RESUMO
Programmed cell death (PCD), also known as regulatory cell death (RCD), is a process that occurs in all organisms and is closely linked to both normal physiological processes and disease states. Various signaling pathways, such as TP53, KRAS, NOTCH, hypoxia, and metabolic reprogramming, have been found to regulate RCD. Polysaccharides, which are essential natural products, have been the subject of extensive research in the fields of food, nutrition, and medicine due to their wide range of pharmacological effects. Studies have shown that polysaccharides have biological activities and the potential to target signal transduction pathways for the treatment of diseases. This paper provides a review of the mechanisms through which polysaccharides exert their therapeutic effects at different levels and explores the relationship between different types of RCD and human diseases. The aim of this review is to provide a theoretical basis for the further clinical use and application of polysaccharide bioactivities.
Assuntos
Apoptose , Produtos Biológicos , Humanos , Apoptose/fisiologia , Morte Celular , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Transdução de Sinais , Produtos Biológicos/farmacologiaRESUMO
Ferroptosis, a type of cell death involving iron and lipid peroxidation, has been found to be closely associated with the development of many diseases. Mitochondria are vital components of eukaryotic cells, serving important functions in energy production, cellular metabolism, and apoptosis regulation. Presently, the precise relationship between mitochondria and ferroptosis remains unclear. In this study, we aim to systematically elucidate the mechanisms via which mitochondria regulate ferroptosis from multiple perspectives to provide novel insights into mitochondrial functions in ferroptosis. Additionally, we present a comprehensive overview of how mitochondria contribute to ferroptosis in different conditions, including cancer, cardiovascular disease, inflammatory disease, mitochondrial DNA depletion syndrome, and novel coronavirus pneumonia. Gaining a comprehensive understanding of the involvement of mitochondria in ferroptosis could lead to more effective approaches for both basic cell biology studies and medical treatments.
Assuntos
Doenças Cardiovasculares , Ferroptose , Humanos , Apoptose , Morte Celular , MitocôndriasRESUMO
Asthma is a persistent respiratory ailment that displays periodicity and is linked to the equilibrium of T cells. Several compounds obtained from Chinese herbal medicines display beneficial impacts on T cell regulation and the attenuation of inflammatory mediator synthesis. Schisandrin A, an active lignan derived from the Schisandra fruit, exhibits anti-inflammatory characteristics. In the present study, the network analysis conducted revealed that the nuclear factor-kappaB (NF-κB) signaling pathway is likely a prominent contributor to the anti-asthmatic effects of schisandrin A. In addition, it has been established that the inhibition of cyclooxygenase 2 (COX-2/PTGS2) is likely a significant factor in this process. The results of in vitro experiments have substantiated that schisandrin A can effectively lower the expression of COX-2 and inducible nitric oxide synthase (iNOS) in 16 HBE cells and RAW264.7 cells in a manner that is dependent on the dosage administered. It was able to effectively reduce the activation of the NF-κB signaling pathway while simultaneously improving the injury to the epithelial barrier function. Furthermore, an investigation utilizing immune infiltration as a metric revealed an inequity in Th1/Th2 cells and a surge in Th2 cytokines in asthma patients. In the OVA-induced asthma mice model, it was observed that schisandrin A treatment effectively suppressed inflammatory cell infiltration, reduced the Th2 cell ratio, inhibited mucus secretion, and prevented airway remodeling. To summarize, the administration of schisandrin A has been found to effectively alleviate the symptoms of asthma by impeding the production of inflammation, which includes reducing the Th2 cell ratio and improving the integrity of the epithelial barrier function. These findings offer valuable insights into the potential therapeutic applications of schisandrin A for the treatment of asthma.
Assuntos
Asma , Lignanas , Camundongos , Animais , NF-kappa B/metabolismo , Ciclo-Oxigenase 2/metabolismo , Lignanas/farmacologia , Lignanas/uso terapêutico , Inflamação/metabolismo , Citocinas/metabolismo , Camundongos Endogâmicos BALB C , Modelos Animais de Doenças , Ovalbumina , Líquido da Lavagem BroncoalveolarRESUMO
Ferroptosis, a form of regulated cell death caused by iron-mediated lipid peroxidation, has become a potential strategy to overcome drug resistance and improve the efficacy of traditional cancer treatments. In this study, we investigated whether treatment with the combination of Gracilariopsis lemaneiformis polysaccharides and cisplatin (CP) potentiated the antitumor activity in a Colon-26 carcinoma tumor-bearing mouse model by ferroptosis activation. The G. lemaneiformis polysaccharide GP90 was mainly composed of (1â3) linked 4-O-sulfate-ß-D-galactose and (1â4) linked 3,6-anhydro-α-L-galactose with a molecular weight of 12.45 kDa. Compared with the CP group, the combination of GP90 and CP significantly suppressed tumor growth. Based on the transcriptomic and metabolomic analyses of tumor tissue, GP90 enhanced the antitumor effect of CP by promoting ferroptosis and regulating ferroptosis-related metabolic pathways. Moreover, the accumulation of 4-hydroxy-2-nonenal (4-HNE) and down-regulation of the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (Gpx4) were verified by immunohistochemistry staining. Finally, gene set enrichment analysis showed that positive immunoregulatory pathways were significantly enriched in the GP90 and CP combination group. Our results indicate that GP90 potentiates chemotherapy sensitivity by targeting the transferrin receptor and SLC7A11/Gpx4 pathway to induce ferroptosis, which might be a useful therapeutic target in colorectal cancer patients.
Assuntos
Carcinoma , Ferroptose , Animais , Camundongos , Cisplatino/farmacologia , Sulfatos/farmacologia , Polissacarídeos/farmacologia , ColoRESUMO
BACKGROUND: Renal interstitial fibrosis (RIF) seriously threatens the health of individuals. MiRNAs regulate the progression of fibrosis. Nevertheless, the detailed function of miR-449a in RIF is largely unknown. METHODS: In vitro and in vivo models of RIF were developed to evaluate the function of miR-449a. The relationship among miR-449a, KLF4, and MFN2 was explored using a dual-luciferase reporter assay and chromatin immunoprecipitation. Additionally, the pathological changes in the mice were detected using Masson staining. The mRNA and protein expressions were assessed using quantitative reverse transcription polymerase chain reaction and western blot, respectively. RESULTS: TGF-ß1 downregulated the expressions of KLF4 and MFN2 in TCMK-1 cells, but upregulated the level of miR-449a. The downregulation of miR-449a significantly inhibited TGF-ß1-induced upregulation of fibrotic proteins in TCMK-1 cells. Meanwhile, miR-449a directly targeted KLF4. Moreover, KLF4 overexpression activated MFN2 transcription and reversed TGF-ß1-induced fibrosis by positively regulating MFN2. Furthermore, the downregulation of miR-449a could obviously alleviate the symptoms of RIF in mice with unilateral ureteral obstruction. CONCLUSION: MiR-449a downregulation attenuated the development of RIF by mediating the KLF4/MFN2 axis. Therefore, miR-449a might act as a target in treating RIF.
Assuntos
Nefropatias , MicroRNAs , Animais , Camundongos , Regulação para Baixo , Fibrose , Nefropatias/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Aims: The authors aim to investigate the function of circPlekha7 in renal fibrosis. Methods: Human renal tissues from chronic kidney disease patients, kidney cell line and primary cultured renal tubular epithelial cells were used. TGF-ß1-treated human kidney 2 cells/tubular epithelial cells and a unilateral ureteral obstruction mouse model were employed to study renal fibrosis. Results: circPlekha7 was diminished in renal tissues from chronic kidney disease patients and TGF-ß1-treated human kidney 2 cells and tubular epithelial cells, while miR-493-3p was upregulated. Overexpression of circPlekha7 or knockdown of miR-493-3p suppressed TGF-ß1 induced enhancements on epithelial to mesenchymal transition and fibrogenesis, as well as attenuated renal fibrosis and injury in mice subjected to unilateral ureteral obstruction. circPlekha7 bound with miR-493-3p, which directly targeted KLF4. Conclusion: circPlekha7 inhibits epithelial to mesenchymal transition of renal tubular epithelial cells and fibrosis via targeting miR-493-3p to de-repress KLF4/mitofusin2 expression.
Chronic kidney disease (CKD) ultimately leads to complete kidney dysfunction. The incidence of CKD continues to rise as a result of the increasingly aging population, and the treatment is very limited. In this study, the authors identified a novel molecule, circPlekha7, that plays a crucial role in CKD development and progression. The level of circPlekha7 is lower in the kidney tissues of CKD patients, and increasing its level could attenuate kidney injury and fibrosis. This work helps researchers understand the disease better and, more importantly, provides new avenues to develop therapy.
Assuntos
MicroRNAs , RNA Circular , Insuficiência Renal Crônica , Animais , Transição Epitelial-Mesenquimal , Fibrose , Humanos , Rim/patologia , Fator 4 Semelhante a Kruppel/genética , Fator 4 Semelhante a Kruppel/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Transdução de SinaisRESUMO
Purpose: The combination therapy of rosuvastatin (RSV) and the platelet inhibitor clopidogrel (CP) is widely accepted in the management of cardiovascular diseases. The objective of the present study was to identify the mechanism of RSV-CP DDI and evaluate the risk of hepatotoxicity associated with the concomitant use of CP. Methods: We first studied the effect of CP and its major circulating metabolite, carboxylic acid metabolite (CPC), on RSV transport by overexpressing cells and membrane vesicles. Second, we investigated whether a rat model could replicate this DDI and then be used to conduct mechanistic studies and assess the risk of hepatotoxicity. Then, cytotoxicity assay in hepatocytes, biochemical examination, and histopathology were performed to measure the magnitude of liver injury in the presence and absence of DDI. Results: CP inhibited OATP1B1-mediated transport of RSV with an IC50 value of 27.39 µM. CP and CPC inhibited BCRP-mediated RSV transport with IC50 values of <0.001 and 5.96 µM, respectively. The CP cocktail (0.001 µM CP plus 2 µM CPC) significantly inhibited BCRP-mediated transport of RSV by 26.28%. Multiple p.o. doses of CP significantly increased intravenous RSV plasma AUC0-infinity by 76.29% and decreased intravenous RSV CL by 42.62%. Similarly, multiple p.o. doses of CP significantly increased p.o. RSV plasma AUC0-infinity by 87.48% and decreased p.o. RSV CL by 43.27%. CP had no effect on cell viability, while RSV exhibited dose-dependent cytotoxicity after 96 h incubation. Co-incubation of 100 µM CP and RSV for 96 h significantly increased intracellular concentrations and cell-to-medium concentration ratios of RSV and reduced hepatocyte viability. Histological evaluation of liver specimens showed patterns of drug-induced liver injury. Cholestasis was found in rats in the presence of DDI. Conclusion: CP is not a clinically relevant inhibitor for OATP1B1 and OATP1B3. The primary mechanism of RSV-CP DDI can be attributed to the inhibition of intestinal BCRP by CP combined with the inhibition of hepatic BCRP by CPC. The latter is likely to be more clinically relevant and be a contributing factor for increased hepatotoxicity in the presence of DDI.
RESUMO
Cancer-associated fibroblasts (CAFs) play an important role in the initiation, metastasis, and invasion of breast cancer. However, whether autophagy acts as a tumor promotion mechanism by inducing epithelial-mesenchymal transition (EMT) is still controversial and remains undefined at the mechanistic levels. In this study, we investigated whether autophagy or FAP-α is required for the invasion, pulmonary metastasis and EMT of breast cancer cells and underlying mechanism. We employed an in vitro model of NIH3T3 fibroblasts treated with H2O2 and confirmed that TGF-ß1 could convert fibroblasts into CAFs through autophagy under oxidative stress in the tumor microenvironment. Modulation of autophagy by rapamycin, 3-methyladenine or ATG-5 knockdown regulated the expression of CAFs markers, suggesting a role of autophagy in the tumor promotion mechanism of TGF-ß1-induced CAFs activation. Furthermore, we established an indirect co-culture model and a mixed xenograft as a corresponding in vivo model. We demonstrated that TGF-ß1-activated CAFs promote tumor invasion, pulmonary metastasis and EMT, which act through autophagy and overexpression of FAP-α in both models, while autophagy inhibitor 3-methyladenine blocked these effects induced by TGF-ß1-activated CAFs. Moreover, the co-localization of LC3ß and EMT marker vimentin in mixed xenograft also revealed that TGF-ß1-activated CAFs promote tumor growth, pulmonary metastasis, and EMT program partly through autophagy. In addition, knockdown of FAP-α resulted in reversed EMT and abolished tumor invasion and pulmonary metastasis induced by TGF-ß1-activated CAFs. Taken together, we conclude that both autophagy and FAP-α are required for breast cancer cell invasion and metastasis. Targeting autophagy or FAP-α rather than both can serve as a potential approach to improve the prognosis for human breast cancer.
Assuntos
Autofagia/fisiologia , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Endopeptidases/biossíntese , Transição Epitelial-Mesenquimal/fisiologia , Proteínas de Membrana/biossíntese , Fator de Crescimento Transformador beta1/farmacologia , Animais , Autofagia/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endopeptidases/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Invasividade Neoplásica/patologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
WHAT IS KNOWN AND OBJECTIVE: Clinical use of fluconazole against fungal infections in renal transplant patients is complicated by the potentially marked and unpredictable drug-drug interactions (DDIs). We report a case of tacrolimus-fluconazole DDI in a stable renal transplant recipient and describe the mechanism, magnitude and duration of this DDI through a literature review. CASE SUMMARY: A 38-year-old woman experienced a 9.1-fold increase in dose-normalized tacrolimus trough level (trough concentration/weight-normalized daily dose) and an 87% decrease in weight-normalized daily dose (daily dose/body weight) in the treatment of documented Candida albicans oesophagitis by fluconazole. After discontinuation of fluconazole for 161 day, a 26% reduction in weight-normalized daily dose was required to maintain therapeutic exposure. WHAT IS NEW AND CONCLUSION: Oral fluconazole has a more significant impact on its drug interactions with tacrolimus than intravenous fluconazole. Gene screening for CYP3A5 6986 A>G and ABCB1 3435 C>T in organ transplant recipients may help in preventing DDI and facilitating tacrolimus dose adjustment.
Assuntos
Antifúngicos/farmacologia , Fluconazol/farmacologia , Imunossupressores/farmacocinética , Tacrolimo/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Fluconazol/administração & dosagem , Humanos , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Tacrolimo/administração & dosagemRESUMO
A simple, sensitive, specific, accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for determination of chlorzoxazone in human plasma was developed and validated to evaluate the pharmacokinetic characteristics of chlorzoxazone test or reference formulation. Sample preparation was achieved by one step protein precipitation and dilution with acetontrile. The chromatographic separation was performed at 40°C with a gradient mobile phase (0.3 mL/min) and a Shimadzu VP-ODS C18 analytical column (column size: 150 × 2.0 mm). TSQ quantum access triple-quadrapole MS/MS detection was operated in a negative mode by multiple reaction monitoring. Ion transitions at m/z 168.0â132.1 for chlorzoxazone and m/z 451.3â379.3 for repaglinide (internal standard) were used for the LC-MS/MS analysis. The calibration was linear (r ≥ 0.995) over the tested concentration range of 0.2-20 µg/mL for chlorzoxazone in plasma. Precision, accuracy, recovery, matrix effect and stability for chlorzoxazone were evaluated and were excellent within the range of tested concentrations. This method was successfully applied to a bioequivalence study in 20 healthy Chinese volunteers. This method could also contribute to the personalized medication and therapeutic drug monitoring of chlorzoxazone.
Assuntos
Clorzoxazona/sangue , Clorzoxazona/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Adulto , Monitoramento de Medicamentos , Humanos , Equivalência Terapêutica , Adulto JovemRESUMO
OBJECTIVES: The present study was designed to assess the pharmacokinetic and pharmacodynamic performance of inhaled recombinant human insulin (rh-insulin) dry powders together with their safety profiles after 14-day inhalation. METHODS: In the pharmacokinetic and pharmacodynamic study, pulmonary surfactant (PS)-loaded and phospholipid hexadecanol tyloxapol (PHT)-loaded rh-insulin dry powders were intratracheally administered to male rats at the dose of 20 U/kg. Novolin R was used as control. Serum glucose and rh-insulin concentrations were determined by glucose oxidase method and human rh-insulin CLIA kit, respectively. For the safety study, rats were exposed to rh-insulin dry powders or air for 14-day by nose-only inhalation chambers. Bronchoalveolar lavage and histopathology examinations were performed after inhalation. KEY FINDINGS: There were no significant differences in the major pharmacokinetic and pharmacodynamic parameters between PS-loaded and PHT-loaded rh-insulin dry powders. The relative bioavailabilities and pharmacodynamic availabilities were 39.9%, 25.6% for PS-loaded dry powders and 30.1%, 23% for PHT-loaded dry powders, respectively. Total protein was the only injury marker that was significantly altered. Histopathology examinations showed the ranking of irritations (from slight to severe) were PHT-loaded rh-insulin, negative air control and PS-loaded rh-insulin. CONCLUSIONS: Both PS- and PHT-loaded rh-insulin dry powders were able to deliver rh-insulin systemically with appropriate pharmacokinetic, pharmacodynamic and safety profiles.
Assuntos
Inaladores de Pó Seco , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Administração por Inalação , Animais , Disponibilidade Biológica , Glicemia/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Insulina/farmacocinética , Insulina/farmacologia , Masculino , Polietilenoglicóis/química , Pós , Ratos , Ratos Sprague-Dawley , Proteínas RecombinantesRESUMO
PURPOSE: A three-period digoxin-bupropion drug-drug interaction study was performed in cynomolgus monkeys to assess the effect of bupropion and its metabolites on digoxin disposition. METHODS: Monkeys were administered either an i.v. infusion (0.1 mg/kg) or an oral dose of digoxin (0.2 mg/kg) as control. In single-dosing period, monkeys received an i.v. infusion of bupropion at 1.5 mg/kg together with an infusion or oral dosing of digoxin, respectively. During multiple-dosing period, bupropion was orally administered q.d. at 7.72 mg/kg for 12-day. Then it was co-administered with an i.v. infusion or oral dosing of digoxin, respectively. Renal expression of OATP4C1 and P-gp was examined. RESULTS: Bupropion significantly increased i.v. digoxin CLrenal0-48h by 1 fold in single-dosing period. But it had no effect on the systemic disposition of digoxin. In multiple-dosing period, bupropion significantly increased oral digoxin CLrenal0-48h, CLtotal0-48h, CLnon-renal0-48h and decreased its plasma exposure. Bupropion and its metabolites did not alter creatinine clearance. OATP4C1 was located at the basolateral membrane of proximal tubule cells, while P-gp was on the apical membrane. CONCLUSIONS: The effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48h contributed to the decrease in AUC of digoxin in some extent, but certainly is not the major driving force. The lack of systemic exposure after a single dose but a significant decrease in exposure mediated by an increase in the digoxin CLnon-renal0-48h with repeated dosing is likely to be the more clinically relevant.
Assuntos
Bupropiona/farmacocinética , Digoxina/farmacocinética , Administração Oral , Animais , Bupropiona/administração & dosagem , Bupropiona/efeitos adversos , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Macaca fascicularis , Metaboloma , Metabolômica , Distribuição TecidualRESUMO
1. ß-caryophyllene alcohol (BCPA) has shown therapeutic promise in the treatment of asthma and inflammation with low toxicity. The aim of the current study was to report the pharmacokinetic profiles of BCPA in rats and dogs. 2. Following intravenous administration, BCPA exhibited moderate volumes of distribution (Vz) ranging from 5.63 to 8.97 L/kg in rats and low Vz (2.89 ± 1.12 L/kg) in dogs. Systemic plasma clearance was high in both species, resulting in a short elimination half-life ranging from 29.6 to 48.3 min. In rats, the intravenous pharmacokinetics was dose dependent. The measured oral bioavailability was low in rats for BCPA solution (1.17 ± 0.78%), suspension (1.21 ± 0.33%) and PEG formulation (6.22 ± 2.63%). The bioavailability was lower in dogs for BCPA solution (0.12 ± 0.05%) and PEG formulation (0.25 ± 0.07%), indicating significant species difference. However, treatment of plasma samples with ß-glucuronidase increased the systematic exposure of BCPA as assessed from AUC (0-∞) by 24.7- or 2.62-fold in rats and dogs, respectively, which suggested glucuronidation was a significant metabolic pathway for BCPA possibly due to first-pass metabolism. 3. In summary, this was the first preclinical pharmacokinetic investigation of BCPA in animals, providing vital knowledge for further preclinical research and subsequent clinical trials.
Assuntos
Sesquiterpenos/farmacologia , Sesquiterpenos/farmacocinética , Animais , Cães , Feminino , Masculino , Sesquiterpenos Policíclicos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Common genetic polymorphisms at chromosome 4q25 were associated with increased susceptibility to atrial fibrillation (AF). However, it remained controversial whether these variants could be used as risk predictors for AF recurrence after catheter ablation. We therefore performed a metaanalysis to quantify the association between rs2200733 C>T/rs10033464 G>T and AF recurrence. METHODS: Relevant studies were systematically retrieved from PubMed, Web of Science, Elsevier database and Cochrane library through November 2016. Data were abstracted and pooled using Stata 12.0 software. RESULTS: A total of 2,145 patients undergoing catheter ablation were included. Patients with rs2200733 TT or TT+CT showed an overall increased susceptibility to AF recurrence (homozygous model [TT vs. CC]: odds ratio [OR] = 2.03, 95% confidence interval [CI] 1.49-2.76, p = 0.000; dominant model [TT+TC vs. CC]: OR = 1.48, 95% CI 1.17-1.87, p = 0.001; recessive model [TT vs. TC+CC]: OR = 1.88, 95% CI 1.12-3.15, p = 0.017). Subgroup analysis also identified a positive relation in Caucasians and late recurrence of AF in allelic, homozygous and dominant comparison. Moreover, a significant increased risk of AF recurrence was observed in patients with rs10033464 TG or TT+TG (heterozygous model [TG vs. GG]: OR = 1.46, 95% CI 1.01-2.12, p = 0.047; dominant model [TT+TG vs. GG]: OR = 1.51, 95% CI 1.04-2.17, p = 0.029). CONCLUSIONS: After catheter ablation, rs2200733 (TT or TT+TC) and rs10033464 (TT+TG or TG) were associated with increased risk of AF recurrence.
Assuntos
Fibrilação Atrial , Ablação por Cateter/efeitos adversos , Cromossomos Humanos Par 4/genética , DNA/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Alelos , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/cirurgia , Genótipo , Humanos , Período Pós-Operatório , Recidiva , Fatores de RiscoRESUMO
Propofol is a sedative-hypnotic agent used as a general anaesthetic with a good safety profile. However, the potential risk for patients with systemic lupuserythematosus (SLE) receiving propofol remains unclear. We report the case of a patient who received an intravenous infusion of propofol for painless gastroscopy which exacerbated acute SLE despite no history of allergies. The adverse effect might be because propofol increased T helper cells and trigged the induction of B cell differentiation and plasmablast formation, which further promoted the secretion of auto-antibodies. This case shows that propofol can exacerbate SLE symptoms in some patients and highlights the importance of identifying potential immune-related factors before propofol administration, especially in patients with autoimmune diseases. It is important to be aware of and differentiate this uncommon and non-specific SLE manifestation from a myriad of disorders presenting with a primary digestive disorder in the outpatient clinic.
RESUMO
Multidrug resistance protein 2 (Mdr2), encoded by ATP-binding cassette b4 (Abcb4), serves as a phospholipid flippase that is indispensable for phosphatidylcholine translocation. However, little was known about the regulation of Mdr2 in Sprague-Dawley rats, although they are commonly used for pre-clinical investigation as well as mechanistic study. Present study aims at determining the tissue distribution, gender difference and ontogeny of Mdr2 in rats on both gene and protein levels. Results showed that Mdr2 was highly expressed in liver, modestly enriched in brain and testis, and less distributed in gastrointestinal tracts. Gender-divergent and male-dominated distribution was observed in the Mdr2 mRNA expression of liver and generative organs. Developmental pattern of rat Mdr2 on protein level was not exactly consistent with that on mRNA level. In conclusion, there was a considerable distribution of rat Mdr2 in the brain, testis and intestine besides liver, and the ontogeny of Mdr2 performed in an age-dependent pattern with the post-transcriptional regulation.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Encéfalo/metabolismo , Fígado/metabolismo , Fosfatidilcolinas/metabolismo , Testículo/metabolismo , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/fisiologiaRESUMO
An enantioselective high-performance liquid chromatography method was developed and validated for the determination of oxiracetam enantiomers, a cognition and memory enhancer, in beagle dog plasma. The plasma samples were prepared by methanol extraction from 200µL plasma, and then the baseline resolution was achieved on a Chiralpak ID column (250mm×4.6mm, 5µm) with mobile phase of hexane-ethanol-trifluoroacetic acid (78:22:0.1, v/v/v) at flow rate of 1.0mL/min. The column elute was monitored using ultraviolet detection at 214nm. The method was linear over concentration range 0.50-100µg/mL for both enantiomers. The relative standard deviation values for intra- and inter-day precision were 0.78-13.61 and 0.74-8.92% for (R)- and (S)-oxiracetam, respectively. The relative error values of accuracy ranged from -4.74 to 10.48% for (R)-oxiracetam and from -0.19 to 11.48% for (S)-oxiracetam. The method was successfully applied to a pharmacokinetic study of individual enantiomer and racemic oxiracetam in beagle dogs after oral administration. The disposition of the two enantiomers was not stereoselective and chiral inversion was not observed in beagle dogs. The pharmacokinetic profiles of (S)-oxiracetam were similar with racemic oxiracetam in beagle dogs.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Nootrópicos/sangue , Nootrópicos/química , Pirrolidinas/sangue , Pirrolidinas/química , Animais , Cães , Estabilidade de Medicamentos , Nootrópicos/farmacocinética , Pirrolidinas/farmacocinética , EstereoisomerismoRESUMO
Oxiracetam (ORC), a nootropic drug used for improving the cognition and memory, has an asymmetric carbon in its structure and exists as (S)- and (R)-ORC. The pharmacokinetic profiles of racemic oxiracetam and its pure enantiomers in rats were evaluated and compared by enantioselective high-performance liquid chromatography, which was performed on a Chiralpak ID column with a mobile phase of hexane-ethanol-trifluoroacetic acid (78:22:0.1, v/v/v). The method was validated with respect to selectivity, linearity, accuracy and precision, stability and the limit of quantification. The validation acceptance criteria were met in all cases. A saturating phenomenon of (S)-ORC was observed when the dosage ranged from 200 mg/kg to 800 mg/kg. The two enantiomers showed similar profiles in the absorb phase, and reached the maximum concentration at 2h after oral administration. However, compared with the racemate group, the AUC/dose and Cmax/dose ratios of (S)-ORC were higher and Cl/f was lower in enanpure (S)-ORC group. The Cmax of (S)-ORC decreased from 21.3 ± 5.0 µg/ml to 13.2 ± 4.2 when (R)-ORC was co-administrated at the dose of 200mg/kg. AUC0-t values of (S)-ORC were different after oral administration of 200 mg/kg (S)-ORC and 400 mg/kg racemic ORC (96.7 ± 15.5 and 50.1 ± 16.3 µg h/ml). The higher absorption and slower elimination suggest that enantiopure (S)-ORC could be a promising drug that efficiently reduces clinical dosage, improves therapeutic indices, decreases toxicology risks, and results in increased therapeutic ration.
Assuntos
Pirrolidinas/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão/métodos , Ratos , Ratos Sprague-Dawley , EstereoisomerismoRESUMO
UNLABELLED: A novel positron emission tomography (PET) tracer, [(11)C]-rosuvastatin (RSV), was developed to dynamically and noninvasively measure hepatobiliary transport and tissue distribution of [(11)C]-RSV in rats. METHODS: Male Sprague-Dawley rats were administered either an Oatp inhibitor, rifampin (RIF, 40 mg/kg iv bolus plus 1.85 mg/min/kg iv infusion, n = 3), or the corresponding vehicle (saline, n = 3) for at least 90 min. Then, while these infusions were ongoing, the animals received [(11)C]-rosuvastatin (â¼1 mCi/30 s, iv infusion). After [(11)C]-RSV administration, the lower abdominal region of the rats was imaged for 90 min. Time-activity curves for liver, intestine, and kidney were obtained and corrected for vascular content prior to noncompartmental and compartmental (five-compartment model) analysis. RESULTS: The majority of the [(11)C]-RSV dose was distributed into the liver. In the presence of RIF, the area under the [(11)C]-RSV radioactivity blood concentration-time profile (AUC0-90 min) was increased by â¼3-fold. Relative to the control animals, RIF reduced the distribution of [(11)C]-RSV radioactivity into the liver and kidney (tissue AUC0-15 min/blood AUC0-15 min) by 54% and 73% respectively. Compartmental modeling showed that RIF decreased CLBL, CLLI, CLBK, and CLK0 but had no effect on CLLB, where B, L, I, K, and 0 represent blood, liver, intestine, kidney, and irreversible loss. CONCLUSION: [(11)C]-RSV can be used to dynamically and noninvasively quantify hepatobiliary transport and hepatic concentration of the drug, in the absence and presence of drug interactions, in rats and could be used for the same purpose in humans.
Assuntos
Ductos Biliares/efeitos dos fármacos , Fluorbenzenos/farmacocinética , Fígado/efeitos dos fármacos , Transportadores de Ânions Orgânicos/metabolismo , Tomografia por Emissão de Pósitrons , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Animais , Área Sob a Curva , Bile/metabolismo , Ductos Biliares/diagnóstico por imagem , Transporte Biológico , Hepatócitos/efeitos dos fármacos , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Fígado/diagnóstico por imagem , Masculino , Ratos , Ratos Sprague-Dawley , Rosuvastatina Cálcica , Fatores de Tempo , Distribuição TecidualRESUMO
An unusual, but clinically significant, digoxin (DIG)-bupropion (BUP) drug interaction (DDI), in which BUP increased DIG renal clearance by 80% is reported. To investigate the mechanism(s) of this unusual DDI, first the effect of BUP, its circulating metabolites or their combination on [(3) H]-DIG transport by cells expressing human P-gp or human OATP4C1 was determined. Second, the study asked whether this DDI could be replicated in the rat so that it could be used to conduct mechanistic studies. Then, the effect of BUP and its rat metabolites on [(3) H]-DIG transport were tested by cells expressing rat Oatp4c1. Bupropion and its metabolites had no effect on human P-gp mediated transepithelial transport of [(3) H]-DIG. Bupropion and hydroxybupropion (HBUP) significantly stimulated H-OATP4C1 mediated transport of [(3) H]-DIG. In addition, BUP cocktail (BUP plus its metabolites) significantly increased the H-OATP4C1 mediated transport of [(3) H]-DIG, and partially reversed the inhibition by 100 µm DIG. However, erythro-hydrobupropion (EBUP) and threo-hydrobupropion (TBUP) did not affect the [(3) H]-DIG uptake by H-OATP4C1 cells. Bupropion administration significantly increased digoxin renal clearance in rats. Surprisingly, bupropion significantly inhibited r-Oatp4c1 mediated transport of [(3) H]-DIG at clinically relevant unbound plasma concentrations of BUP or those observed in the rat study, while HBUP or TBUP did not. These data support our hypothesis that at clinically relevant plasma concentrations, bupropion and its metabolites activate H-OATP4C1 mediated DIG tubular secretion, and could possibly explain the increase in digoxin renal clearance produced by bupropion. While bupropion increased digoxin renal clearance in the rat, it appeared to do so by inhibiting r-Oatp4c1-mediated digoxin renal reabsorption.