibition in a HCT116 xenograft mouse model without any apparent toxicity. Notably, 19g exhibited excellent potency in disrupting the phosphorylation of FGFR4 and downstream signaling proteins mediated by FGF18 and FGF19. Compound 19g might be a potential antitumor drug candidate for the treatment of colorectal cancer.
Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Animales , Ratones , Transducción de Señal , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular , Neoplasias Colorrectales/tratamiento farmacológico , Naftiridinas/farmacología , Naftiridinas/uso terapéutico , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos , Línea Celular Tumoral , Proliferación Celular , Neoplasias Hepáticas/tratamiento farmacológicoRESUMEN
Purpose: To evaluate the value of positron emission tomography/computed tomography (PET/CT) combined with high-resolution CT (HRCT) in determining the degree of differentiation of lung adenocarcinoma. Methods: From January 2018 to January 2022, 88 patients with solid density nodules that are lung adenocarcinoma were surgically treated. All patients were examined using HRCT and PET/CT before surgery. During HRCT, two independent observers assessed the presence of lobulation, spiculation, pleural indentation, vascular convergence, and air bronchial signs (bronchial distortion and bronchial disruption). The diameter and CT value of the nodules were measured simultaneously. During PET/CT, the maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the nodules were measured. The risk factors of pathological classification were predicted by logistic regression analysis. Results: All 88 patients (mean age 60 ± 8 years; 44 males and 44 females) were evaluated. The average nodule size was 2.6 ± 1.1 cm. The univariate analysis showed that carcinoembryonic antigen (CEA), pleural indentation, vascular convergence, bronchial distortion, and higher SUVmax were more common in poor differentiated lung adenocarcinoma, and in the multivariate analysis, pleural indentation, vascular convergence, and SUVmax were predictive factors. The combined diagnosis using these three factors showed that the area under the curve (AUC) was 0.735. Conclusion: SUVmax >6.99 combined with HRCT (pleural indentation sign and vascular convergence sign) is helpful to predict the differentiation degree of lung adenocarcinoma dominated by solid density.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Masculino , Femenino , Humanos , Persona de Mediana Edad , Anciano , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos , Adenocarcinoma del Pulmón/diagnóstico , Neoplasias Pulmonares/diagnósticoRESUMEN
Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme overexpressed in many tumors and associated with angiogenesis. Ginkgetin, isoginkgetin, sciadopitysin, and amentoflavone, the primary biflavones found in Ginkgo biloba, have excellent anti-inflammatory and anti-tumor effects. However, the effect of biflavones on CYP1B1 activities remains unknown. In this study, 7-ethoxyresorufin O-deethylation (EROD) was used to characterize the activities of CYP1 families. The impacts of four ginkgo biflavones on CYP1B1 activity and the cellular protein expression of CYP1B1 were systematically investigated. The results showed that amentoflavone with six hydroxyl substituents exhibited the most potent selective inhibitory effect on CYP1B1 activity with IC50 of 0.054 µM in four biflavones. Sciadopitysin, with three hydroxyl and three methoxy substituents, had the weakest inhibitory activity against CYP1B1. Ginkgetin and isoginkgetin, both with four hydroxyl and two methoxy substituents, showed similar inhibitory intensity towards CYP1B1 with IC50 values of 0.289 and 0.211 µM, respectively. Kinetic analysis showed that ginkgetin and amentoflavone inhibited CYP1B1 in a non-competitive mode, whereas sciadopitysin and isoginkgetin induced competitive or mixed types of inhibition. Notably, four ginkgo biflavones were also confirmed to suppress the protein expressions of CYP1B1 and AhR in MCF-7. Furthermore, molecular docking studies indicated more hydrogen bonds formed between amentoflavone and CYP1B1, which might explain the strongest inhibitory action towards CYP1B1. In summary, these findings suggested that biflavones remarkably inhibited both the activity and protein expression of CYP1B1 and the inhibitory activities enhanced with the increasing hydroxyl substitution, providing new insights into the anti-tumor potentials of biflavones.
Asunto(s)
Citocromo P-450 CYP1A1 , Ginkgo biloba , Humanos , Ginkgo biloba/química , Células MCF-7 , Simulación del Acoplamiento Molecular , Cinética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismoRESUMEN
This study aimed to investigate the potential nephrotoxicity of icaritin and the underlying mechanism by in vitro-in vivo experiment technology combined with proteomics technology. First, icaritin showed a significant cytotoxic effect on HK-2 cells, which was accompanied by increased LDH and TNF-α in the supernatant, decreased protein expressions of Bcl-2 and increased Bax and enhanced apoptosis of HK-2 cells as measured by TUNEL staining. Moreover, icaritin induced obvious tubular damage and up-regulation of BUN and CRE levels in plasma in mice. Second, intracellular uptake of icaritin was considerably higher in hOAT1-HEK293 cells than in mock-HEK293 cells, suggesting that icaritin might accumulate in renal cells via OAT1 uptake. Importantly, icaritin caused significant changes in the PPAR signaling pathway in HK2 cells through proteomic analysis. Then, in vitro and in vivo results verified that icaritin significantly downregulated the protein expression of PPAR-α as well as downregulated APOB, ACSL3, ACSL4, and upregulated 5/12/15-HETE, implying that a lipid metabolism disorder was involved in the icaritin-induced nephrotoxicity. Finally, icaritin was found to increase the accumulation of iron and LPO levels while reducing the activity of GPX4, suggesting that ferroptosis was involved in the nephrotoxicity induced by icaritin.
Asunto(s)
Receptores Activados del Proliferador del Peroxisoma , Proteómica , Humanos , Ratones , Animales , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/farmacología , Células HEK293 , Riñón , ApoptosisRESUMEN
CYP46A1 is a brain-specific enzyme responsible for cholesterol homeostasis. Inhibition of CYP46A1 activity serves as a therapeutic target for excitatory neurotoxicity. Sesame is a common medicine and food resource; its component lignans possess various pharmacological activities. In this study, the inhibitory effects of sesame lignans on CYP46A1 activity were investigated. Inhibition kinetics analyses revealed that sesamin and sesamolin produce mixed partial competitive inhibition of CYP46A1, while sesamol produces non-competitive inhibition. Notably, molecular simulations revealed that the sesame lignans have excellent orientations within the active cavity of CYP46A1. Importantly, the sesame lignans had high permeability coefficients and low efflux ratios. Furthermore, sesamin significantly reduced the levels of 24S-hydroxycholesterol in rat plasma and brain tissues, and down-regulated the protein expressions of CYP46A1, NMDAR2A, NMDAR2B, and HMGCR. Collectively, sesame lignans exhibit significant inhibitory effects on CYP46A1 activity, highlighting their potential therapeutic role in treating excitatory neurotoxicity.
RESUMEN
Cancer patients generally has a high risk of thrombotic diseases. However, anticoagulant therapy always aggravates bleeding risks. Rivaroxaban is one of the most widely used direct oral anticoagulants, which is used as anticoagulant treatment or prophylaxis in clinical practice. The present study aimed to systemically estimate the combination safety of rivaroxaban with tyrosine kinase inhibitors (TKIs) based on human cytochrome P450 (CYPs) and efflux transporters and to explore the drug-drug interaction (DDI) mechanisms in vivo and in vitro. In vivo pharmacokinetic experiments and in vitro enzyme incubation assays and bidirectional transport studies were conducted. Imatinib significantly increased the rivaroxaban Cmax value by 90.43% (p < 0.05) and the area under the curve value by 119.96% (p < 0.01) by inhibiting CYP2J2- and CYP3A4-mediated metabolism and breast cancer resistance protein (BCRP)- and P-glycoprotein (P-gp)-mediated efflux transportation in the absorption phase. In contrast, the combination of sunitinib with rivaroxaban reduced the exposure in vivo by 62.32% (p < 0.05) and the Cmax value by 72.56% (p < 0.05). In addition, gefitinib potently inhibited CYP2J2- and CYP3A4-mediated rivaroxaban metabolism with Ki values of 2.99 µΜ and 4.91 µΜ, respectively; however, it almost did not affect the pharmacokinetics of rivaroxaban in vivo. Taken together, clinically significant DDIs were observed in the combinations of rivaroxaban with imatinib and sunitinib. Imatinib increased the bleeding risks of rivaroxaban, while sunitinib had a risk of reducing therapy efficiency. Therefore, more attention should be paid to aviod harmful DDIs in the combinations of rivaroxaban with TKIs.
RESUMEN
BACKGROUND: Cytochrome P450 1B1(CYP1B1) is an extrahepatic P450 isoenzyme that can participate in processes of undermining the effectiveness and safety of anti-cancer therapy. Ginsenosides are the main active ingredients in ginseng, which possesses rich pharmacological activities, including anti-cancer activity and organ protection. However, the effect of ginsenosides on the activity of CYP1B1 remains unclear. OBJECTIVE: The present study aimed to investigate the inhibitory effect of ginsenosides on CYP1B1 and reveal the structure-inhibitory activity relationship. METHODS: Firstly, recombinant CYP1B1 and EROD reactions were used to evaluate the inhibitory effect of ginsenosides. Secondly, molecular docking was used to simulate the interactions between ginsenosides and CYP1B1. Finally, the structure-inhibitory activity relationship was analyzed. RESULTS: The ginsenosides, Rb2, Rd, and Rg3, significantly inhibited CYP1B1; the ginsenoside Rd showed the strongest inhibition effect, with a Ki value of 47.37 µM in non-competitive mode. Notably, ginsenoside Rd formed hydrogen bonds with two key amino acid residues of CYP1B1, and one bond was between the glycosyl in position 20 and ALA330, which also made ginsenoside Rd close to the heme iron of CYP1B1. In contrast, ginsenosides, Rb2 and Rg3, which showed weaker inhibition, interacted with only one CYP1B1 residue by the hydrogen bond, which was far away from the heme iron. Finally, the structure-inhibitory activity relationship analysis demonstrated that the number of glycosyls in position 20 and the type of sapogenins in the ginsenoside structure are the key factors determining inhibitory activity. Meanwhile, ALA330 was a vital amino acid in the potent inhibition of CYP1B1 by ginsenosides. CONCLUSION: A structure-dependent inhibitory effect on CYP1B1 was revealed for ginsenosides, among which ginsenoside Rd showed the strongest inhibition due to its mono-glycosyl in position 20 of the ginsenoside parent structure. These findings would provide evidence for the synthesis of novel CYP1B1 inhibitors to augment the anti-cancer therapeutic effect.
Asunto(s)
Ginsenósidos , Panax , Sapogeninas , Humanos , Aminoácidos , Citocromo P-450 CYP1A1 , Ginsenósidos/farmacología , Ginsenósidos/química , Ginsenósidos/metabolismo , Hemo , Hierro , Isoenzimas , Simulación del Acoplamiento Molecular , Panax/químicaRESUMEN
BACKGROUND: Hypericin is the main active ingredient of St. John's wort, a Chinese herb commonly used for treating depression. Previous studies shown that hypericin can strongly inhibit human cytochrome P450 (CYP) enzyme activities; however, its potential interactions that inhibit human carboxylesterases 2 (hCE2) are unclear. PURPOSE: This study aimed to investigate the inhibitory effect of hypericin on hCE2. METHODS: The inhibition mechanism of hypericin on hCE2 was studied by using N-(2-butyl-1,3-dioxo-2,3-dihydro- 1H-phenalen-6-yl)-2-chloroacetamide (NCEN). The type of inhibition of hypericin on hCE2 and the corresponding inhibition constant (Ki) value were determined. The inhibition of hypericin on hCE2 in living cells was discussed. The risk of herb-drug interactions (HDI) of hypericin in vivo was predicted by estimating the area under the drug concentration-time curve (AUC) in the presence or absence of hypericin. To understand the inhibition mechanism of hypericin on the activity of hCE2 in-depth, molecular docking was performed. RESULTS: The half-maximal inhibitory concentration (IC50) values of hypericin against the hydrolysis of NCEN and irinotecan (CPT-11) were calculated to be 26.59 µM and 112.8 µM, respectively. Hypericin inhibited the hydrolysis of NCEN and CPT-11. Their Ki values were estimated as 10.53 µM and 81.77 µM, respectively. Moreover, hypericin distinctly suppressed hCE2 activity in living cells. In addition, the AUC of hCE2 metabolic drugs with metabolic sites similar to NCEN was estimated to increase by up to 5 % in the presence of hypericin. More importantly, the exposure of CPT-11 in the intestinal epithelium was predicted to increase by 2 % - 69 % following the oral coadministration of hypericin. Further, molecular simulations indicated that hypericin could strongly interact with ASP98, PHE307, and ARG355 to form four hydrogen bonds within hCE2. CONCLUSION: These findings regarding the combination of hypericin-containing herbs and drugs metabolized by hCE2 are of considerable clinical significance.
Asunto(s)
Antracenos , Hypericum , Combinación de Medicamentos , Interacciones de Hierba-Droga , Humanos , Irinotecán , Simulación del Acoplamiento Molecular , Perileno/análogos & derivadosRESUMEN
PURPOSE: Rivaroxaban, an oral anticoagulant, undergoes the metabolism mediated by human cytochrome P450 (CYP). The present study is to quantitatively analyze and compare the contributions of multiple CYPs in the metabolism of rivaroxaban to provide new information for medication safety. METHODS: The metabolic stability of rivaroxaban in the presence of human liver microsomes (HLMs) and recombinant CYPs was systematically evaluated to estimate the participation of various CYP isoforms. Furthermore, the catalytic efficiency of CYP isoforms was compared via metabolic kinetic studies of rivaroxaban with recombinant CYP isoenzymes, as well as via CYP-specific inhibitory studies. Additionally, docking simulations were used to illustrate molecular interactions. RESULTS: Multiple CYP isoforms were involved in the hydroxylation of rivaroxaban, with decreasing catalytic rates as follows: CYP2J2 > 3A4 > 2D6 > 4F3 > 1A1 > 3A5 > 3A7 > 2A6 > 2E1 > 2C9 > 2C19. Among the CYPs, 2J2, 3A4, 2D6, and 4F3 were the four major isoforms responsible for rivaroxaban metabolism. Notably, the intrinsic clearance of rivaroxaban catalyzed by CYP2J2 was nearly 39-, 64-, and 100-fold that catalyzed by CYP3A4, 2D6, and 4F3, respectively. In addition, rivaroxaban hydroxylation was inhibited by 41.1% in the presence of the CYP2J2-specific inhibitor danazol, which was comparable to the inhibition rate of 43.3% by the CYP3A-specific inhibitor ketoconazole in mixed HLMs. Furthermore, molecular simulations showed that rivaroxaban is principally bound to CYP2J2 by π-alkyl bonds, carbon-hydrogen bonds, and alkyl interactions. CONCLUSION: CYP2J2 dominated the hydroxylation of rivaroxaban, which may provide new insight into clinical drug interactions involving rivaroxaban.
Asunto(s)
Citocromo P-450 CYP2J2/metabolismo , Inhibidores del Factor Xa/farmacocinética , Microsomas Hepáticos/metabolismo , Rivaroxabán/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Danazol/farmacología , Interacciones Farmacológicas , Humanos , Isoenzimas , Microsomas Hepáticos/enzimología , Simulación del Acoplamiento MolecularRESUMEN
ABSTRACT: The aim of this study was to retrospectively analyze 18F-FDG positron emission tomography/computed tomography (18F-FDG PET/CT) metabolic variables, programmed death-ligand 1 (PD-L1) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) tumor expression, and other factors as predictors of disease-free survival (DFS) in patients with lung adenocarcinoma (LUAD) (stage IA-IIIA) who underwent surgical resection. We still lack predictor of immune checkpoint (programmed cell death-1 [PD-1]/PD-L1) inhibitors. Herein, we investigated the correlation between metabolic parameters from 18F-FDG PET/CT and PD-L1 expression in patients with surgically resected LUAD.Seventy-four patients who underwent 18F-FDG PET/CT prior to treatment were consecutively enrolled. The main 18F-FDG PET/CT-derived variables were primary tumor maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Surgical tumor specimens were analyzed for PD-L1 and p-STAT3 expression using immunohistochemistry. Correlations between immunohistochemistry results and 18F-FDG PET/CT-derived variables were compared. Associations of PD-L1 and p-STAT3 tumor expression, 18F-FDG PET/CT-derived variables, and other factors with DFS in resected LUAD were evaluated.All tumors were FDG-avid. The cutoff values of low and high SUVmax, MTV, and TLG were 12.60, 14.87, and 90.85, respectively. The results indicated that TNM stage, PD-L1 positivity, and high 18F-FDG PET/CT metabolic volume parameters (TLG ≥90.85 or MTV ≥14.87) were independent predictors of worse DFS in resected LUAD. No 18F-FDG metabolic parameters associated with PD-L1 expression were observed (chi-square test), but we found that patients with positive PD-L1 expression have significantly higher SUVmax (Pâ=â.01), MTV (Pâ=â.00), and TLG (Pâ=â.00) than patients with negative PD-L1 expression.18F-FDG PET/CT metabolic volume parameters (TLG ≥90.85 or MTV ≥14.87) were more helpful in prognostication than the conventional parameter (SUVmax), PD-L1 expression was an independent predictor of DFS in patients with resected LUAD. Metabolic parameters on 18F-FDG PET/CT have a potential role for 18F-FDG PET/CT in selecting candidate LUAD for treatment with checkpoint inhibitors.
Asunto(s)
Adenocarcinoma del Pulmón/cirugía , Antígeno B7-H1/análisis , Radioisótopos de Flúor/farmacología , Radioisótopos de Flúor/farmacocinética , Adenocarcinoma del Pulmón/sangre , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/sangre , Femenino , Radioisótopos de Flúor/uso terapéutico , Humanos , Pulmón/diagnóstico por imagen , Pulmón/cirugía , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Alcoholic liver disease (ALD) is a progressive disease beginning with simple steatosis but can progress to alcoholic steatohepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. The morbidity of ALD is on the rise and has been a large burden on global healthcare system. It is unfortunately that there are currently no approved therapeutic drugs against ALD. Hence, it is of utmost urgency to develop the efficacious therapies. The ability of many molecular targets against ALD is under investigation. Farnesoid X receptor (FXR), a member of the ligand-activated transcription factor superfamily, has been recently demonstrated to have a crucial role in the pathogenesis and progression of ALD. PURPOSE: The purpose of the study is to determine whether Yangonin (YAN), a FXR agonist previously demonstrated by us, exerts the hepatoprotective effects against ALD and further to clarify the mechanisms in vitro and in vivo. STUDY DESIGN: The alcoholic liver disease model induced by Lieber-Decarli liquid diet was established with or without Yan treatment. METHODS: We determined the liver to body weight ratios, the body weight, serum and hepatic biochemical indicators. The alleviation of the liver histopathological progression was evaluated by H&E and immunohistochemical staining. Western blot and quantitative real-time PCR were used to demonstrate YAN treatment-mediated alleviation mechanisms of ALD. RESULTS: The data indicated that YAN existed hepatoprotective activity against ALD via FXR activation. YAN improved the lipid homeostasis by decreasing hepatic lipogenesis and increasing fatty acid ß-oxidation and lipoprotein lipolysis through modulating the related protein. Also, YAN ameliorated ethanol-induced cholestasis via inhibiting bile acid uptake transporter Ntcp and inducing bile acid efflux transporter Bsep and Mrp2 expression. Besides, YAN improved bile acid homeostasis via inducing Sult2a1 expression and inhibiting Cyp7a1 and Cyp8b1 expression. Furthermore, YAN attenuated ethanol-triggered hepatocyte damage by inhibiting cellular senescence marker P16, P21 and Hmga1 expression. Also, YAN alleviated ethanol-induced inflammation by down-regulating the inflammation-related gene IL-6, IL-1ß and TNF-α expression. Notably, the protective effects of YAN were cancelled by FXR siRNA in vitro and FXR antagonist GS in vivo. CONCLUSIONS: YAN exerted significant hepatoprotective effects against liver injury triggered by ethanol via FXR-mediated target gene modulation.
Asunto(s)
Senescencia Celular , Colestasis , Metabolismo de los Lípidos , Hepatopatías Alcohólicas , Pironas/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Ácidos y Sales Biliares , Homeostasis , Hígado , Hepatopatías Alcohólicas/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BLRESUMEN
The aim of the present study was to investigate the protective effect of S-ketamine (S-KET) against carbon tetrachloride (CCl4) - induced liver damage and oxidative stress, as well as to elucidate the related underlying mechanisms. Blood was collected to measure biochemical parameters (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (TB) and γ-glutamyltransferase (γ-GT)) and the liver was harvested for histopathological analysis of enzymes related to the antioxidant response (malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX)). Liver cell apoptosis was evaluated using the TUNEL assay. In addition, the expression levels of apoptosis-related proteins and the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway were detected by Western blot analysis to explore potential mechanisms. S-KET protected the liver from CCl4-induced damage. The changes to the liver biochemical parameters (increased ALT, AST, ALP, TB, and γ-GT) and oxidative stress-related indicators (increased MDA; depleted SOD, GSH, and GSH-PX) induced by CCl4 were inhibited by S-KET. S-Ket also inhibited CCl4-induced cell apoptosis, the changes in expression of related proteins, and blocked CCl4-induced liver injury and oxidative stress via activation of the Nrf2/HO-1 signaling pathway. S-KET effectively protected the liver by inhibition of CCl4-induced damage via upregulation the Nrf2/HO-1 signaling pathway.
Asunto(s)
Tetracloruro de Carbono/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Hemo Oxigenasa (Desciclizante)/metabolismo , Ketamina/farmacología , Ketamina/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Masculino , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Both clotrimazole and ketoconazole have been verified to have an inhibitory effect on CYP3A4. hCE2 is an enzyme closely related to the side effects of several anti-cancer drugs. However, the interactions between hCE2, clotrimazole, and ketoconazole remain unclear. OBJECTIVE: The objective of this study was to investigate and compare the inhibition behaviors of the two antifungal agents, ketoconazole and clotrimazole, on the human liver microsome hCE2 and to explore their underlying mechanism. METHODS: The inhibitory effects were investigated in human liver microsomes (HLMs) using fluorescein diacetate (FD), N-(2-butyl-1,3-dioxo-2,3-dihydro-1H-phenalen-6-yl)-2-chloroacetamide (NCEN) and irinotecan (CPT- 11) as substrates of hCE2. RESULTS: Clotrimazole significantly inhibited the hCE2 activity, which was manifested by attenuated fluorescence when the substrates were FD and NCEN. The inhibitory effect of clotrimazole towards hCE2 was much stronger than that of ketoconazole, and the inhibitory behaviors displayed substrate-dependent inhibition. The IC50 value of clotrimazole, with CPT-11 as the substate, increased by 5 and 37 times more than that with FD and NCEN, respectively. Furthermore, the inhibitions of clotrimazole towards hCE2-mediated hydrolysis of FD, NCEN, and CPT-11 were all in competitive mode with the Ki values of 0.483 µM, 8.63 µM, and 29.0 µM, respectively. Molecular docking result of clotrimazole binding to hCE2 illustrated that clotrimazole could efficiently orient itself in the Z site cavity of hCE2. CONCLUSION: Clotrimazole displayed a strong inhibitory effect against hCE2, which might be used as a potential combined agent co-administrated with CPT-11 to alleviate the hCE2-mediated severe side effects.
Asunto(s)
Antifúngicos/farmacología , Carboxilesterasa/antagonistas & inhibidores , Clotrimazol/farmacología , Cetoconazol/farmacología , Citocromo P-450 CYP3A , Humanos , Cinética , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: A number of anesthetics have protective effect against ischemia-reperfusion (I/R) injury, including desflurane. But the function and molecular mechanism of desflurane in liver I/R injury have not been fully understood. The aim of this study was to investigate the effect of desflurane on liver I/R injury and further investigated the molecular mechanisms involving in miR-135b-5p. METHODS: The models of liver I/R injury in rats were established, and received desflurane treatment throughout the injury. Serum alanine transaminase (ALT) and aspartate transaminase (AST) were measured and compared between groups. H/R-induced cell model in L02 was established, and were treated with desflurane before hypoxia. Quantitative real-time polymerase chain reaction was performed to determine the expression of miR-135b-5p in different groups. The cell apoptosis was detected using flow cytometry assay. Western blot was used for the measurement of protein levels. RESULTS: I/R significantly increased serum levels of ALT and AST in rats, which were reversed by desflurane treatment. Desflurane also significantly attenuated the increase of cell apoptosis induced by I/R in both vivo and vitro. MiR-135b-5p significantly reversed the protective effect of desflurane against liver I/R injury. Additionally, Janus protein tyrosine kinase (JAK)2 was shown to be a target gene of miR-135b-5p, and miR-135b-5p overexpression significantly decreased the protein levels of p-JAK2, JAK2, p-STAT3. CONCLUSION: Desflurane attenuated liver I/R injury through regulating miR-135b-5p, and JAK2 was the target gene of mIR-135b-5p. These findings provide references for further development of therapeutic strategies in liver injury.