RESUMEN
A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.
Asunto(s)
Antineoplásicos/química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Rotenona/análogos & derivados , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Sitios de Unión , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Rotenona/química , Rotenona/metabolismo , Rotenona/farmacología , Relación Estructura-ActividadRESUMEN
Dollar spot is one of the most economically important diseases of turfgrasses. Recent taxonomic revisions have placed the dollar spot fungal pathogens in the new genus Clarireedia, with five species described. The main goal of this study was to develop a quantitative real-time PCR (qPCR) molecular detection assay based on the internal transcribed spacer (ITS) of the ribosomal RNA genes to quantify the abundance of Clarireedia spp. from environmental (field) samples. The qPCR assay was able to detect isolates of the four tested Clarireedia spp. but did not cross react with nontarget fungi, including closely related taxa, other turfgrass pathogens, or other fungal species commonly isolated from turfgrass. The assay is capable of detecting as little as 38.0 fg (3.8 × 10-14 g) of Clarireedia genomic DNA in 3 h. The qPCR assay detected Clarireedia spp. in both symptomatic and asymptomatic creeping bentgrass (Agrostis stolonifera) foliar tissue. Clarireedia spp. were rarely detected in the thatch or soil, indicating that these pathogens are not widely distributed in these areas of the environment. The fact that the pathogen was detected in asymptomatic tissue suggests that creeping bentgrass may be able to tolerate a certain quantity of the pathogens in leaves before disease symptoms appear; however, further research is needed to validate this hypothesis.
Asunto(s)
Agrostis , Ascomicetos , Agrostis/genética , Ascomicetos/genética , Enfermedades de las Plantas , Hojas de la Planta , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Leucyl-tRNA synthetase (LRS) plays an important role in amino acid-dependent mTORC1 signaling, which is known to be associated with cellular metabolism and proliferation. Therefore, LRS-targeting small molecules that can suppress mTORC1 activation may provide an alternative strategy to current anticancer therapy. In this work, we developed a library of leucyladenylate sulfate analogues by extensively modifying three different pharmacophoric regions comprising adenine, ribose and leucine. Several effective compounds were identified by cell-based mTORC1 activation assays and further tested for anticancer activity. The selected compounds mostly exhibited selective cytotoxicity toward five different cancer cell lines, supporting the hypothesis that the LRS-mediated mTORC1 pathway is a promising alternative target to current therapeutic approaches.
Asunto(s)
Leucina-ARNt Ligasa/metabolismo , Leucina/análogos & derivados , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Leucina/química , Leucina/metabolismo , Leucina/farmacología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Rotenona/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Rotenona/síntesis química , Rotenona/química , Rotenona/farmacología , Relación Estructura-ActividadRESUMEN
According to recent studies, leucyl-tRNA synthetase (LRS) acts as a leucine sensor and modulates the activation of the mammalian target of rapamycin complex 1 (mTORC1) activation. Because overactive mTORC1 is associated with several diseases, including colon cancer, LRS-targeted mTORC1 inhibitors represent a potential option for anti-cancer therapy. In this work, we developed a series of simplified leucyladenylate sulfamate analogues that contain the N-(3-chloro-4-fluorophenyl)quinazolin-4-amine moiety to replace the adenine group. We identified several compounds with comparable activity to previously reported inhibitors and exhibited selective mTORC1 inhibition and anti-cancer activity. This study further supports the hypothesis that LRS is a promising target to modulate the mTORC1 pathway.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Leucina-ARNt Ligasa/antagonistas & inhibidores , Leucina/análogos & derivados , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Leucina/síntesis química , Leucina/química , Leucina/farmacología , Leucina-ARNt Ligasa/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a N-(3,4-dimethoxybenzyl)benzenesulfonamide (2a) or a N-(2-phenoxyethyl)benzenesulfonamide groups (2b) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers. Among these simplified analogues, compound 16 and its constrained analogue 22 effectively inhibited S6K phosphorylation in a dose-dependent manner and exhibited cancer cell specific cytotoxicity against six different types of cancer cells. This result supports that LRS is a viable target for novel anticancer therapy.
Asunto(s)
Descubrimiento de Drogas , Leucina-ARNt Ligasa/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Ácidos Sulfónicos/química , Ácidos Sulfónicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Espectrometría de Masas/métodos , Fosforilación , Espectroscopía de Protones por Resonancia Magnética , Proteínas Quinasas S6 Ribosómicas/metabolismoRESUMEN
OBJECTIVE: Oil-based contrast media such as Pantopaque have not used for imaging for several decades, but because these contrast media have an extremely low clearance rate, the remnant contrast media or residual sequelae of these materials may be encountered in the clinical field. CLINICAL PRESENTATION: A 63-year-old woman presented to our hospital complaining of increasing lower back pain and lower extremity paresthesia with incontinence for 2 years. A plain X-ray film revealed single droplet-like mass at the lower thoracic T9-T10. A magnetic resonance image (MRI) study revealed a dorsally placed extramedullary intradural lesion, compressing the thoracic cord and minimally displacing it anteriorly. Spinal stenosis was also noted at the L4-5 level. INTERVENTION: The patient was performed for two consecutive surgeries. Total laminectomy was performed at T9-T10 to remove mass. A 0.5 × 0.5 × 4 cm yellowish intradural extramedullary cystic mass was removed without any leakage of cystic contents. Partial hemi-laminectomy and foraminotomy was then done at L4-5 levels for radiculopathy symptom relief. The fluid from the cyst was composed mainly of iodide. CONCLUSION: Intraspinal masses showing metal-like density in X-ray or computed tomography but in MRI showing only lipoma or cystic lesions, not metallic characteristics, the differential diagnosis should include iophendylate (Pantopaque) cyst. Oil-based contrast medium is believed to have the potential to make a syrinx formation via arachnoiditis, which can lead to severe neurologic deteriorations, so even if the patients do not represent with an acute neurologic deficit, surgical total removal of remnant material without leaking should be considered.
Asunto(s)
Medios de Contraste/efectos adversos , Quistes/diagnóstico , Quistes/etiología , Diagnóstico Diferencial , Yofendilato/efectos adversos , Lipoma/diagnóstico , Neoplasias de la Médula Espinal/diagnóstico , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Vértebras Torácicas/patologíaRESUMEN
Krukovine (KV) is an alkaloid isolated from the bark of Abuta grandifolia (Mart.) Sandw. (Menispermaceae) with anticancer potential in some cancers with KRAS mutations. In this study, we explored the anticancer efficacy and mechanism of KV in oxaliplatin-resistant pancreatic cancer cells and patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutation. After treatment with KV, mRNA and protein levels were determined by RNA-seq and Western blotting, respectively. Cell proliferation, migration, and invasion were measured by MTT, scratch wound healing assay, and transwell analysis, respectively. Patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutations were treated with KV, oxaliplatin (OXA), and a combination of KV and OXA. KV suppresses tumor progression via the downregulation of the Erk-RPS6K-TMEM139 and PI3K-Akt-mTOR pathways in oxaliplatin-resistant AsPC-1 cells. Furthermore, KV showed an antiproliferative effect in PDPCOs, and the combination of OXA and KV inhibited PDPCO growth more effectively than either drug alone.
RESUMEN
OBJECT: The aim of this retrospective study was to present and investigate axillary nerve injuries associated with sports. METHODS: This study retrospectively reviewed 26 axillary nerve injuries associated with sports between the years 1985 and 2010. Preoperative status of the axillary nerve was evaluated by using the Louisiana State University Health Science Center (LSUHSC) grading system published by the senior authors. Intraoperative nerve action potential recordings were performed to check nerve conduction and assess the possibility of resection. Neurolysis, suture, and nerve grafts were used for the surgical repair of the injured nerves. In 9 patients with partial loss of function and 3 with complete loss, neurolysis based on nerve action potential recordings was the primary treatment. Two patients with complete loss of function were treated with resection and suturing and 12 with resection and nerve grafting. The minimum follow-up period was 16 months (mean 20 months). RESULTS: The injuries were associated with the following sports: skiing (12 cases), football (5), rugby (2), baseball (2), ice hockey (2), soccer (1), weightlifting (1), and wrestling (1). Functional recovery was excellent. Neurolysis was performed in 9 cases, resulting in an average functional recovery of LSUHSC Grade 4.2. Recovery with graft repairs averaged LSUHSC Grade 3 or better in 11 of 12 cases CONCLUSIONS: Surgical repair can restore useful deltoid function in patients with sports-associated axillary nerve injuries, even in cases of severe stretch-contusion injury.
Asunto(s)
Traumatismos en Atletas/fisiopatología , Traumatismos en Atletas/cirugía , Neuropatías del Plexo Braquial/fisiopatología , Neuropatías del Plexo Braquial/cirugía , Músculo Deltoides/inervación , Procedimientos Neuroquirúrgicos/métodos , Traumatismos en Atletas/clasificación , Plexo Braquial/lesiones , Plexo Braquial/patología , Plexo Braquial/cirugía , Neuropatías del Plexo Braquial/etiología , Músculo Deltoides/irrigación sanguínea , Músculo Deltoides/fisiopatología , Disección/métodos , Humanos , Masculino , Debilidad Muscular/diagnóstico , Debilidad Muscular/etiología , Debilidad Muscular/fisiopatología , Estudios RetrospectivosRESUMEN
OBJECT: This study analyzes 84 cases of peroneal nerve injuries associated with sports-related knee injuries and their surgical outcome and management. METHODS: The authors retrospectively reviewed the cases of peroneal nerve injury associated with sports between the years 1970 and 2010. Each patient was evaluated for injury mechanism, preoperative neurological status, electrophysiological studies, lesion type, and operative technique (neurolysis and graft repair). Preoperative status of injury was evaluated by using a grading system published by the senior authors. All lesions in continuity had intraoperative nerve action potential recordings. RESULTS: Eighty-four (approximately 18%) of 448 cases of peroneal nerve injury were found to be sports related, which included skiing (42 cases), football (23 cases), soccer (8 cases), basketball (6 cases), ice hockey (2 cases), track (2 cases) and volleyball (1 case). Of these 84 cases, 48 were identified as not having fracture/dislocation and 36 cases were identified with fracture/dislocation for surgical interventions. Good functional outcomes from graft repair of graft length < 6 cm (70%) and neurolysis (85%) in low-intensity peroneal nerve injuries associated with sports were obtained. Recovery from graft repair of graft length between 6 and 12 cm (43%) was good and measured between Grades 3 and 4. However, recovery from graft repair of graft length between 13 and 24 cm was obtained in only 25% of patients. CONCLUSIONS: Traumatic knee-level peroneal nerve injury due to sports is usually associated with stretch/contusion, which more often requires graft repair. Graft length is the factor to be considered for the prognosis of nerve repair.
Asunto(s)
Traumatismos en Atletas/epidemiología , Traumatismos de la Rodilla/epidemiología , Procedimientos Neuroquirúrgicos/métodos , Nervio Peroneo/lesiones , Nervio Peroneo/fisiopatología , Neuropatías Peroneas/epidemiología , Traumatismos en Atletas/clasificación , Traumatismos en Atletas/fisiopatología , Comorbilidad , Humanos , Traumatismos de la Rodilla/fisiopatología , Masculino , Neuropatías Peroneas/fisiopatología , Estudios RetrospectivosRESUMEN
Ossification of the posterior longitudinal ligament (OPLL) is most commonly found in men, the elderly, and Asian patients. There are many diseases associated with OPLL, such as diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and other spondyloarthropathies. Several factors have been reported to be associated with OPLL formation and progression, including genetic, hormonal, environmental, and lifestyle factors. However, the pathogenesis of OPLL is still unclear. Most symptomatic patients with OPLL present with neurological deficits such as myelopathy, radiculopathy, and/or bowel and bladder symptoms. There are some reports of asymptomatic OPLL. Both static and dynamic factors are related to the development of myelopathy. Plain radiography, CT, and MR imaging are used to evaluate OPLL extension and the area of spinal cord compression. Management of OPLL continues to be controversial. Each surgical technique has some advantages and disadvantages, and the choice of operation should be made case by case, depending on the patient's condition, level of pathology, type of OPLL, and the surgeon's experience. In this paper, the authors attempt to review the incidence, pathology, pathogenesis, natural history, clinical presentation, classification, radiological evaluation, and management of OPLL.
Asunto(s)
Osificación del Ligamento Longitudinal Posterior/diagnóstico , Osificación del Ligamento Longitudinal Posterior/cirugía , Progresión de la Enfermedad , Humanos , Ligamentos Longitudinales/patología , Ligamentos Longitudinales/cirugía , Osificación del Ligamento Longitudinal Posterior/patología , Compresión de la Médula Espinal/diagnóstico , Compresión de la Médula Espinal/patología , Compresión de la Médula Espinal/cirugíaRESUMEN
The principal objective of the present study was to evaluate the antimetastatic activity of decursin and decursinol isolated from Angelica gigas. Decursin and decursinol inhibited the proliferation and invasion of CT-26 colon carcinoma cells. The expressions of matrix metalloproteinase (MMP)-2 and MMP-9 in cells and the activities in the culture medium were also reduced by decursin and decursinol treatment. In CT-26 cells, the extracellular signal-regulated kinase (ERK) inhibitor inhibited cell proliferation, invasion and MMP-9 expression, and the c-Jun N-terminal kinase (JNK) inhibitor suppressed the expression of both MMPs, as well as cell proliferation and cell invasion. The phosphatidylinositol-3 kinase (PI3K) inhibitor reduced only the expression of MMP-2. In addition, the invasion of CT-26 cells was inhibited by the treatment with anti-MMP-9 antibody, rather than anti-MMP-2 antibody. These results indicate that MMP-9 expression via ERK and JNK plays a critical role for the invasion of CT26 cells. Decursin and decursinol downregulated ERK and JNK phosphorylation. Moreover, oral administration of decursin and decursinol reduced the formation of tumor nodules in the lungs and the increase in lung weight caused by CT-26 metastases. Therefore, both decursin and decursinol may be beneficial antimetastatic agents, targeting MMPs and their upstream signaling molecules.
Asunto(s)
Angelica/química , Antineoplásicos Fitogénicos/farmacología , Benzopiranos/farmacología , Butiratos/farmacología , Neoplasias del Colon/patología , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Neoplasias Pulmonares/secundario , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia/tratamiento farmacológicoRESUMEN
Inflammation is a very common and important basic pathological process. There is still a great need for the isolation of effective anti-inflammatory agents from plants. In this paper, five new isobutylamides, zanthoxylumamides E-I (1-5), and four known isobutylamides (6-9) were isolated from Zanthoxylum nitidum var. tomentosum (Rutaceae). Chiral resolution of seven racemic isobutylamides (1-4 and 6-8) was successfully performed, and the absolute configurations of two stereoisomers of 1-4 were validated by ECD and NMR. The obtained isobutylamides were evaluated in vitro anti-inflammatory activity with the lipopolysaccharide (LPS)-stimulated production of nitric oxide (NO) in murine macrophage RAW264.7 cells. Compound 8 exhibited significant inhibition of LPS-induced NO production. The underlying molecular mechanisms of the anti-inflammatory activity of 8 revealed that it suppressed the NO production through the modulation of myeloid differentiation factor 88 (MyD88) and interferon regulatory factor 3 (IRF3) signaling pathways.
Asunto(s)
Amidas/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Zanthoxylum/química , Amidas/química , Animales , Supervivencia Celular , Lipopolisacáridos/toxicidad , Ratones , Modelos Moleculares , Estructura Molecular , Óxido Nítrico/metabolismo , Células RAW 264.7RESUMEN
Anhua dark tea known as the earliest produced Chinese dark tea, has been commercially available and famous for its unique flavor and health care effect. NMDA receptors are glutamate-coupled ion channels that critically involved in survival of neuronal cells and neurodegenerative diseases. Thus, it is considered a promising target for the therapy of neurodegenerative disease. In this study, four catechins including two new catechins derivatives (1-2), together with thirteen known flavonoids were isolated from Anhua dark tea. The structures of compounds 1-2 [2S,3R-6-methoxycarbonylgallocatechin (1) and 2R,3R-6-methoxycarbonylgallocatechin (2)] were determined on the basis of their spectroscopic data. The preliminary bioassay indicated that compound 1 showed the best neuroprotective effects via N-methyl-d-aspartate (NMDA) receptors inhibition. Compound 1 protected SH-SY5Y cells against NMDA-induced injury and cell apoptosis via the modulation of NR2B expression, the activation of PI3K/Akt signaling and caspase-dependent pathway. The results suggested compound 1 would be a potent dietary therapy reagent for prevention of excitable brain injury.
Asunto(s)
Catequina/farmacología , Flavonoides/farmacología , Fármacos Neuroprotectores/farmacología , Té/química , Apoptosis , Catequina/análogos & derivados , Línea Celular Tumoral , Flavonoides/aislamiento & purificación , Humanos , Estructura Molecular , Neuroblastoma , Fármacos Neuroprotectores/aislamiento & purificación , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of cancer. Among the different PI3K subtypes, the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in majority of human cancers. Therefore, the inhibition of PI3Kα has been considered to be an efficient approach for the treatment of cancer. In this study, two series compounds containing hydrophilic group in imidazo[1,2-a]pyridine and quinazolin-4(3H)-one were synthesized and their antiproliferative activities against five cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638 and A549, were evaluated. Compound 1i with most potent antiproliferative activity was selected for further biological evaluation. PI3K kinase assay showed that 1i has selectivity for PI3Kα distinguished from other isoforms. The western blot assay indicated that 1i is more effective than HS-173, an imidazopyridine-based PI3Ka inhibitor, in reducing the levels of phospho-Akt. All these results suggested that 1i is a potent PI3Kα inhibitor and could be considered as a potential candidate for the development of anticancer agents.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Quinazolinonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Quinazolinonas/síntesis química , Quinazolinonas/química , Relación Estructura-ActividadRESUMEN
Recent studies indicate that LRS may act as a leucine sensor for the mTORC1 pathway, potentially providing an alternative strategy to overcome rapamycin resistance in cancer treatments. In this study, we developed leucyladenylate sulfamate derivatives as LRS-targeted mTORC1 inhibitors. Compound 18 selectively inhibited LRS-mediated mTORC1 activation and exerted specific cytotoxicity against colon cancer cells with a hyperactive mTORC1, suggesting that 18 may offer a novel treatment option for human colorectal cancer.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Leucina-ARNt Ligasa/antagonistas & inhibidores , Leucina/análogos & derivados , Complejos Multiproteicos/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Leucina/síntesis química , Leucina/química , Leucina/farmacología , Leucina-ARNt Ligasa/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina , Estructura Molecular , Complejos Multiproteicos/metabolismo , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Several studies have been conducted to identify the pathogenesis of and manage disk degeneration. To further this research, reliable animal models of disk degeneration are required. In the present study, a percutaneous technique is used to create a rabbit model of degenerative disk disease, and the reproducibility and efficacy of this technique is reported. METHODS: Ten mature male New Zealand white rabbits were included in the present study. The intervertebral disk was injured by a percutaneous technique at the L2-L3, L3-L4, and L4-L5 levels. The center of the disk was identified by C-arm guidance. A 19-gauge spinal needle with a 10-mL syringe was inserted into the center of the disk, and negative pressure was applied. Radiographs including magnetic resonance imaging (MRI) with T2 and lateral x-rays were collected at 1, 4, 9, 15, and 20 weeks. Degeneration was examined using histology at 24 weeks. RESULTS: Narrowed disk height was not observed until 4 weeks after injury, and a significant change was observed at 9 weeks compared with the control L1-L2 level (P < 0.05). MRI revealed disk degeneration beginning at 9 weeks and full degeneration at 15 weeks. Injured intervertebral disks had higher degeneration, seen using MRI, than uninjured control disks. Disk degeneration was confirmed in all injured levels by histologic examination. Cortical osteophyte formation was not found. CONCLUSIONS: Our percutaneous technique provides a suitable rabbit model of degenerative disk disease to test the safety and efficacy of treatments for disk degeneration, such as stem cell transplantation.
Asunto(s)
Modelos Animales de Enfermedad , Degeneración del Disco Intervertebral/etiología , Disco Intervertebral/lesiones , Vértebras Lumbares , Agujas , Punciones/métodos , Animales , Disco Intervertebral/diagnóstico por imagen , Disco Intervertebral/patología , Masculino , Conejos , Radiografía , Reproducibilidad de los ResultadosRESUMEN
Neurological deficits after brain surgery are not uncommon, and correct and prompt differential diagnosis is essential to initiate appropriate treatment. We describe a patient suffering from loss of consciousness due to hyperammonemia, following valproic acid treatment after surgery for an unruptured cerebral aneurysm. A 57-year-old female patient underwent successful aneurysmal neck clipping to correct an unruptured aneurysm. Her postoperative course was good, and she received anti-epileptic therapy (valproic acid) and a soft diet. Within a few days the patient experienced mental deterioration. Her serum valproic acid reached toxic levels (149.40 mg/L), and serum ammonia was fifteen times the upper normal limit (553 mmol/L; normal range, 9-33 mmol/L). After discontinuation of valproic acid and with conservative treatment, the patient recovered without any complications. Valproate-induced hyperammonemic encephalopathy is an unusual but serious neurosurgical complication, and should not be disregarded as a possible cause of neurological deficits after neurovascular surgery. Early diagnosis is crucial, as discontinuation of valproic acid therapy can prevent serious complications, including death.
RESUMEN
Curcumin is a natural product widely used as a spice in food. It has been shown to inhibit cyclooxygenase (COX)-1 and -2 and to suppress lipopolysaccharide-induced COX-2 and iNOS gene expression. In the present study, curcumin and 22 of its derivatives were evaluated for their chemopreventive potential. Based on COX-2 inhibition, curcumin (IC50=15.9 microM), 1,7-bis(3-fluoro-4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (19) (IC50=23.7 microM) and 2,6-bis(3-fluoro-4-hydroxybenzylidene)cyclohexanone (23) (IC50=5.5 microM) were found to be most potent. Tricyclic derivatives 2,6-bis(4-hydroxy-3-methoxybenzylidene)cyclohexanone (10), 2,6-bis(4-hydroxy-3,5-dimethoxybenzylidene)cyclohexanone (13) and 2,5-bis(4-hydroxy-3,5-dimethoxybenzylidene)cyclopentanone (21) inhibited LPS-induced COX-2 and iNOS gene expression in murine macrophages with potency equal to curcumin. RT-PCR experiments demonstrated suppression of COX-2 and iNOS gene expression occurred at the transcriptional level. The most active compounds in the macrophage assays, 13 and 23, were also the most cytotoxic, however. Topical application of curcumin, 10, 13, 21, and 6, a methoxy derivative of curcumin, showed strong inhibition of 12-O-tetradecanoyl-13-acetate (TPA)-induced ornithine decarboxylase (ODC) activity in mouse skin. These data suggest that structural elements responsible for COX-1 and COX-2 inhibition do not correlate well with those responsible for inhibiting COX-2 and iNOS gene expression, but elements capable of inhibiting COX-2 and iNOS gene expression also contribute to inhibition of TPA-induced ODC activity. The most potent compounds in these assays, 10, 13 and 21, as well as curcumin, were further evaluated for inhibition of 7,12-dimethylbenz(a)anthracene (DMBA)-induced preneoplastic lesion formation in a mouse mammary organ culture model, and dose-dependent responses were observed. Most potent effects were at concentrations between 1 and 5 microM for 10, 13 and 21, and at 10 microM for curcumin. These data demonstrate the substitution pattern on the aromatic moiety is especially crucial for activity.
Asunto(s)
Anticarcinógenos/farmacología , Curcumina/análogos & derivados , Curcumina/farmacología , Animales , Antineoplásicos Fitogénicos/farmacología , Línea Celular , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Femenino , Isoenzimas/antagonistas & inhibidores , Neoplasias Mamarias Experimentales/prevención & control , Proteínas de la Membrana , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Inhibidores de la Ornitina Descarboxilasa , Monoéster Fosfórico Hidrolasas/metabolismo , Prostaglandina-Endoperóxido SintasasRESUMEN
OBJECTIVE: Life-threatening hemispheric stroke is associated with a high mortality and morbidity. Decompressive hemicraniectomy has been regarded as an effective treatment option for refractory intracranial hypertension. Here, we reported the clinical course of 5 children with decompressive craniectomy and duroplasty after non-traumatic refractory intracranial hypertension. METHODS: Four toddlers and one preschool-girl were included in this study; there were 3 boys and 2 girls with a mean age of 34.6 months (range 17-80). Decompressive craniectomy including duroplasty was performed in cases of dilatation of pupil size after intensified standard medical therapy had proven insufficient. All children had a Pediatric Glasgow Coma Scale score <8 at pre-operation state. The mean time-point of craniectomy after stroke attack was 12 hours (range 4-19). RESULTS: During the long-term follow-up period (mean 47.6 months), no children died. One year later, when we checked their Glasgow Outcome Scale scores, only one toddler received a score of 4 (moderate disability). But the others had good recoveries although they had minor physical or mental deficits. According to the Pediatric Cerebral Performance Category Scale, 4 children received a score of 2 (mild disability). CONCLUSION: Despite our small cases, we suggest that decompressive hemicraniectomy and duroplasty is an acceptable and life-saving treatment for refractory intracranial hypertension after unilateral hemispheric stroke in toddlers and preschool children.