RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: With the features of multiple-components and targets as well as multifunction, traditional Chinese medicine (TCM) has been widely used in the prevention and treatment of various diseases for a long time. During the application of TCM, the researches about bioavailability enhancement of the bioactive constituents in formula are flourishing. Bushen-Yizhi formula (BSYZ), a TCM prescription with osthole (OST) as one of the main bioactive ingredients, have been widely used to treat kidney deficiency, mental retardation and Alzheimer's disease. However, the underlying biological mechanism and compound-enzyme interaction mediated bioavailability enhancement of OST are still not clearly illuminated. AIM OF THE STUDY: The aim of this study is to explore the material basis and molecular mechanism from BSYZ in the bioavailability enhancement of OST. Screening the potential CYP3A4 inhibitors using theoretical prediction and then verifying them in vitro, and pharmacokinetics study of OST in rat plasma under co-administrated of screened CYP3A4 inhibitors and BSYZ were also scarcely reported. MATERIALS AND METHODS: Screening of CYP3A4 inhibitors from BSYZ was performed with molecular docking simulation from systems pharmacology database. The screened compounds were verified by using P450-Glo Screening Systems. A multiple reaction monitoring (MRM) mass spectrometry method was established for OST quantification. Male Sprague-Dawley rats divided into four groups and six rats in each group were employed in the pharmacokinetics study of OST. The administrated conditions were group I, OST (20 mg/kg); group II, BSYZ (containing OST 1 mg/mL, at the dose of 20 mg/kg OST in BSYZ); group III, co-administration of ketoconazole (Ket, 75 mg/kg) and OST (20 mg/kg); group IV, co-administration of CYP3A4 inhibitor (10 mg/kg) and OST (20 mg/kg). They were determined by using HPLC-MS/MS (MRM) and statistical analysis was performed using student's t-test with p < 0.05 as the level of significance. RESULTS: 21 potential CYP3A4 inhibitors were screened from BSYZ compounds library. From the results of verification in vitro, we found 4 compounds with better CYP3A4 inhibition efficiency including Oleic acid, 1,2,3,4,6-O-Pentagalloylglucose, Rutin, and Schisantherin B. Under further verification, Schisantherin B exhibited the best inhibitory effect on CYP3A4 (IC50 = 0.339 µM), and even better than the clinically used drug (Ket) at the concentration of 5 µM. In the study of pharmacokinetics, the area under the curve (AUC, ng/L*h) of OST after oral administration of BSYZ, Ket and Schisantherin B (2196.23 ± 581.33, 462.90 ± 92.30 and 1053.03 ± 263.62, respectively) were significantly higher than that of pure OST treatment (227.89 ± 107.90, p < 0.01). CONCLUSIONS: Schisantherin B, a profoundly effective CYP3A4 inhibitor screened from BSYZ antagonized the metabolism of CYP3A4 on OST via activity inhibition, therefore significantly enhanced the bioavailability of OST in rat plasma. The results of this study will be helpful to explain the rationality of the compatibility in TCM formula, and also to develop new TCM formula with more reasonable drug compatibility.
Asunto(s)
Cumarinas/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A/metabolismo , Medicamentos Herbarios Chinos/química , Animales , Antifúngicos/administración & dosificación , Antifúngicos/farmacocinética , Disponibilidad Biológica , Cumarinas/administración & dosificación , Cumarinas/sangre , Ciclooctanos/administración & dosificación , Ciclooctanos/farmacocinética , Dioxoles/administración & dosificación , Dioxoles/farmacocinética , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Interacciones de Hierba-Droga , Cetoconazol/administración & dosificación , Cetoconazol/farmacocinética , Lignanos/administración & dosificación , Lignanos/farmacocinética , Masculino , Compuestos Policíclicos/administración & dosificación , Compuestos Policíclicos/farmacocinética , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Due to poor targeting ability of anti-tumor drugs and self-adaptation of tumors, the chemotherapy of ovarian cancer is still poorly effective. In recent years, the treatment of tumor with nano-targeted agents has become a potential research focus. In this study, a new type of short cell-penetrating peptide RPV-modified paclitaxel plus schisandrin B liposomes were constructed to disrupt VM channels, angiogenesis, proliferation and migration for the treatment of ovarian cancer. MATERIALS AND METHODS: In this study, clone assay, TUNEL, Transwell, wound-healing, CAM and mimics assay were used to detect the effects of RPV-modified liposomes on ovarian cancer SK-OV-3 cells before and after treatment. HE-staining, immunofluorescence and ELISA were used to further detect the expression of tumor-related proteins. KEY FINDINGS: RPV-modified paclitaxel plus schisandrin B liposomes can inhibit angiogenesis, VM channel formation, invasion and proliferation of ovarian SK-OV-3 cells. In vitro and in vivo studies showed that tumor-related protein expression was down-regulated. Modification of RPV can prolong the retention time of liposome in vivo and accumulate in the tumor site, increasing the anti-tumor efficacy. SIGNIFICANCE: The RPV-modified paclitaxel plus schisandrin B liposomes have good anti-tumor effect, thus may provide a new avenue for the treatment of ovarian cancer.
Asunto(s)
Antineoplásicos/administración & dosificación , Péptidos de Penetración Celular , Lignanos/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/administración & dosificación , Compuestos Policíclicos/administración & dosificación , Animales , Antineoplásicos/química , Línea Celular Tumoral , Ciclooctanos/administración & dosificación , Ciclooctanos/química , Femenino , Humanos , Lignanos/química , Liposomas , Ratones , Ratones Endogámicos BALB C , Paclitaxel/química , Compuestos Policíclicos/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Developing novel activatable photosensitizers with excellent plasma membrane targeting ability is urgently needed for smart photodynamic therapy (PDT). Herein, a tumor acidity-activatable photosensitizer combined with a two-step bioorthogonal pretargeting strategy to anchor photosensitizers on the plasma membrane for effective PDT is developed. Briefly, artificial receptors are first anchored on the cell plasma membrane using cell-labeling agents (Az-NPs) via the enhanced permeability and retention effect to achieve the tumor cell labeling. Then, pH-sensitive nanoparticles (S-NPs) modified with dibenzocyclooctyne (DBCO) and chlorin e6 (Ce6) accumulate in tumor tissue and disassemble upon protonation of their tertiary amines in response to the acidic tumor environment, exposing the contained DBCO and Ce6. The selective, highly specific click reactions between DBCO and azide groups enable Ce6 to be anchored on the tumor cell surface. Upon laser irradiation, the cell membrane is severely damaged by the cytotoxic reactive oxygen species, resulting in remarkable cellular apoptosis. Taken together, the membrane-localized PDT by our bioorthogonal pretargeting strategy to anchor activatable photosensitizers on the plasma membrane provides a simple but effective method for enhancing the therapeutic efficacy of photosensitizers in anticancer therapy.
Asunto(s)
Membrana Celular/metabolismo , Ciclooctanos/administración & dosificación , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Animales , Línea Celular Tumoral , Clorofilidas , Ciclooctanos/farmacocinética , Ciclooctanos/uso terapéutico , Humanos , Ratones , Nanopartículas/administración & dosificación , Nanopartículas/uso terapéutico , Neoplasias/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacocinética , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/farmacocinética , Porfirinas/uso terapéutico , Receptores Artificiales/metabolismoRESUMEN
Cefepime/zidebactam is in clinical development for the treatment of carbapenem-resistant Gram-negative infections. MICs of cefepime/zidebactam (1:1) and comparators against Enterobacterales (n = 563), Pseudomonas (n = 172) and Acinetobacter baumannii (n =181) collected from 15 Greek hospitals (2014-2018) were determined by reference broth microdilution method. The isolates exhibited high carbapenem resistance rates [(Enterobacterales (75%), Pseudomonas (75%) and A. baumannii (98.3%)]. Cefepime/zidebactam showed MIC50/90 of 0.5/2 mg/L, against Enterobacterales including metallo-ß-lactamases (MBL)-producers. Reduced susceptibility rates to tigecycline (16.8%), colistin (47.4%), ceftazidime/avibactam (59.8%), and imipenem/relebactam (61%) indicated high prevalence of multi-drug resistance among Greek Enterobacterales. Cefepime/zidebactam exhibited MIC50/90 of 8/16 mg/L against Pseudomonas including MBL-producers. The MIC50/90 of ceftazidime/avibactam and imipenem/relebactam were high (≥32 mg/L). Cefepime/zidebactam showed MIC90 of 64 mg/L against A. baumannii which is within its therapeutic scope. Other antibiotics including colistin showed limited activity against A. baumannii. The activity of cefepime/zidebactam against multi-drug-resistant isolates is attributable to zidebactam mediated novel ß-lactam-enhancer mechanism.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Cefepima/farmacología , Cefalosporinas/farmacología , Ciclooctanos/farmacología , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas/efectos de los fármacos , Piperidinas/farmacología , Antibacterianos/farmacología , Compuestos de Azabiciclo/administración & dosificación , Cefepima/administración & dosificación , Ciclooctanos/administración & dosificación , Grecia , Hospitales , Humanos , Pruebas de Sensibilidad Microbiana , Piperidinas/administración & dosificaciónRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Recently, a new drug combination GRS comprising ginsenoside Rb1 (G-Rb1), ruscogenin (R-Rus) and schisandrin (S-SA) was screened based on ShengMai preparations, which exhibited a prominent cardioprotective effects against myocardial ischemia/reperfusion (MI/R) injury. AIM OF THE STUDY: To investigate their systemic and individual mechanism of each compound in combination GRS. MATERIALS AND METHODS: The mice model of MI/R and hypoxia/reoxygenation (H/R)-induced cardiomyocytes injury were performed to explore the respective characteristics of each compound in GRS against myocardial injury. RESULTS: Each component in the combination GRS attenuated MI/R injury as evidenced by decreased myocardial infarct size, ameliorated histological features, and improved biochemical indicators. Meanwhile, ingredient G, R and S in combination also individually performed a significant decrease of apoptotic index in MI/R mice and H/R-induced cardiomyocytes injury. Mechanistically, component G in GRS could markedly increase the ATP content in cardiomyocytes through activation of AMPKα phosphorylation. Interestingly, the anti-apoptotic actions of G were profoundly attenuated by knockdown of AMPKα, while no alteration was observed on composition R and S. Moreover, component R in GRS significantly reduced the IL-6 and TNF-α mRNA expression, as well as the content of IL-6 via the modulation of NF-κB signaling pathway. Further, component S exhibited the most powerful anti-oxidative capacity in GRS and remarkably decreased the production of MDA and ROS, and potential mechanisms might at least in part through activating the Akt-14-3-3 signaling pathway and inhibiting the phosphorylation of Bad and ERK1/2. CONCLUSIONS: Our results indicated that the respective mechanism of each compound in combination GRS against MI/R injury might closely associated with energy metabolism modulation, suppression of inflammation and oxidative stress.
Asunto(s)
Ciclooctanos/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Ginsenósidos/administración & dosificación , Lignanos/administración & dosificación , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Compuestos Policíclicos/administración & dosificación , Espirostanos/administración & dosificación , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Ciclooctanos/aislamiento & purificación , Combinación de Medicamentos , Medicamentos Herbarios Chinos/aislamiento & purificación , Ginsenósidos/aislamiento & purificación , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Lignanos/aislamiento & purificación , Masculino , Ratones , Ratones Endogámicos ICR , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Compuestos Policíclicos/aislamiento & purificación , Ratas , Espirostanos/aislamiento & purificación , Resultado del TratamientoRESUMEN
It has been established that poor outcomes in ischemic stroke patients are associated with the post-reperfusion inflammatory response and up-regulation of TLR4. Therefore, suppression of the TLR4 signaling pathway constitutes a potential neuroprotective therapeutic strategy. Schisandrin B, a compound extracted from Schisandra chinensis, has been shown to possess anti-inflammatory and neuroprotective properties. However, the mechanism remains unclear. In the present study, the therapeutic effect of schisandrin B was assessed following cerebral ischemia and reperfusion (I/R) injury in a model of middle cerebral artery occlusion and reperfusion (MCAO/R) in rats. The effects of schisandrin B were investigated with particular emphasis on TLR4 signal transduction and on the inflammatory response. Schisandrin B treatment conferred significant protection against MCAO/R injury, as evidenced by decreases in infarct volume, neurological score, and the number of apoptotic neurons and inflammatory signaling molecules. ABBREVIATIONS: I/R: schemia/reperfusion; IL: interleukin; MCAO/R: middle cerebral artery occlusion and reperfusion; NF-κB: nuclear; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor-α.
Asunto(s)
Antiinflamatorios/administración & dosificación , Isquemia Encefálica/metabolismo , Lignanos/administración & dosificación , Compuestos Policíclicos/administración & dosificación , Daño por Reperfusión/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Isquemia Encefálica/complicaciones , Isquemia Encefálica/prevención & control , Ciclooctanos/administración & dosificación , Masculino , FN-kappa B/metabolismo , Ratas Sprague-Dawley , Daño por Reperfusión/complicaciones , Daño por Reperfusión/prevención & control , Receptor Toll-Like 4/metabolismoRESUMEN
Abstract: Currently, Angiostrongylus cantonensis infections are predominantly treated with albendazole. However, the use of albendazole can provoke certain neurological symptoms as a result of the immune response triggered by the dead worms. Therefore, treatment usually involves co-administration of corticosteroids to limit the inflammatory reaction. Corticosteroids play a useful role in suppressing inflammation in the brain; however, long-term usage or high dosage may make it problematic.Schisandrin B, an active ingredient from Schisandra chinensis, has been shown to have anti-inflammatory effects on the brain. This study aimed to investigate the effects and potential of schisandrin B in combination with albendazole to treat Angiostrongylus-induced meningoencephalitis. Here, we show that albendazole-schisandrin B co-treatment suppressed neuroinflammation in Angiostrongylus-infected mice and increased the survival of the mice. Accordingly, albendazole-schisandrin B co-treatment significantly inhibited inflammasome activation, pyroptosis, and apoptosis. The sensorimotor functions of the mice were also repaired after albendazole-schisandrin B treatment. Immune response was shown to shift from Th2 to Th1, which reduces inflammation and enhances immunity against A. cantonensis. Collectively, our study showed that albendazole-schisandrin B co-therapy may be used as an encouraging treatment for Angiostrongylus-induced meningoencephalitis.
Asunto(s)
Albendazol/administración & dosificación , Angiostrongylus cantonensis/parasitología , Lignanos/administración & dosificación , Meningoencefalitis/tratamiento farmacológico , Compuestos Policíclicos/administración & dosificación , Infecciones por Strongylida/tratamiento farmacológico , Albendazol/farmacología , Angiostrongylus cantonensis/efectos de los fármacos , Animales , Apoptosis , Ciclooctanos/administración & dosificación , Ciclooctanos/farmacología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Inflamasomas/efectos de los fármacos , Lignanos/farmacología , Meningoencefalitis/genética , Meningoencefalitis/parasitología , Ratones , Ratones Endogámicos BALB C , Compuestos Policíclicos/farmacología , Piroptosis , Infecciones por Strongylida/genética , Análisis de Supervivencia , Células TH1/metabolismo , Células Th2/metabolismoRESUMEN
Muscle wasting is caused by various factors, such as aging, cancer, diabetes, and chronic kidney disease, and significantly decreases the quality of life. However, therapeutic interventions for muscle atrophy have not yet been well-developed. In this study, we investigated the effects of schisandrin A (SNA), a component extracted from the fruits of Schisandra chinensis, on dexamethasone (DEX)-induced muscle atrophy in mice and studied the underlying mechanisms. DEX+SNA-treated mice had significantly increased grip strength, muscle weight, and muscle fiber size compared with DEX+vehicle-treated mice. In addition, SNA treatment significantly reduced the expression of muscle degradation factors such as myostatin, MAFbx (atrogin1), and muscle RING-finger protein-1 (MuRF1) and enhanced the expression of myosin heavy chain (MyHC) compared to the vehicle. In vitro studies using differentiated C2C12 myotubes also showed that SNA treatment decreased the expression of muscle degradation factors induced by dexamethasone and increased protein synthesis and expression of MyHCs by regulation of Akt/FoxO and Akt/70S6K pathways, respectively. These results suggest that SNA reduces protein degradation and increases protein synthesis in the muscle, contributing to the amelioration of dexamethasone-induced muscle atrophy and may be a potential candidate for the prevention and treatment of muscle atrophy.
Asunto(s)
Ciclooctanos/farmacología , Ciclooctanos/uso terapéutico , Dexametasona/efectos adversos , Expresión Génica/efectos de los fármacos , Lignanos/farmacología , Lignanos/uso terapéutico , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/prevención & control , Fitoterapia , Compuestos Policíclicos/farmacología , Compuestos Policíclicos/uso terapéutico , Schisandra/química , Animales , Células Cultivadas , Ciclooctanos/administración & dosificación , Ciclooctanos/aislamiento & purificación , Lignanos/administración & dosificación , Lignanos/aislamiento & purificación , Masculino , Ratones Endogámicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Atrofia Muscular/inducido químicamente , Atrofia Muscular/fisiopatología , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Miostatina/genética , Miostatina/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Compuestos Policíclicos/administración & dosificación , Compuestos Policíclicos/aislamiento & purificación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The design of multiple stimuli-responsive, stable polymeric drug carriers is key for efficient drug release against solid tumors. Herein, core-crosslinked micelles were readily prepared from a pair of redox/pH-sensitive clickable copolymers. The two copolymers comprised the same poly(ethylene glycol) (PEG)-poly(ε-benzyloxycarbonyl-l-lysine) (PZLL) block but with either disulfide-linked azadibenzocyclooctyne (DBCO) or azide (AZ) group-tagged branched polyethylenimine (BPEI, 1.8 kDa). The data showed that an equivalent of the two copolymers could self-assemble into nanosized micelles with the crosslinked core via the DBCO-AZ click chemistry. The click-crosslinked micelles showed excellent size stability under multiple dilutions but destabilization in an acidic or reductive environment. Besides, they could load doxorubicin (DOX), an anticancer drug, and mediate slow drug release in a neutral environment but sufficient drug unloading under acidic plus reductive conditions. In vitro, DOX-loaded crosslinked micelles led to higher DOX accumulation in the cellular nucleus in comparison with non-crosslinked micelles from the PEG-PZLL-BPEI copolymer (PP), thus causing more marked cytotoxicity in SKOV-3 cells. In vivo, DOX-loaded crosslinked micelles caused significant growth inhibition of SKOV-3 tumors xenografted in BALB/c nude mice, and showed superior anticancer efficacy to non-crosslinked PP micelles. Chemotherapy with core-crosslinked micelles had no adverse side effects on the health (serum levels and body weight) of the mice. This study highlights the design of clickable block copolymers to easily construct core-crosslinked and multiple stimuli-responsive micelles for enhanced anticancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Compuestos Aza/administración & dosificación , Azidas/administración & dosificación , Ciclooctanos/administración & dosificación , Doxorrubicina/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Compuestos Aza/química , Compuestos Aza/farmacocinética , Azidas/química , Azidas/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclooctanos/química , Ciclooctanos/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Liberación de Fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Neoplasias/tratamiento farmacológico , Polímeros/administración & dosificación , Polímeros/química , Polímeros/farmacocinética , Distribución TisularRESUMEN
As a malignant tumor, breast cancer is very prone to metastasis. Chemotherapy is one of the most common means for treating breast cancer. However, due to the serious metastasis and the poor targeting effect of traditional chemotherapeutic drugs, even after years of efforts, the therapeutic effect is still unsatisfied. Therefore, in this study, we constructed a kind of PFV modified epirubicin plus schisandrin B liposomes to solve the above disadvantages. In vitro experiments showed that the targeting liposomes with ideal physicochemical property could increase the cytotoxicity of MDA-MB-435S cells, destroy the formation of vasculogenic mimicry (VM), and inhibit tumor invasion and migration. Action mechanisms indicated that the inhibition of targeting liposomes on tumor metastasis was attributed to the regulation of the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), vimentin (VIM), and E-cadherin (E-cad). In vivo pharmacodynamic experiments showed that the targeting liposomes could significantly improve the antitumor effect in mice. H&E staining and TUNEL results showed that the targeting liposomes could promote the apoptosis of tumor cells. Hence, the PFV modified epirubicin plus schisandrin B liposomes constructed in this study provided a new therapeutic strategy for breast cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Epirrubicina/administración & dosificación , Lignanos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Policíclicos/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Embrión de Pollo , Membrana Corioalantoides , Ciclooctanos/administración & dosificación , Femenino , Humanos , Liposomas , Neoplasias Pulmonares/secundario , Ratones , Invasividad Neoplásica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Antibiotic-tolerant persister bacteria involve frequent treatment failures, relapsing infections and the need for extended antibiotic treatment. The virulence of an intracellular human pathogen C. pneumoniae is tightly linked to its propensity for persistence and means for its chemosensitization are urgently needed. In the current work, persistence of C. pneumoniae clinical isolate CV6 was studied in THP-1 macrophages using quantitative PCR and quantitative culture. A dibenzocyclooctadiene lignan schisandrin reverted C. pneumoniae persistence and promoted productive infection. The concomitant administration of schisandrin and azithromycin resulted in significantly improved bacterial eradication compared to sole azithromycin treatment. In addition, the closely related lignan schisandrin C was superior to azithromycin in eradicating the C. pneumoniae infection from the macrophages. The observed chemosensitization of C. pneumoniae was associated with the suppression of cellular glutathione pools by the lignans, implying to a previously unknown aspect of chlamydia-host interactions. These data indicate that schisandrin lignans induce a phenotypic switch in C. pneumoniae, promoting the productive and antibiotic-susceptible phenotype instead of persistence. By this means, these medicinal plant -derived compounds show potential as adjuvant therapies for intracellular bacteria resuscitation.
Asunto(s)
Bioensayo/métodos , Chlamydophila pneumoniae/fisiología , Ciclooctanos/farmacología , Lignanos/farmacología , Macrófagos/microbiología , Azitromicina/administración & dosificación , Azitromicina/farmacología , Chlamydophila pneumoniae/efectos de los fármacos , Chlamydophila pneumoniae/crecimiento & desarrollo , Ciclooctanos/administración & dosificación , Ciclooctanos/química , Glutatión/metabolismo , Humanos , Cinética , Lignanos/administración & dosificación , Lignanos/química , Macrófagos/efectos de los fármacos , Oxidación-Reducción , Fenotipo , Compuestos Policíclicos/administración & dosificación , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Células THP-1RESUMEN
Schisandrin A (Sch A) is one of the principal bioactive lignans isolated from Fructus schisandrae. In this study, we demonstrated its protective effect and biochemical mechanism of action in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson's disease. Sch A significantly ameliorated behavioural abnormalities and increased the number of nigral dopaminergic neurons detected by tyrosine hydroxylase immunohistochemistry. Pre-treatment with Sch A significantly decreased the levels of the inflammatory mediators IL-6, IL-1ß, and TNF-α and markedly improved antioxidant defences by inhibiting the activity of MDA and increasing that of SOD. Furthermore, Sch A activated expression of the autophagy-related proteins LC3-II, beclin1, parkin, and PINK1 and increased mTOR expression. Taken together, these findings indicate that Sch A has neuroprotective effects against the development of Parkinson's disease via regulation of brain autophagy.
Asunto(s)
Autofagia/efectos de los fármacos , Ciclooctanos/administración & dosificación , Lignanos/administración & dosificación , Intoxicación por MPTP/tratamiento farmacológico , Fármacos Neuroprotectores/administración & dosificación , Compuestos Policíclicos/administración & dosificación , Sustancia Negra/inmunología , Animales , Proteínas Relacionadas con la Autofagia/inmunología , Proteínas Relacionadas con la Autofagia/metabolismo , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/inmunología , Neuronas Dopaminérgicas/patología , Humanos , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Intoxicación por MPTP/inmunología , Intoxicación por MPTP/patología , Masculino , Ratones , Células PC12 , Ratas , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patologíaRESUMEN
We aim to describe the influence of principal ingredients of Wuzhi capsule, schisandrin A (SIA) and schisantherin A (STA), on the pharmacokinetics of cyclosporin A (CsA) and to quantify the herb-drug interactions (HDIs) between SIA, STA, and CsA. CsA is a first-line immunosuppressant for anti-rejection therapy after solid organ transplantation, while narrow therapeutic window associated with strong hepatotoxicity largely limited its use. Wuzhi capsule, a liver-protective drug, was approved for coadministration with CsA to reduce the hepatotoxicity. There are few studies exploring HDIs of CsA when coadministered with Wuzhi capsule. The essential adjusted physicochemical data and pharmacokinetic parameters of SIA, STA, and CsA were collected. Then physiologically based pharmacokinetic (PBPK) models of SIA, STA, and CsA were built and verified in healthy subjects using Simcyp respectively. The refined PBPK models were used to estimate potential HDIs between CsA and SIA, STA. The simulated plasma concentration-time curves of CsA, SIA, and STA were in good accordance with the observed profiles respectively. CsA pharmacokinetics were improved after coadministration. After a single dose and multiple doses, the area under the plasma concentration-time curve (AUC) of CsA was increased by 47% and 226% when coadministered with STA, respectively, and by 8% and 36% when coadministered with SIA, respectively. PBPK models sufficiently described the pharmacokinetics of CsA, SIA, and STA. Compared with SIA, STA inhibited CsA metabolism to a greater extent. Our result revealed the dose of CsA can be reduced to maintain similar profile when used concomitantly with Wuzhi capsule.
Asunto(s)
Ciclooctanos/administración & dosificación , Ciclosporina/farmacocinética , Dioxoles/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Inmunosupresores/farmacocinética , Lignanos/administración & dosificación , Compuestos Policíclicos/administración & dosificación , Adulto , Ciclooctanos/química , Ciclosporina/administración & dosificación , Dioxoles/química , Interacciones de Hierba-Droga , Humanos , Inmunosupresores/administración & dosificación , Lignanos/química , Masculino , Compuestos Policíclicos/químicaRESUMEN
Schisandra chinensis fructus (SCF) is widely used traditional Chinese medicine, which possesses hepato-protective potential. Schisandrin (SD), schisantherin (ST), and γ-schizandrin (SZ) are the major bioactive lignans. The main problem associated with the major bioactive lignans oral administration is low oral bioavailability due to the lignans' poor aqueous solubility and taste. The aim of the present research work was to develop liposome (SCL) encapsulated ß-cyclodextrin (ß-CD) inclusion complex loaded with SCF extract (SCF-E). The SD, ST, and SZ were selected as effective candidates to perform comparisons of liver targeting among the solution (SES), ß-cyclodextrin inclusion compound (SCF-E-ß-CD), liposome (SEL), and SCL of SCF-E to characterize the pharmacokinetic behaviors and liver targeting in rats. The ß-CD inclusion complex (SCF-E-ß-CD) was used to improve the solubility. The concentrations were determined using high-performance liquid chromatography (HPLC) and analyzed by DAS3.0. The pharmacokinetic results indicate that the plasma concentration-time courses were fitted well to the one-compartment model with the first weighing factor. The half-life period (t1/2) and area under the concentration-time curve (AUC) of the three components in SCL were the largest. The SCL exhibit a relatively high liver targeting effect. The results would be helpful for guiding the clinical application of this herbal medicine.
Asunto(s)
Ciclooctanos/farmacocinética , Lignanos/farmacocinética , Hígado/metabolismo , Extractos Vegetales/farmacocinética , Compuestos Policíclicos/farmacocinética , Schisandra/química , beta-Ciclodextrinas/química , Administración Oral , Animales , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Ciclooctanos/administración & dosificación , Ciclooctanos/efectos adversos , Composición de Medicamentos , Lignanos/administración & dosificación , Lignanos/efectos adversos , Liposomas , Tamaño de la Partícula , Extractos Vegetales/administración & dosificación , Extractos Vegetales/efectos adversos , Compuestos Policíclicos/administración & dosificación , Compuestos Policíclicos/efectos adversos , Ratas WistarRESUMEN
The traditional Chinese herbal formula Shenmai-Yin (SY) and nifedipine have both been used to treat patients with cardiovascular disorders. Nifedipine is primarily oxidized by cytochrome P450 (CYP) 3A. The oxidation and pharmacokinetics of nifedipine were studied in rats in vitro and in vivo to illustrate the interaction of SY with nifedipine. Schisandrol A, schisandrin A and schisandrin B were identified as the main lignans in SY. In the study in vitro, the ethanolic extract of SY was used due to the solubility and the extract inhibited nifedipine oxidation (NFO) activity in a time-dependent manner. Among lignans, schisandrin B caused the most potent inhibition. According to the time-dependent inhibition behavior, rats were treated with SY 1 h before nifedipine administration. After oral treatment with 1.9 g/kg SY, nifedipine clearance decreased by 34% and half-life increased by 142%. SY treatment decreased hepatic NFO activity by 49%. Compared to the change caused by ketoconazole, the SY-mediated reduction of nifedipine clearance was moderate. These findings demonstrate that SY causes a time-dependent inhibition of NFO and schisandrin B contributes to the inhibition. The decreased nifedipine clearance by SY in rats warrants further human study to examine the clinical impact of this decrease.
Asunto(s)
Medicamentos Herbarios Chinos/administración & dosificación , Nifedipino/farmacocinética , Animales , Ciclooctanos/administración & dosificación , Ciclooctanos/análisis , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Medicamentos Herbarios Chinos/análisis , Humanos , Lignanos/administración & dosificación , Lignanos/análisis , Masculino , Nifedipino/administración & dosificación , Compuestos Policíclicos/administración & dosificación , Compuestos Policíclicos/análisis , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: Schisanhenol is a compound derived from the fruit of a traditional Chinese herb Schisandra rubriflora. The aim of the present study was to evaluate the effect of Schisanhenol on the cognitive impairment induced by scopolamine. MATERIAL AND METHODS: Male mice were randomly divided into three Schisanhenol groups (10, 30, 100 mg/kg), Galantamine group (3 mg/kg), model group (1mg/kg scopolamine), and vehicle control group (normal saline). The learning and memory ability of mice was monitored by water morris maze. Hippocampus of mice were collected after behavioral testing and the activity of SOD, MDA, GSH-px, AChE were measured with standard biochemical procedures. Western blotting was used to analyze the expression of SIRT1, PGC-1α, phosphorylated Tau proteins. RESULTS: Intraperitoneal administration of Schisanhenol (10, 30 or 100 mg/kg) significantly attenuated scopolamine-induced cognitive impairment in water morris maze. In addition, Schisanhenol increased the activity of SOD and GSH-px while decreased the content of AChE and MDA. Furthermore, western blotting analysis revealed that Schisanhenol increased the levels of SIRT1 and PGC-1α and decreased the level of phosphorylated Tau protein (Ser 396) significantly in the hippocampal tissues. CONCLUSIONS: Our findings indicated that Schisanhenol can attenuate scopolamine-induced learning impairment and enhance cognitive function, the mechanism via improve the cholinergic system and antioxidant ability, activate SIRT1-PGC1α signaling, inhibit the phosphorylation of Tau, and would be an effective candidate against cognitive disorders, such as Alzheimer's disease.
Asunto(s)
Acetilcolinesterasa/metabolismo , Ciclooctanos/administración & dosificación , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Compuestos Policíclicos/administración & dosificación , Sirtuina 1/metabolismo , Proteínas tau/metabolismo , Animales , Hipocampo/metabolismo , Masculino , Memoria/efectos de los fármacos , Ratones , Estrés Oxidativo , Escopolamina/administración & dosificación , Transducción de SeñalRESUMEN
INTRODUCTION: Schisandrin B (SchB), the main active constituent in Schisandra chinensis, has antioxidant activities. Endothelial dysfunction leads to various cardiovascular diseases. Oxidative stress is a crucial pathophysiological mechanism underpinning endothelial dysfunction. METHODS: We elucidated the role and underlying mechanisms of SchB in angiotensin II-induced rat aortic endothelial-cell deficits and explored targets of SchB through siRNA analysis and molecular docking. We measured apoptosis by TUNEL and oxidative stress by dihydroethidium (DHE) and 2',7' -dichlorofluorescin diacetate (DCF) staining. RESULTS: Our results demonstrated that SchB significantly ameliorated oxidative stress, mitochondrial membrane-potential depolarization and apoptosis in angiotensin II-challenged rat aortic endothelial cells. We further discovered that these antioxidative effects of SchB were mediated through induction of Nrf2. Importantly, using molecular docking and molecular dynamic simulation, we identified that Keap1, an adaptor for the degradation of Nrf2, was a target of SchB. CONCLUSION: These findings support the potential use of SchB as a Keap1 inhibitor for attenuating oxidative stress, and Keap1 might serve as a therapeutic target in the treatment of cardiovascular diseases.
Asunto(s)
Angiotensina II/farmacología , Células Endoteliales/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/antagonistas & inhibidores , Lignanos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Compuestos Policíclicos/farmacología , Animales , Células Cultivadas , Ciclooctanos/administración & dosificación , Ciclooctanos/farmacología , Células Endoteliales/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Lignanos/administración & dosificación , Masculino , Estrés Oxidativo/efectos de los fármacos , Compuestos Policíclicos/administración & dosificación , Ratas , Ratas Sprague-DawleyRESUMEN
Gomisin N (GN), a lignan derived from Schisandra chinensis, has been shown to possess antioxidant, anti-inflammatory, and anticancer properties. In the present study, we investigated the protective effect of GN against ethanol-induced liver injury using in vivo and in vitro experiments. Histopathological examination revealed that GN administration to chronic-binge ethanol exposure mice significantly reduced ethanol-induced hepatic steatosis through reducing lipogenesis gene expression and increasing fatty acid oxidation gene expression, and prevented liver injury by lowering the serum levels of aspartate transaminase and alanine transaminase. Further, it significantly inhibited cytochrome P450 2E1 (CYP2E1) gene expression and enzyme activity, and enhanced antioxidant genes and glutathione level in hepatic tissues, which led to decreased hepatic malondialdehyde levels. It also lowered inflammation gene expression. Finally, GN administration promoted hepatic sirtuin1 (SIRT1)-AMP-activated protein kinase (AMPK) signaling in ethanol-fed mice. Consistent with in vivo data, treatment with GN decreased lipogenesis gene expression and increased fatty acid oxidation gene expression in ethanol-treated HepG2 cells, thereby preventing ethanol-induced triglyceride accumulation. Furthermore, it inhibited reactive oxygen species generation by downregulating CYP2E1 and upregulating antioxidant gene expression, and suppressed inflammatory gene expression. Moreover, GN prevented ethanol-mediated reduction in SIRT1 and phosphorylated AMPK. These findings indicate that GN has therapeutic potential against alcoholic liver disease through inhibiting hepatic steatosis, oxidative stress and inflammation.
Asunto(s)
Hígado Graso Alcohólico/metabolismo , Lignanos/farmacología , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Compuestos Policíclicos/farmacología , Alanina Transaminasa/sangre , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Aspartato Aminotransferasas/sangre , Ciclooctanos/administración & dosificación , Ciclooctanos/farmacología , Etanol/toxicidad , Hígado Graso Alcohólico/tratamiento farmacológico , Células Hep G2 , Humanos , Lignanos/administración & dosificación , Hígado/lesiones , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Compuestos Policíclicos/administración & dosificaciónRESUMEN
Deoxyschizandrin (DS) is a bioactive benzocyclooctadiene lignan found in the fruit of Schisandra chinensis. However, poor bioavailability and non-specificity of DS frequently caused low therapeutic efficacy. In the present study, DS-liposome (DS-lipo) was implemented to enhance the hepatic targeting and inhibition effects on adipocyte differentiation in 3T3-L1 cells. The formulations enabled encapsulation of as much as 24.14% DS. The DS-lipo prepared was about 73.08 nm, as measured by laser light scattering (LLS) morphology. In the visual field of a scanning electron microscope (SEM), the liposomes were spherical with similar size and uniform dispersion. Fluorescence live imaging study exhibited hepatic targeting of liposomes in vivo. Furthermore, High-Content Analysis (HCS) imaging microassay analyses revealed DS-lipo and DS reduced cytoplasmic lipid droplet in 3T3-L1 adipocytes, with the IC50 value of 8.68 µM and 31.08 µM, respectively. The lipid droplet accumulation inhibition rate of 10 µM DS-lipo was above 90%, which was even superior to the effect of 30 µM DS solution. The current findings suggest that DS-lipo was a therapeutic strategy for alleviating lipid-associated diseases and nonalcoholic fatty liver disease (NAFLD).
Asunto(s)
Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Ciclooctanos/administración & dosificación , Lignanos/administración & dosificación , Metabolismo de los Lípidos/efectos de los fármacos , Liposomas , Compuestos Policíclicos/administración & dosificación , Células 3T3-L1 , Animales , Ciclooctanos/química , Ciclooctanos/farmacocinética , Liberación de Fármacos , Lignanos/química , Lignanos/farmacocinética , Gotas Lipídicas , Liposomas/química , Liposomas/ultraestructura , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacocinética , TemperaturaRESUMEN
Schisantherin A (SCA) was evaluated for possible function in restoring the learning and memory impairment induced by D-galactose in mice. ICR mice were treated with D-galactose subcutaneously (220 mg·kg-1), and followed by SCA in different doses (1.25, 2.50 and 5.00 mg·kg-1, administered orally) for 42 days. Effects of SCA on learning and memory were examined by step-through tests and Morris water maze tests. The activity of superoxide dismutase (SOD), the content of malondialdehyde (MDA) in the peripheral blood and hippocampus of mice were assayed by water-soluble tetrazolium-1 (WST-1) and thiobarbituric acid (TBA) methods. The contents of 8 hydroxy deoxy guanosine (8-OHdG) in the hippocampus of mice were detected by immunosorbent assay methods, respectively. Quantitative real-time PCR and Western Blot were respectively used to detect the expression of p19, p53, p21, cyclin D1, CDK4 and RB genes, and the phosphorylation of RB in the hippocampus of mice. We found that SCA significantly improved the learning and memory impairment induced by D-galactose in mice. After SCA treatment, SOD activity was increased and the content of MDA was decreased in both peripheral blood and hippocampus of mice. 8-OHDG content was also decreased in the hippocampus of mice. Furthermore, the expression of p19, p53 and p21 genes was reduced and the expression of cyclin D1 and CDK4 and the phosphorylation of RB protein were elevated in the hippocampus. SCA may improve the learning and memory impairment induced by D-galactose by enhancing the antioxidant capacity, and regulating the expression of p19/p53/p21/cyclinD1/CDK4 genes, and the phosphorylation of RB protein in the hippocampus of mice.