RESUMEN
The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.
RESUMEN
Aptamers are functional oligonucleotide ligands used for the molecular recognition of various targets. The natural characteristics of aptamers make them an excellent alternative to antibodies in diagnostics, therapeutics, and biosensing. DNA aptamers are mainly single-stranded oligonucleotides (ssDNA) that possess a definite binding to targets. However, the application of aptamers to the fields of brain health and neurodegenerative diseases has been limited to date. Herein, a DNA aptamer against the brain-derived neurotrophic factor (BDNF) protein was obtained by in vitro selection. BDNF is a potential biomarker of brain health and neurodegenerative diseases and has functions in the synaptic plasticity and survival of neurons. We identified eight aptamers that have binding affinity for BDNF from a 50-nucleotide library. Among these aptamers, NV_B12 showed the highest sensitivity and selectivity for detecting BDNF. In an aptamer-linked immobilized sorbent assay (ALISA), the NV_B12 aptamer strongly bound to BDNF protein, in a dose-dependent manner. The dissociation constant (Kd) for NV_B12 was 0.5 nM (95% CI: 0.4-0.6 nM). These findings suggest that BDNF-specific aptamers could be used as an alternative to antibodies in diagnostic and detection assays for BDNF.
Asunto(s)
Aptámeros de Nucleótidos , Enfermedades Neurodegenerativas , Humanos , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/química , Factor Neurotrófico Derivado del Encéfalo/genética , ADN de Cadena Simple , Biblioteca de GenesRESUMEN
The extract of Sappan Lignum, the heartwood of Caesalpinia sappan L., has been used in medicine to improve blood circulation. Recently, the application of microwave extraction methods has been a major focus of research into the extraction of components from natural sources. In this experiment, we compared the antiinflammatory effects of Sappan Lignum prepared by heat70% EtOH extraction (CSEH70E) and microwave70% EtOH extraction (CSEMW70E). Highperformance liquid chromatography analysis was used to identify the compounds in these extracts. The heat70% EtOH and microwave70% EtOH extracts of Sappan Lignum had different chromatograms. CSEMW70E significantly inhibited the protein expression of iNOS and COX2, PGE2, TNFα, and reduced NO and IL1ß production in macrophages exposed to LPS, whereas, only high concentrations of CSEH70E (20 µg/ml) resulted in any effects. Furthermore, CSEMW70E upregulated heme oxygenase1 (HO1) expression. In addition, the use of tin protoporphyrin, an inhibitor of HO1, confirmed the inhibitory effects of CSEMW70E on proinflammatory mediators. These results suggested that the CSEMW70Emediated upregulation of HO1 played an important role in the antiinflammatory effects of macrophages. Therefore, these findings showed that microwave extraction can be utilized to improve the extraction efficiency and biological activity of Sappan Lignum.
Asunto(s)
Antiinflamatorios/farmacología , Fabaceae/química , Hemo-Oxigenasa 1/metabolismo , Microondas , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Animales , Cromatografía Líquida de Alta Presión , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , ADN/metabolismo , Dinoprostona/metabolismo , Hemo-Oxigenasa 1/genética , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Metaloporfirinas/farmacología , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/metabolismo , Unión Proteica/efectos de los fármacos , Protoporfirinas/farmacología , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Previous phytochemical investigations of Akebiae Caulis resulted in the isolation of triterpenes, triterpene glycosides, phenylethanoid glycosides and megastigmane glycoside. Amyloid beta (Aß), the main component of the senile plaques detected in Alzheimer's disease, induces cell death. However, only a limited number of studies have addressed the biological and pharmacological effects of Akebiae Caulis. In particular, the inhibitory activity of Akebiae Caulis against Aß42 fibrillogenesis remains unclear. Herein, a new triterpene glycoside, akequintoside F (1), along with nine known compounds pulsatilla saponin A (2), collinsonidin (3), akebonic acid (4), hederagenin (5), 1-(3',4'-dihydroxycinnamoyl) cyclopentane-2,3-diol (6), asperosaponin C (7), leontoside A (8), quinatic acid (9), and quinatoside A (10) were isolated from Akebiae Caulis using repeated column chromatography with silica gel, LiChroprep RP-18, and MCI gel. The chemical structures of compounds 1-10 were illustrated based on 1D and 2D NMR spectroscopy, including 1H-1H COSY, HSQC, HMBC and NOESY spectroscopic analyses. Compound 1 a novel compound and known compounds 6 and 7 were isolated for the first time from this plant. Among these compounds, 1, 3, 4, 5 and 7 displayed significant inhibitory effects on Aß42 induced fibrillogenesis. We present the first report of new compound 1 and the inhibitory effects of components from Akebiae Caulis on Aß42 fibrillogenesis.
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Péptidos beta-Amiloides/antagonistas & inhibidores , Ovillos Neurofibrilares/patología , Ácido Oleanólico/análogos & derivados , Fragmentos de Péptidos/antagonistas & inhibidores , Plantas Medicinales/química , Placa Amiloide/prevención & control , Triterpenos/farmacología , Modelos Moleculares , Ácido Oleanólico/farmacología , Raíces de Plantas/química , Tallos de la Planta/química , Placa Amiloide/inducido químicamente , Espectrofotometría InfrarrojaRESUMEN
A new indole glycoside, ß-D-glucopyranosyl 2-(methylthio)-1H-indole-3-carboxylate, named raphanuside A (1), as well as eight known compounds, ß-D-fructofuranosyl-(2 â 1)-(6-O-sinapoyl)-α-D-glucopyranoside (2), (3-O-sinapoyl)-ß-D-fructofuranosyl-(2 â 1)-α-D-glucopyranoside (3), (3-O-sinapoyl)-ß-D-fructofuranosyl-(2 â 1)-(6-O-sinapoyl)-α-D-glucopyranoside (4), (3,4-O-disinapoyl)-ß-D-fructofuranosyl-(2 â 1)-(6-O-sinapoyl)-α-D-glucopyranoside (5), isorhamnetin 3,4'-di-O-ß-D-glucoside (6), isorhamnetin 3-O-ß-D-glucoside-7-O-α-L-rhamnoside (7), isorhamnetin 3-O-ß-D-glucoside (8) and 3'-O-methyl-(-)-epicatechin 7-O-ß-D-glucoside (9) were isolated from the seeds of Raphanus sativus. Furthermore, compounds 1-3 and 6-9, were isolated from this plant for the first time. The structures of compounds 1-9 were identified using 1D and 2D NMR, including (1)H-(1)H COSY, HSQC, HMBC and NOESY spectroscopic analyses. The inhibitory activity of these isolated compounds against interleukin-6 (IL-6) production in TNF-α stimulated MG-63 cells was also examined.
Asunto(s)
Antiinflamatorios/aislamiento & purificación , Descubrimiento de Drogas/métodos , Glicósidos/aislamiento & purificación , Indoles/aislamiento & purificación , Interleucina-6/biosíntesis , Raphanus/química , Antiinflamatorios/farmacología , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Glicósidos/farmacología , Humanos , Indoles/farmacología , Estructura Molecular , Semillas/química , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Diarrhea is one of the most common causes for thousands of deaths every year. Therefore, identification of new source of antidiarrheal drugs becomes one of the most prominent focuses in modern research. Our aim was to investigate the antidiarrheal and cytotoxic activities of methanolic extract of Maranta arundinacea linn. (MEMA) leaves in rats and brine shrimp, respectively. Antidiarrheal effect was evaluated by using castor oil-induced diarrhea, enteropooling, and gastrointestinal motility tests at 200 mg/kg and 400 mg/kg body weight in rats where the cytotoxic activity was justified using brine shrimp lethality bioassay at different concentrations of MEMA. The extract showed considerable antidiarrheal effect by inhibiting 42.67% and 57.75% of diarrheal episode at the doses of 200 and 400 mg/kg, respectively. MEMA also significantly (p < 0.01) reduced the castor oil-induced intestinal volume (2.14 ± 0.16 to 1.61 ± 0.12 mL) in enteropooling test as well as intestinal transit (33.00 to 43.36%) in GI motility test, compared to their respective control. These observed effects are comparable to that of standard drug loperamide (5 mg/kg). On the other hand, in brine shrimp lethality test after 24 h, surviving brine shrimp larvae were counted and LD50 was assessed. Result showed that MEMA was potent against brine shrimp with LD50 value of 420 µg/mL. So the highest dose of 400 µg/mL of MEMA was not toxic to mice. So these results indicate that bioactive compounds are present in methanolic extract of Maranta arundinacea leaves including significant antidiarrheal activity and could be accounted for pharmacological effects.
RESUMEN
Ten compounds, 1',3'-propanediol,2'-amino-1'-(1,3-benzodioxol-5-yl) (1), artanomaloide (2), canin (3), eupatilin (4), quercetin-3-O-ß-D-glucoside-7-O-α-L-rhamnoside (5), 1,3-di-O-caffeoylquinic acid (6), isoquercitrin (7), pinoresinol-4-O-ß-D-glucoside (8), scopolin (9), and isofraxidin-7-O-ß-D-glucopyranoside (10) were isolated from the aerial parts of A. selengensis. The structures of compounds (1-10) were identified based on 1D and 2D NMR, including (1)H-(1)H COSY, HSQC, HMBC and NOESY spectroscopic analyses. Among them, compound 1 was isolated from this plant for the first time as a naturally occurring compound. The inhibitory activity of these isolated compounds against interleukin-6 (IL-6) production in TNF-α stimulated MG-63 cells was also examined.