RESUMEN
Forsythiaside, one of the main bioactive components of Chinese medicine Lian Qiao, exerts antioxidant, anti-bacterial, and anti-inflammatory effects. To date, the mechanism of Forsythiaside in cardiomyocyte injury remains unclear. However, the antioxidant effects of Forsythiaside on cardiac cells are currently unknown. This study investigated the effect and mechanism of Forsythiaside on oxidative stress in H9c2 cardiomyocytes. H9c2 cells were treated with H2O2 and Forsythiaside and then transfected with small-interfering RNA against nuclear factor erythroid 2-related factor 2 (siNrf2). Cell viability, apoptosis, accumulation of reactive oxygen species (ROS), and mitochondrial membrane potential were measured using methyl thiazolyl tetrazolium (MTT), terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA), and rhodamine 123, respectively. The levels of oxidative stress-related markers were determined using their respective detection kits. Furthermore, the levels of apoptosis- and Nrf2 pathway-related molecules were determined via Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Forsythiaside had no obvious toxicity on H9c2 cells. H2O2 suppressed the viability, and reduced the levels of mitochondrial membrane potential, B-cell lymphoma-2 (Bcl-2), glutathione peroxidase (GSH-Px) and catalase (CAT) and superoxide dismutase (SOD), while promoted apoptosis, ROS accumulation, and elevated the levels of cleaved caspase 3, BCL2-Associated X (Bax) and malondialdehyde (MDA) in H9c2 cells. Contrarily, Forsythiaside reversed the aforementioned effects. H2O2 advanced the levels of cytoplasm Nrf2, heme oxygenase-1 (HO-1), and nucleus Nrf2 in H9c2 cells, whereas Forsythiaside enhanced these effects. SiNrf2 reversed the functions of H2O2 or Forsythiaside in cell viability, MDA, SOD, GSH-Px, CAT, Nrf2, and HO-1 in H9c2 cells, whereas Forsythiaside reversed the aforementioned effects of siNrf2. In sum, Forsythiaside protected H9c2 cells from oxidative stress and apoptosis induced by H2O2 by activating the Nrf2/HO-1 pathway.
Asunto(s)
Hemo-Oxigenasa 1 , Factor 2 Relacionado con NF-E2 , Antiinflamatorios/farmacología , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis , Caspasa 3/metabolismo , Catalasa/metabolismo , Catalasa/farmacología , ADN Nucleotidilexotransferasa/metabolismo , ADN Nucleotidilexotransferasa/farmacología , Colorantes Fluorescentes/metabolismo , Colorantes Fluorescentes/farmacología , Glutatión Peroxidasa/metabolismo , Glicósidos , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/farmacología , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/toxicidad , Malondialdehído/metabolismo , Miocitos Cardíacos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , ARN/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rodamina 123/metabolismo , Rodamina 123/farmacología , Transducción de Señal , Superóxido Dismutasa/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Despite its extreme significance, dynamic linearity measurement for high-g accelerometers has not been discussed experimentally in previous research. In this study, we developed a novel method using a dual-warhead Hopkinson bar to measure the dynamic linearity of a high-g acceleration sensor with a laser interference impact experiment. First, we theoretically determined that dynamic linearity is a performance indicator that can be used to assess the quality merits of high-g accelerometers and is the basis of the frequency response. We also found that the dynamic linearity of the dual-warhead Hopkinson bar without an accelerometer is 2.5% experimentally. Further, we verify that dynamic linearity of the accelerometer is 3.88% after calibrating the Hopkinson bar with the accelerometer. The results confirm the reliability and feasibility of measuring dynamic linearity for high-g accelerometers using this method.
RESUMEN
Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41.
Asunto(s)
Inhibidores de Captación de Dopamina/química , Tetrahidroisoquinolinas/química , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/metabolismo , Cinética , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Unión Proteica , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/metabolismoRESUMEN
The asymmetric synthesis of the antibacterial natural product, streptophenazine G, has been achieved by employing asymmetric alkylation and asymmetric aldol reactions using chiral oxazolidinones as the key steps. The originally proposed structure for streptophenazine G has been revised, and its absolute configuration has been determined to be 1'S,2'R,6'S. The asymmetric total synthesis of 6'-epi-streptophenazine G is also described.
Asunto(s)
Antibacterianos/química , Antibacterianos/síntesis química , Productos Biológicos/química , Productos Biológicos/síntesis química , Fenazinas/química , Fenazinas/síntesis química , Streptomyces/química , Alquilación , Estructura Molecular , EstereoisomerismoRESUMEN
A total synthesis of both diastereomers of the originally proposed structure for streptophenazine A (1) has been achieved. However, both synthetic compounds are different from the natural product. Re-examination of NMR data reported for streptophenazine A and a concise total synthesis of both diastereomers of 17 (17a and 17b) led to the structural revision of streptophenazine A to 17b. Asymmetric synthesis of (-)-streptophenazine A was also conducted, and its absolute configuration was determined to be 1'S,2'R.
Asunto(s)
Fenazinas/química , Fenazinas/síntesis química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Estereoisomerismo , Streptomyces/químicaRESUMEN
A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Descubrimiento de Drogas , Receptores de Serotonina 5-HT3/efectos de los fármacos , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacologíaRESUMEN
The asymmetric total synthesis of (+)-crassalactone D (4), a naturally occurring antitumor agent, has been achieved by employing an oxidative spirocyclization of furan 11 as the key step. Two close analogues, 7-epi-crassalactone D (14) and 5-epi-7-epi-crassalactone D (15), also have been prepared in the course of the synthesis of (+)-crassalactone D.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Furanos/síntesis química , Compuestos de Espiro/síntesis química , Antineoplásicos Fitogénicos/química , Ciclización , Furanos/química , Compuestos de Espiro/química , EstereoisomerismoRESUMEN
The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.