Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 122
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-34628186

RESUMO

A simple, selective, rapid, and reliable ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine CX3002 in human plasma using CX3002-d3 as the internal standard (IS). After a rapid protein precipitation with acetonitrile (3:1, v/v), the chromatographic separation of CX3002 and IS was performed on a Thermo Hypersil GOLD C18 column (2.1 mm × 50 mm, 1.9 µm) with gradient elution at a flow rate of 0.4 ml/min. Gradient elution was achieved with mobile phase A consisting of water containing 0.1% formic acid and 5 mmol/L ammonium formate and mobile phase B consisting of methanol containing 0.1% formic acid. The detection was performed on AB SCIEX QTRAP® 5500 tandem mass spectrometry in the positive ion mode. Multiple reactions monitoring (MRM) was used for quantitative analysis at transition of m/z 460.3 â†’ 199.3 for CX3002 and m/z 463.3 â†’ 202.3 m/z for IS. The method was fully validated and displayed good linearity over a concentration range of 0.2-400 ng/mL with the correlation coefficient above 0.997. The intra-run and inter-run precision (coefficient of variation, CV) ranged from 0.60%-16.46% and the accuracy bias ranged from -7.09%-9.75%. The mean IS-normalized extraction recovery ranged from 98.30% to 104.52%. The CV(%) of IS-normalized matrix factors at the low and high QC concentration were 4.09% and 1.68%, respectively. The storage stability under different conditions was in accordance with the bioanalytical guidelines. The method was successfully applied to the pharmacokinetic study of CX3002 (30 mg) in healthy Chinese subjects.

2.
Neuroreport ; 32(14): 1216-1222, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34406989

RESUMO

Recently, we have identified a functional expression of farnesoid X receptor (FXR) in neurons in vitro and in vivo. However, whether the FXR is expressed in astrocytes remains unclear. In the present study, we addressed this issue by using an array of experimental methods such as immunofluorescence and western blot. Results showed that the FXR mRNA and protein were expressed in mouse brain primary cultured astrocytes. In mouse primary cultured astrocytes in vitro the FXR was predominantly localized in the nucleus with an obvious punctuate distribution property. Unlike its expressional characteristic in cultured astrocytes, the FXR was not detected in astrocytes in the mouse hippocampus and prefrontal cortex, suggesting that the FXR is not expressed in astrocytes at conditions in vivo. Functional studies in vitro showed that activation of the FXR in primary cultured astrocytes by chenodeoxycholic acid or GW4064 induced a marked increase in expression levels of small heterodimer partner mRNA and protein. Taken together, these findings show a differential expression of FXR in astrocytes at conditions in vitro but not in vivo, and in mouse primary cultured astrocytes the FXR can be activated by its ligands.

3.
Pathol Res Pract ; 225: 153580, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34391182

RESUMO

BACKGROUND: O-linked ß-N-acetylglucosamine transferase (O-GlcNAc transferase, OGT) is a key enzyme that regulates O-GlcNAc modification, which is significantly up-regulated and participates in the regulation of tumorigenesis. Although previous research indicated that OGT promotes epithelial-mesenchymal transition (EMT) of lung cancer, the underlying molecular mechanisms, especially within the tumor inflammatory microenvironment, require further elucidation. METHODS: The role of the inflammatory signaling Interleukin 6/Signal Transducer and activator of transcription 3 (IL-6/STAT3) in Non-small cell lung cancer (NSCLC) cells A549 were confirmed by Transwell assay, Scratch wound healing assay, Western blot, Immunofluorescence staining, and Nuclear and cytoplasmic extraction experiment. Western blot detected OGT expression and whole protein O-GlcNacylation after IL-6 stimulation in NSCLCs cells. The biological effects and related mechanism of OGT in NSCLC cells were investigated by Western blot, Transwell assay, Immunofluorescence staining and Immunoprecipitation. The up-stream mechanism of OGT expression was explored by employing the specific chemical inhibitors, and the expression and distribution of OGT and phosphorylated STAT3 in NSCLC samples were confirmed by immunohistochemical analysis. RESULTS: IL-6/STAT3 promoted the migration and invasion of NSCLC cells. IL-6 stimulation elevated OGT expression and the total protein O-GlcNacylation in A549 cells. Silencing OGT by shRNA significantly inhibited the IL-6 induced EMT marker (N-cadherin and Slug) expression, migration and invasion in A549 cells. OGT interacted with and mediated O-GlcNacylation of STAT3, which promoted STAT3 Y705 phosphorylation in IL-6 treated NSCLC cells. OGT expression was positively regulated by NF-κB p65 signaling pathway after IL-6 stimulation, instead of STAT3 signaling. OGT and phosphorylated STAT3 had an obviously higher expression in human NSCLC tissues, and phosphorylated STAT3 was mainly expressed in the nucleus. CONCLUSION: The above results showed that OGT regulated O-GlcNacylation promoted migration and invasion by activating IL-6/STAT3 signaling in lung cancer.

4.
Clin Nutr ; 40(8): 4830-4837, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34358823

RESUMO

BACKGROUND & AIMS: Increasing data suggests that chronic low-grade inflammation plays an important role on development of sarcopenia. The present study was designed to identify the association between fibrinogen, fibrin degradation products (FDP) and sarcopenia risk in hospitalized old patients. METHODS: A total of 437 patients were enrolled in this cross-sectional study (148 with sarcopenia and 289 without sarcopenia). Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Body composition, grip strength and gait speed were performed to participants. Fibrinogen, FDP levels were measured. Logistic regression analyses were carried out to assess the association between fibrinogen and sarcopenia, between FDP and sarcopenia, respectively. RESULTS: Compared to non-sarcopenic patients, fibrinogen and FDP levels were found to be higher in the sarcopenic group (3.07 g/L vs 2.79 g/L, 1.75 µg/mL vs 1.00 µg/mL, respectively, p < 0.05). Multiple linear regression analysis showed a significant negative association between fibrinogen and gait speed (ß: -0.164, p = 0.008), and muscle strength (ß: -0.231, p < 0.001). Multivariable logistic regression analysis showed that fibrinogen and FDP were independently associated with sarcopenia (odds ratio 1.32 [95% confidence interval 1.03, 1.70], p = 0.009; odds ratio 1.07 [95% confidence interval 1.01, 1.19], p = 0.049, respectively). ROC curve revealed that the cutoff values of fibrinogen and FDP to predict sarcopenia risk were 2.54 g/L and 1.15 µg/mL, respectively. CONCLUSIONS: In hospitalized old patients, serum fibrinogen and FDP levels are elevated in sarcopenia patients than those without sarcopenia. Fibrinogen and FDP are associated with sarcopenia in a concentration-dependent manner.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34453416

RESUMO

Tadalafil is an effective, reversible, and competitive phosphodiesterase 5 inhibitor mainly used to treat erectile dysfunction. This study investigated the bioequivalence of generic and marketed formulations of 10-mg tadalafil tablets under fasted and fed conditions. This open-label, randomized, single-dose, 2-period crossover study included 53 healthy Chinese men (aged 20-43 years). Plasma samples were collected from 0.5 hours before treatment to 72 hours after each dose and analyzed using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety assessments were performed throughout the study. For the fasted state, the 90% confidence intervals of the geometric mean ratios between the generic and marketed formulations were 86.1% to 99.1% for the maximum plasma concentration and 88.4% to 100.3% for the area under the plasma concentration-time curve from time 0 to infinity, and the corresponding values under the fed state were and 99.9% to 108.4% and 95.7% to 104.3%, respectively. All data were within the accepted bioequivalence range of 80% to 125%. After consuming high-fat, high-calorie meals in the fed condition, the time to the maximum plasma concentration was similar between the formulations, and area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration were 10.2% and 6.55% higher, respectively, for the marketed formulation. Thus, food had no clinically relevant effect on tadalafil exposure following a single oral dose in healthy Chinese men. No serious adverse reactions were reported. These results indicated that the analyzed generic and marketed tadalafil tablets were bioequivalent with similar safety profiles.

6.
PLoS Med ; 18(8): e1003731, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34339416

RESUMO

BACKGROUND: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412). CONCLUSIONS: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.


Assuntos
Terapia de Reposição de Estrogênios/estatística & dados numéricos , Estrogênios/uso terapêutico , Menopausa/fisiologia , Progestinas/uso terapêutico , Saúde da Mulher/estatística & dados numéricos , Feminino , Humanos , Pessoa de Meia-Idade
7.
Front Oncol ; 11: 693670, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290987

RESUMO

Extramedullary relapse of acute promyelocytic leukemia is a rare phenomenon and is associated with a poor prognosis, with the central nervous system being the most common site of relapse. The current treatments are still limited. Venetoclax, a selective inhibitor of BCL2, is a small molecule that can cross the blood-brain barrier and shows a potential efficacy in the treatment of chronic lymphocytic leukemia with central nervous system involvement. Although venetoclax has also been used in the treatment of acute myeloid leukemia in recent years, there are no reports of its use in the treatment of central nervous system relapse in acute promyelocytic leukemia. Here, we report a case of central nervous system relapse in acute promyelocytic leukemia that achieved complete remission after oral treatment with venetoclax. The presence of venetoclax in the patient's CSF was confirmed by testing CSF and plasma by mass spectrometry. The concentration of venetoclax in CSF was approximately 1/300 of that in plasma trough concentration. The treatment experience in this case demonstrates the potential ability of venetoclax to treat of central nervous system relapse/involvement in acute promyelocytic leukemia, thus providing a new treatment option for this kind of patient.

8.
Front Plant Sci ; 12: 681145, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220901

RESUMO

Carbon metabolism in higher plants is a basic physiological metabolism, and carbon allocation and conversion require the activity of various enzymes in metabolic processes that alter the content and overall composition of sugars in the sink organ. However, it is not known how various enzymes affect carbon metabolism when tomato plants are subjected to water stress or treated with potassium. Although the process of carbon metabolism is very complex, we used the carbon conversion rate to compare and analyze the enzyme activities related to sugar metabolism and find out which carbon conversion rate are the most important. Results showed that water stress and potassium increased carbon import flux in the fruit, which was beneficial to carbon accumulation. Water deficit increased the activity of sucrose synthase (SuSy) and starch phosphorylase (SP) and decreased the activity of sucrose phosphate synthase (SPS) and adenosine diphosphate glucose pyrophosphorylase (AGPase) in the source. Water stress increased the activity of acid invertase (AI), SuSy and SP but decreased the activity of AGPase in the sink. Potassium modified the balance of enzymes active in sugar and starch metabolism by increasing the activity of AI, SuSy, SPS and SP and significantly decreasing the activity of AGPase, resulting in increase of hexose. Canonical correlational analysis revealed that the carbon conversion rate was mainly affected by the relative rate of conversion of sucrose to fructose and glucose [p1(t)] and glucose to starch [p5m(t)]. SuSy and AGPase had the greatest effect on enzyme activity in the fruit; respectively regulated p 1(t) and p 5m(t).

9.
Front Oncol ; 11: 654812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34136390

RESUMO

G protein-coupled receptor kinase 6 (GRK6) is expressed in various tissues and is involved in the development of several diseases including lung cancer. We previously reported that GRK6 is down-regulated in lung adenocarcinoma patients, which induces cell invasion and metastasis. However, further understanding of the role of GRK6 in lung adenocarcinoma is required. Here we explored the functional consequence of GRK6 inhibition in lung epithelial cells. Analysis of TCGA data was coupled with RNA sequencing (RNA-seq) in alveolar epithelial type II (ATII) cells following depletion of GRK6 with RNA interference (RNAi). Findings were validated in ATII cells followed by tissue microarray analysis. Pathway analysis suggested that one of the Hallmark pathways enriched upon GRK6 inhibition is 'Hallmark_Hypoxia' (FDR = 0.014). We demonstrated that GRK6 depletion induces HIF1α (hypoxia-inducible factor 1 alpha) levels and activity in ATII cells. The findings were further confirmed in lung adenocarcinoma samples, in which GRK6 expression levels negatively and positively correlate with HIF1α expression (P = 0.015) and VHL expression (P < 0.0001), respectively. Mechanistically, we showed the impact of GRK6 on HIF activity could be achieved via regulation of VHL levels. Taken together, targeting the HIF pathway may provide new strategies for therapy in GRK6-depleted lung adenocarcinoma patients.

10.
Neuropharmacology ; 193: 108621, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062163

RESUMO

Innate immune activation has been shown to reduce the severity of nervous system disorders such as brain ischemia and traumatic brain damage. Macrophage-colony stimulating factor (M-CSF), a drug that is used to treat hematological system disease, is an enhancer of the innate immune response. In the present study, we evaluated the effect of M-CSF preconditioning on chronic social defeat stress (CSDS)-induced depression-like behaviors in mice. Results showed that a single M-CSF injection 1 day before stress exposure at the dose of 100 and 500 µg/kg, or a single M-CSF injection (100 µg/kg) 1 or 5 days but not 10 days before stress exposure prevented CSDS-induced depression-like behaviors in mice. Further analysis showed that a second M-CSF injection 10 days after the first M-CSF injection and a 2 × or 4 × M-CSF injections 10 days before stress exposure also prevented CSDS-induced depression-like behaviors. Molecular studies revealed that a single M-CSF injection prior to stress exposure skewed the neuroinflammatory responses in the brain in CSDS-exposed mice towards an anti-inflammatory phenotype. These behavioral and molecular actions of M-CSF were correlated with innate immune stimulation, as pre-inhibiting the innate immune activation by minocycline pretreatment (40 mg/kg) abrogated the preventive effect of M-CSF on CSDS-induced depression-like behaviors and neuroinflammatory responses. These results provide evidence to show that innate immune activation by M-CSF pretreatment may prevent chronic stress-induced depression-like behaviors via preventing the development of neuroinflammatory response in the brain, which may help to develop novel strategies for the prevention of depression.

11.
Int J Biol Markers ; 36(2): 64-76, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34142593

RESUMO

OBJECTIVE: Our study aimed to observe and evaluate the clinical value of interleukin (IL)-11 in the serum and exhaled breath condensate of patients with non-small cell lung cancer (NSCLC). METHODS: A total of 91 patients with NSCLC and 72 healthy volunteers were included in this study. IL-11 concentration was determined by ELISA, and the relationship between IL-11 expression in serum and exhaled breath condensate specimens, and the clinicopathological characteristics of patients with NSCLC were analyzed. The relationship between serum IL-11 expression and traditional tumor markers and inflammation indicators of NSCLC was also analyzed. The correlation between serum IL-11 and exhaled breath condensate IL-11 level was determined. The receiver operating characteristic curve was used to evaluate the diagnostic value of IL-11 and carcinoembryonic antigen single and combined detection for NSCLC. The published data from online databases were used to analyze the relationship between the expression of IL-11 and the prognosis of NSCLC. RESULTS: IL-11 concentration in serum and exhaled breath condensate specimens of patients with NSCLC were significantly increased. IL-11 expression was positively correlated with lymph node metastasis, distant metastasis, tumor node metastasis stage, and tumor differentiation degree of NSCLC. The expression of IL-11 in serum was positively correlated with that in exhaled breath condensate specimens. IL-11 expression was closely related to that of neutrophil-to-lymphocyte ratio and carcinoembryonic antigen. The combination of serum IL-11 with exhaled breath condensate IL-11 and carcinoembryonic antigen showed significantly higher diagnostic value than any one marker alone. Besides, the high IL-11 expression was closely related to the poor prognosis of NSCLC. CONCLUSION: IL-11 can be used as a potential diagnostic and prognostic biomarker for NSCLC.

12.
Front Oncol ; 11: 692136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113576

RESUMO

Background: Understanding common and unique mechanisms driving oncogenic processes in human tumors is indispensable to develop efficient therapies. Recent studies have proposed Twinfilin Actin Binding Protein 1 (TWF1) as a putative driver gene in lung cancer, pancreatic cancer and breast cancer, however a systematic pan-cancer analysis has not been carried out. Methods: Here, we set out to explore the role of TWF1 in 33 tumor types using TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus) dataset, Human Protein Atlas (HPA), and several bioinformatic tools. Results: As part of our analysis, we have assessed TWF1 expression across tumors. We found that over-expression of TWF1 generally predicted poor OS for patients with tumors with high TWF1 expression, such as mesothelioma, lung adenocarcinoma, cervical cancer and pancreatic adenocarcinoma. We also assessed the mutation burden of TWF1 in cancer and the TWF1-associated survival of cancer patients, compared the phosphorylation of TWF1 between normal and primary tumor tissues and explored putative functional mechanisms in TWF1-mediated oncogenesis. Conclusions: Our pan-cancer analysis provides a comprehensive overview of the oncogenic roles of TWF1 in multiple human cancers.

14.
Biomed Chromatogr ; 35(10): e5150, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33894005

RESUMO

A simple, sensitive, and fully automated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of cilostazol (CIL) and its active metabolite, 3,4-dehydro cilostazol (CIL-M), in human plasma. Plasma samples were processed by protein precipitation in 2 mL 96-deep-well plates, and all liquid transfer steps were performed through robotic liquid handling workstation, enabling the whole procedure fast, compared to the reported methods. Separation of analytes was successfully achieved on a UPLC BEH C18 column (2.1 × 100 mm, 1.7 µm) with mobile phase A (5 mM ammonium formate containing 0.1% formic acid) and mobile phase B (methanol) at a flow rate of 0.30 mL min-1 . The total run time was 3.5 min per sample. Mass spectrometric detection was conducted by electrospray ion source in positive ion multiple reaction monitoring mode. Calibration curves were linear over the concentration range of 1.0-800 ng·mL-1 for CIL and 0.05-400 ng·mL-1 for CIL-M. The coefficient of variation for the assay's precision was 12.3%, and the accuracy was 88.8-99.8%. It was fully validated and successfully applied to assess the influence of CYP genotypes on the pharmacokinetics of CIL after oral administration of 50 mg tablet formulations of CIL to healthy Chinese volunteers. The results suggest that, in Chinese population, the genotype of CYP3A5 affects the plasma exposure of CIL.


Assuntos
Cromatografia Líquida/métodos , Cilostazol/análogos & derivados , Cilostazol/sangue , Sistema Enzimático do Citocromo P-450/genética , Espectrometria de Massas em Tandem/métodos , China , Cilostazol/química , Cilostazol/farmacocinética , Genótipo , Humanos , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
Eur J Drug Metab Pharmacokinet ; 46(3): 427-436, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33779967

RESUMO

BACKGROUND AND OBJECTIVE: Eltrombopag is the first oral, small-molecule, non-peptide thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. This study investigated the pharmacokinetics of eltrombopag in healthy Chinese subjects and evaluated the effect of sex and genetic polymorphisms on its variability. METHODS: Forty-eight healthy subjects were administered a single dose of eltrombopag (25 mg). Plasma concentrations of eltrombopag were determined using a validated liquid chromatography-tandem mass spectrometry method, and platelet counts were determined by blood tests. CYP1A2 rs762551, CYP2C8*3 rs10509681, CYP2C8*3 rs11572080, UGT1A1 rs887829, UGT1A3 rs3806596, and BCRP rs2231142 polymorphisms were genotyped by Sanger sequencing. A back-propagation artificial neural network (BP-ANN) model was constructed to predict pharmacokinetics based on physiological factors and genetic polymorphism data. RESULTS: Compared with male subjects, female subjects who received a single 25-mg dose of eltrombopag exhibited a significantly increased mean maximum plasma concentration (Cmax) and significantly decreased apparent clearance. Additionally, CYP1A2 rs762551 C>A single nucleotide polymorphism influenced distribution and elimination. C-allele carriers exhibited 30% higher systemic exposure and 20% lower apparent clearance compared with homozygous A-allele carriers. Mean percentage increases in platelet counts from baseline to Day 5 were 9.38% and 17.06% in male and female subjects, respectively. The BP-ANN model had a high goodness-of-fit index and good coherence between predicted and measured concentrations (R = 0.98979). CONCLUSION: Sex and CYP1A2 rs762551 C>A were associated with the pharmacokinetic variability of eltrombopag in healthy Chinese subjects. Females exhibited a better platelet-elevating effect compared with males administered the same dosage. The developed BP-ANN model based on physiological factors and genetic polymorphism data could be promising for applications in pharmacokinetic studies. TRIAL REGISTRATIONS: https://www.Chinadrugtrials.org.cn CTR20190898.


Assuntos
Grupo com Ancestrais do Continente Asiático , Benzoatos/farmacocinética , Citocromo P-450 CYP1A2/genética , Hidrazinas/farmacocinética , Redes Neurais de Computação , Pirazóis/farmacocinética , Adolescente , Adulto , Benzoatos/administração & dosagem , Cromatografia Líquida , Feminino , Genótipo , Humanos , Hidrazinas/administração & dosagem , Masculino , Polimorfismo de Nucleotídeo Único , Pirazóis/administração & dosagem , Fatores Sexuais , Espectrometria de Massas em Tandem , Adulto Jovem
16.
New Phytol ; 230(4): 1489-1502, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33550584

RESUMO

The trade-off between yield and quality, a major problem for the production of fleshy fruits, involves fruit expansive growth and sugar metabolism. Here we developed an integrative model by coupling a biophysical model of fleshy fruit growth processes, including water and carbon fluxes and organ expansion, with an enzyme-based kinetic model of sugar metabolism to better understand the interactions between these two processes. The integrative model was initially tested on tomato fruit, a model system for fleshy fruit. The integrative model closely simulated the biomass and major carbon metabolites of tomato fruit developing under optimal or stress conditions. The model also performed robustly when simulating the fruit size and sugar concentrations of different tomato genotypes including wild species. The validated model was used to explore ways of uncoupling the size-sweetness trade-off in fruit. Model-based virtual experiments suggested that larger sweeter tomatoes could be obtained by simultaneously manipulating certain biophysical factors and transmembrane transports. The integrative fleshy fruit model provides a promising tool to facilitate the targeted bioengineering and breeding of tomatoes and other fruits.


Assuntos
Lycopersicon esculentum , Metabolismo dos Carboidratos , Carbono , Frutas , Melhoramento Vegetal
17.
Cancer Lett ; 503: 197-212, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33493586

RESUMO

Patient mortality rates have remained stubbornly high for the past decades in small cell lung cancer (SCLC) because of having no standard targeted therapies with confirmed advantages at present. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models but have had unsatisfactory clinical results in SCLC. By RNA-seq and isobaric tags for relative and absolute quantification (ITRAQ), we revealed that PARP1 inhibition led to the relocalization of forkhead box-O3a (FOXO3a) from nuclear to cytoplasm. By performing co-Immunoprecipitation (co-IP) and CRISPR-Cas9-mediated knockout plasmid we showed that FOXO3a was subject to exportin 1 (XPO1)-dependent nuclear export. We demonstrated the effects of the PARP inhibitor BMN673 on apoptosis and DNA damage were markedly enhanced by simultaneous inhibition of XPO1 in vitro. The combination of BMN673 and the XPO1 inhibitor selinexor inhibited primary SCLC cell proliferation in mini-patient-derived xenotransplants (miniPDXs) and markedly inhibited tumor growth without significant toxicity in xenograft models. The efficacy was enhanced for more than 2.5 times, compared to the single agent. Based on these findings, we further designed a novel dual PARP-XPO1 inhibitor and showed its effectiveness in SCLC. In this work, we illustrated that combining a PARP inhibitor with an XPO1 inhibitor is associated with significantly improved efficacy and tolerability. Dual PARP-XPO1 inhibition restored the FOXO3a balance and activity in SCLC. Collectively, targeting PARP1 and XPO1 opens new avenues for therapeutic intervention against SCLC, warranting further investigation in potential clinical trials.


Assuntos
Proteína Forkhead Box O3/metabolismo , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Ftalazinas/administração & dosagem , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Triazóis/administração & dosagem , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/metabolismo , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrazinas/farmacologia , Neoplasias Pulmonares/metabolismo , Camundongos , Ftalazinas/farmacologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Behav Pharmacol ; 32(1): 62-72, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416256

RESUMO

We have reported that SMIP004, an inhibitor of S-phase kinase-associated protein 2 (Skp2), displays antidepressant-like activities in stress-naïve and chronically stressed mice. Here, we investigated the antidepressant-like effect of C1, another inhibitor of Skp2, in mouse models following acute or chronic drug administration at different doses and treatment times by using the tail suspension test (TST), forced swimming test (FST), and social interaction test (SIT). The time- and dose-dependent results showed that the antidepressant-like effect of C1 occurred 8 days after the drug treatment, and C1 produced antidepressant-like activities at the dose of 5 and 10 but not 1 mg/kg in male or female mice. C1 administration (5 mg/kg) also induced antidepressant-like effects in stress-naïve mice in a three-times administration mode within 24 h (24, 5, and 1 h before the test) but not in an acute administration mode (1 h before the test). The C1 and fluoxetine co-administration produced additive effect on depression-like behaviors in stress-naïve mice. The antidepressant-like effect of C1 was not associated with the change in locomotor activity, as no increased locomotor activity was observed in different treatment modes. Furthermore, the long-term C1 treatment (5 mg/kg) was found to ameliorate the depression-like behaviors in chronic social defeat stress-exposed mice, suggesting that C1 can produce antidepressant-like actions in stress conditions. Since C1 is a specific inhibitor of Skp2, our results demonstrate that inhibition of Skp2 might be a potential strategy for the treatment of depression, and Skp2 may be potential target for the development of novel antidepressants.

19.
Inflammation ; 44(4): 1381-1395, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33511484

RESUMO

Neuroinflammation and oxidative stress play critical roles in pathogenesis of depression. Diallyl disulfide (DADS), an active compound in garlic oil, has been shown to exhibit obvious anti-inflammatory and anti-oxidative activities. Preliminary evidence indicates that depression is associated with high levels of pro-inflammatory cytokines and oxidative markers, suggesting that inhibition of neuroinflammatory response and oxidative stress may be beneficial for depression interruption. Here, we investigated the antidepressant effect of DADS as well as it mechanisms in a depression-like model induced by lipopolysaccharide (LPS). Similarly to imipramine (10 mg/kg), a clinical antidepressant, DADS (40 or 80 mg/kg), which was administered 1 h before LPS treatment (pre-LPS) or 1.5 h and 23.5 h after LPS treatment (post-LPS), prevented and reversed LPS (100 µg/kg)-induced increase in immobility time in the tail suspension test (TST) and forced swim test (FST) in mice. Mechanistic studies revealed that DADS pre-treatment or post-treatment at the dose of 40 and 80 mg/kg prevented and reversed (i) LPS-induced increases in interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) levels in the hippocampus and prefrontal cortex, (ii) LPS-induced increases in contents of malondialdehyde (MDA), a parameter reflecting high levels of oxidative stress, and (iii) LPS-induced decreases in contents of GSH, a marker reflecting weakened anti-oxidative ability, in the hippocampus and prefrontal cortex in mice. These results indicate that DADS is comparable to imipramine in effectively ameliorating LPS-induced depression-like behaviors in mice, providing a potential value for DADS in prevention and/or therapy of depression.

20.
Clin Pharmacol Drug Dev ; 10(2): 166-172, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32416055

RESUMO

A randomized, open-label, 2-period crossover study was performed to evaluate the pharmacokinetic properties and bioequivalence of 2 erlotinib hydrochloride tablets (a test formulation and a reference formulation) in healthy Chinese subjects. Subjects were randomized to receive a single oral dose of the erlotinib hydrochloride test or reference formulation (150 mg) under fasting conditions. The washout period was 12 days. Blood samples were collected at scheduled time points, and plasma concentrations were determined using a high-performance liquid chromatography-tandem mass spectrometry method. A noncompartmental method was used to calculate pharmacokinetic parameters and to evaluate the bioequivalence of the 2 formulations. Safety assessments were performed during the whole study period. The results suggest that the pharmacokinetic parameter values of the test formulation were similar to those of the reference formulation. The 90% confidence intervals of the geometric least-squares mean ratios of the test to reference formulation were 94.06% to 105.43% for maximum concentration, 88.21% to 97.57% for area under the concentration-time curve to last measurement, and 87.37% to 97.14% for area under the curve extrapolated to infinity, which are all within the accepted bioequivalence range of 80% to 125%. No serious adverse events occurred during the study. These findings suggest that the 2 erlotinib hydrochloride tablets were bioequivalent in accordance with predetermined regulatory criteria.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...