RESUMEN
Mononuclear and dinuclear Ru(II) complexes cis-[Ru(κ2-dppm)(bpy)Cl2] (1), cis-[Ru(κ2-dppe)(bpy)Cl2] (2) and [Ru2(bpy)2(µ-dpam)2(µ-Cl)2](Cl)2 ([3](Cl)2) were prepared from the reactions between cis(Cl), cis(S)-[Ru(bpy)(dmso-S)2Cl2] and diphosphine/diarsine ligands (bpy = 2,2'-bipyridine; dppm = 1,1-bis(diphenylphosphino)methane; dppe = 1,2-bis(diphenylphosphino)ethane; dpam = 1,1-bis(diphenylarsino)methane). While methoxy-substituted ruthenafuran [Ru(bpy)(κ2-dppe)(C^O)]+ ([7]+; C^O = anionic bidentate [C(OMe)CHC(Ph)O]- chelate) was obtained as the only product in the reaction between 2 and phenyl ynone HC≡C(C=O)Ph in MeOH, replacing 2 with 1 led to the formation of both methoxy-substituted ruthenafuran [Ru(bpy)(κ2-dppm)(C^O)]+ ([4]+) and phosphonium-ring-fused bicyclic ruthenafuran [Ru(bpy)(P^C^O)Cl]+ ([5]+; P^C^O = neutral tridentate [(Ph)2PCH2P(Ph)2CCHC(Ph)O] chelate). All of these aforementioned metallafuran complexes were derived from Ru(II)-vinylidene intermediates. The potential applications of these metallafuran complexes as anticancer agents were evaluated by in vitro cytotoxicity studies against cervical carcinoma (HeLa) cancer cell line. All the ruthenafuran complexes were found to be one order of magnitude more cytotoxic than cisplatin, which is one of the metal-based anticancer agents being widely used currently.
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Fosfinas , Rutenio , Ligandos , Metano , Fosfinas/farmacología , Rutenio/químicaRESUMEN
Regular blood glucose monitoring and control is necessary for people with type 1 or advanced type 2 diabetes, yet diagnosing and treating patients with diabetes in an accurate, sustained and patient-friendly manner remains limited. Here, a glucose-responsive bifunctional nanosystem (PGOxMns) is constructed via one-pot biomineralisation of manganese dioxide with glucose oxidase and ε-poly-L-lysine. Under hyperglycaemic conditions, the cascade reactions that occur when glucose interacts with PGOxMns can trigger the production of Mn(II), which enhances the magnetic resonance imaging signal. Simultaneously, manganese dioxide catalyses the decomposition of toxic hydrogen peroxide into oxygen, which also maintains glucose oxidase (GOx) activity. In an in vivo model of diabetes, PGOxMns is used to monitor glucose levels (0-20 mm) and allowed identification of diabetic mice via T1-weighted MRI. Furthermore, PGOxMns is found to have a high insulin-loading capacity (83.6%), likely due to its positive charge. A single subcutaneous injection of insulin-loaded nanosystem (Ins-PGOxMns) into diabetic mice resulted in a rapid and efficient response to a glucose challenge and prolonged blood glucose level control (< 200 mg dL-1) for up to 50 h. Overall, this proof-of-concept study demonstrates the feasibility of using biomineralised nanosystems to develop patient-friendly strategies for glucose monitoring and control.
RESUMEN
The present study examined whether a peripheral nerve (PN) graft can rescue developing motoneurons from degeneration and determined when immature motoneurons begin to express a regenerative capacity. Transplantation of a PN graft was unable to rescue motoneurons from degeneration if spinal root avulsion was performed in animals younger than P14. However, this procedure did enhance motoneuron survival when root avulsion was performed at P14 or later. Immature (P1 or P7) motoneurons were unable to regenerate their axons into the transplanted PN graft following root avulsion, whereas in older animals (P14-P28) motoneurons were able to regenerate axons into the PN graft. The percentage of regenerated motoneurons increased from P21 to P28 and was similar to that of adult animals. Therefore, the regenerative capacity of rat spinal motoneurons first begins at about P14, which seems to be critical.
Asunto(s)
Envejecimiento/fisiología , Animales Recién Nacidos/fisiología , Supervivencia Celular/fisiología , Neuronas Motoras/fisiología , Regeneración Nerviosa/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/fisiología , Estilbamidinas , Animales , Animales Recién Nacidos/anatomía & histología , Axotomía , Femenino , Colorantes Fluorescentes , Lateralidad Funcional/fisiología , Supervivencia de Injerto/fisiología , Conos de Crecimiento/fisiología , Conos de Crecimiento/ultraestructura , Neuronas Motoras/citología , Nervios Periféricos/citología , Nervios Periféricos/fisiología , Nervios Periféricos/trasplante , Ratas , Ratas Sprague-Dawley , Rizotomía , Médula Espinal/citología , Traumatismos de la Médula Espinal/patología , Trasplante de TejidosRESUMEN
BACKGROUND: Although up to 30% of patients with colorectal cancer have a positive family history of colorectal neoplasia, few colorectal cancers can be explained by mutations in high-penetrance genes. We investigated whether polymorphisms in DNA mismatch repair genes are associated with the risk of colorectal cancer. METHODS: We genotyped 929 case patients and 1098 control subjects from Ontario and 430 case patients and 275 control subjects from Newfoundland and Labrador for five polymorphisms in the mismatch repair genes MLH1 and MSH2 with the fluorogenic 5' nuclease assay. Tumor microsatellite instability (MSI) was determined with a polymerase chain reaction-based method; MSI status was assigned as high (MSI-H, > or = 30% unstable markers among all markers tested), low (MSI-L, <30% markers unstable), or stable (MSS, no unstable markers). We used unconditional logistic regression to evaluate the association between each polymorphism and colorectal cancer after adjusting for age and sex. The associations between polymorphisms and tumor clinicopathologic features were evaluated with a Pearson's chi-square or Fisher's exact test. All statistical tests were two-sided. RESULTS: We observed strong associations between the MLH1 -93G>A polymorphism and MSI-H tumors among case patients from Ontario (P = .001) and Newfoundland (P = .003). When compared with the control populations, homozygosity for the MLH1 -93G>A variant allele was associated with MSI-H tumors among case patients in Ontario (adjusted odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.65 to 6.30) and in Newfoundland (OR = 8.88, 95% CI = 2.33 to 33.9), as was heterozygosity among case patients in Ontario (OR = 1.84, 95% CI = 1.20 to 2.83) and in Newfoundland (OR = 2.56, 95% CI = 1.14 to 5.75). Genotype frequencies were similar among case patients with MSS and MSI-L tumors and control subjects, and the majority of homozygous variant carriers had MSS tumors. Among case patients from Ontario, an association between the MLH1 -93G>A polymorphism and a strong family history of colorectal cancer (for Amsterdam criteria I and II, P = .004 and P = .02, respectively) was observed. CONCLUSION: In two patient populations, the MLH1 -93G>A polymorphism was associated with an increased risk of MSI-H colorectal cancer.
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Proteínas Portadoras/genética , Neoplasias Colorrectales/genética , Reparación del ADN , Inestabilidad de Microsatélites , Proteínas Nucleares/genética , Polimorfismo Genético , Proteínas Adaptadoras Transductoras de Señales , Adenosina , Estudios de Casos y Controles , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Femenino , Frecuencia de los Genes , Genotipo , Guanina , Humanos , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Terranova y Labrador , Oportunidad Relativa , Ontario , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Proyectos de Investigación , Medición de Riesgo , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
We examined whether (1) a pan-caspase inhibitor, Boc-D-FMK, exerts long-term neuroprotective effects on spinal motoneurons (MNs) after root avulsion in neonatal rats and (2) whether the rescued spinal MNs regenerate their axons into a peripheral nerve (PN) graft and reinnervate a previously denervated target muscle. Eight weeks after root avulsion, 67% of spinal MNs remained in the Boc-D-FMK-treated group, whereas all MNs died in the sham control group. By 12 weeks postinjury, however, all Boc-D-FMK treated MNs died. In the regeneration experiment, a PN graft was implanted at different times after injury. The animals were allowed to survive for 4 weeks following the operation. Without caspase inhibition, MNs did not regenerate at any time point. In animals treated with Ac-DEVD-CHO, a caspase-3-specific inhibitor, and Boc-D-FMK, 44 and 62% of MNs, respectively, were found to regenerate their axons into a PN graft implanted immediately after root avulsion. When the PN graft was implanted 2 weeks after injury, however, MNs failed to regenerate following Ac-DEVD-CHO treatment, whereas 53% of MNs regenerated their axons into the graft after treatment with Boc-D-FMK. No regeneration was observed when a PN graft was implanted later than 2 weeks after injury. In the reinnervation study, injured MNs and the target biceps muscle were reconnected by a PN bridge implanted 2 weeks after root avulsion with administration of Boc-D-FMK. Eight weeks following the operation, 39% of MNs reinnervated the biceps muscle. Morphologically normal synapses and motor endplates were reformed in the muscle fibers. Collectively, these data provide evidence that injured neonatal motoneurons can survive and reinnervate peripheral muscle targets following inhibition of caspases.
Asunto(s)
Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/farmacología , Neuronas Motoras/fisiología , Regeneración Nerviosa/fisiología , Radiculopatía/fisiopatología , Animales , Animales Recién Nacidos , Axotomía , Compuestos de Bencilo/farmacología , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Femenino , Hidrocarburos Fluorados/farmacología , Neuronas Motoras/efectos de los fármacos , Desnervación Muscular , Músculo Esquelético/inervación , Músculo Esquelético/patología , Regeneración Nerviosa/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Radiculopatía/patología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Transection of the optic nerve initiates massive death of retinal ganglion cells (RGCs). Interestingly, despite the severity of the injury, RGC loss was not observed until several days after axotomy. The mechanisms responsible for this initial lack of RGC death remained unknown. In the current study, immunohistochemical analysis revealed that caspases-3 and -9 activation in the RGCs were not detected until day 3 post-axotomy, coinciding with the onset of axotomy-induced RGC loss. Interestingly, elevated Akt phosphorylation was observed in axotomized retinas during the absence of caspase activation. Inhibiting the increase in Akt phosphorylation by intravitreal injection of wortmannin and LY294002, inhibitors of PI3K, resulted in premature nuclear fragmentation, caspases-3 and -9 activation in the ganglion cell layer. Our findings thus indicate that the PI3K/Akt pathway may serve as an endogenous regulator of caspase activation in axotomized RGCs, thereby, contributing to the late onset of RGC death following axotomy.