RESUMEN
The induction of macrophage death is considered a potential mechanism by which components secreted by Clostridium septicum are used to evade the innate immune response and cause tissue damage. This study aimed to determine the effects of partially purified fractions of extracellular proteins secreted by C. septicum on the death of mouse peritoneal macrophages. Elicited mouse peritoneal macrophages were incubated with partially purified fractions of proteins secreted by C. septicum into the culture medium. After incubation, the protein fraction with a molecular weight ≥100 kDa caused significant cell death in macrophages, altered cell morphology, increased the expression of markers of apoptosis and autophagy, and increased the expression (protein and mRNA) of IL-10 and TNFα. Our data suggest that the proteins secreted by C. septicum (MW, ≥100 kDa) induce cell death in macrophages by promoting autophagy-triggered apoptosis. This study may contribute to our understanding of the molecular mechanism of immune evasion by C. septicum at the infection site.
RESUMEN
Neisseria gonorrheae, the causative agent of genitourinary infections, has been associated with asymptomatic or recurrent infections and has the potential to form biofilms and induce inflammation and cell transformation. Herein, we aimed to use computational analysis to predict novel associations between chronic inflammation caused by gonorrhea infection and neoplastic transformation. Prioritization and gene enrichment strategies based on virulence and resistance genes utilizing essential genes from the DEG and PANTHER databases, respectively, were performed. Using the STRING database, proteinâprotein interaction networks were constructed with 55 nodes of bacterial proteins and 72 nodes of proteins involved in the host immune response. MCODE and cytoHubba were used to identify 12 bacterial hub proteins (murA, murB, murC, murD, murE, purN, purL, thyA, uvrB, kdsB, lpxC, and ftsH) and 19 human hub proteins, of which TNF, STAT3 and AKT1 had high significance. The PPI networks are based on the connectivity degree (K), betweenness centrality (BC), and closeness centrality (CC) values. Hub genes are vital for cell survival and growth, and their significance as potential drug targets is discussed. This computational study provides a comprehensive understanding of inflammation and carcinogenesis pathways that are activated during gonorrhea infection.
Asunto(s)
Proteínas Bacterianas , Transformación Celular Neoplásica , Biología Computacional , Gonorrea , Neisseria gonorrhoeae , Mapas de Interacción de Proteínas , Humanos , Gonorrea/microbiología , Gonorrea/genética , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/patogenicidad , Mapas de Interacción de Proteínas/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Transformación Celular Neoplásica/genética , Genes Esenciales , Virulencia/genética , Inflamación/genética , Factores de Virulencia/genética , Interacciones Huésped-Patógeno/genética , MultiómicaRESUMEN
The search for mechanism-based anti-inflammatory therapies is of fundamental importance to avoid undesired off-target effects. Phospholipase A2 (PLA2) activity is a potential molecular target for anti-inflammatory drugs because it fuels arachidonic acid needed to synthesize inflammation mediators, such as prostaglandins. Herein, we aim to investigate the molecular mechanism by which ß-keto amyrin isolated from a methanolic extract of Cryptostegia grandiflora R. Br. Leaves can inhibit inflammation caused by Daboia russellii viper (DR) venom that mainly contains PLA2. We found that ß-keto amyrin neutralizes DR venom-induced paw-edema in a mouse model. Molecular docking of PLA2 with ß-keto amyrin complex resulted in a higher binding energy score of -8.86 kcal/mol and an inhibition constant of 611.7 nM. Diclofenac had a binding energy of -7.04 kcal/mol and an IC50 value of 620 nM, which predicts a poorer binding interaction than ß-keto amyrin. The higher conformational stability of ß-keto amyrin interaction compared to diclofenac is confirmed by molecular dynamics simulation. ß-keto amyrin isolated from C. grandiflora inhibits the PLA2 activity contained in Daboia russellii viper venom. The anti-inflammatory property of ß-keto amyrin is due to its direct binding into the active site of PLA2, thus inhibiting its enzyme activity.
Asunto(s)
Apocynaceae , Daboia , Inflamación , Ácido Oleanólico , Venenos de Víboras , Animales , Ratones , Antiinflamatorios/farmacología , Apocynaceae/química , Diclofenaco/farmacología , Diclofenaco/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacología , Ácido Oleanólico/uso terapéutico , Fosfolipasas A2/efectos de los fármacos , Fosfolipasas A2/metabolismo , Venenos de Víboras/química , Venenos de Víboras/toxicidadRESUMEN
309 gastrostomías percutáneas sucesivas fueron realizadas en 206 pacientes por un solo operador en el Servicio de Endoscopía del Hospital DIPRECA durante los años 1993 al 1998. La edad promedio de los pacientes fue de 71 años (18-91 años). El 15 por ciento requirió al menos de un recambio. El seguimiento fluctuó entre 4 y 20 meses. Hubo un 3.87 por ciento de morbilidad y 0 por ciento de mortalidad. La indicación más frecuente son las enfermedades neurológicas