RESUMEN
Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.
Asunto(s)
Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Retinopatía Diabética/tratamiento farmacológico , Glucosa , SodioRESUMEN
We tested a series of SQ109 analogues against Mycobacterium tuberculosis and M. smegmatis, in addition to determining their uncoupling activity. We then investigated potential protein targets, involved in quinone and cell wall biosynthesis, using "rescue" experiments. There was little effect of menaquinone on growth inhibition by SQ109, but there were large increases in the IC50 of SQ109 and its analogues (up to 20×) on addition of undecaprenyl phosphate (Up), a homologue of the mycobacterial decaprenyl (C50) diphosphate. Inhibition of an undecaprenyl diphosphate phosphatase, an ortholog of the mycobacterial phosphatase, correlated with cell growth inhibition, and we found that M. smegmatis cell growth inhibition could be well predicted by using uncoupler and Up-rescue results. We also investigated whether SQ109 was metabolized inside Mycobacterium tuberculosis, finding only a single metabolite, previously shown to be inactive. The results are of general interest since they help explain the mechanism of SQ109 in mycobacteria.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Antituberculosos/farmacología , Antituberculosos/metabolismo , Difosfatos/farmacología , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Mycobacterium smegmatisRESUMEN
Carotid artery thrombosis following carotidynia is an uncommon manifestation of systemic lupus erythematosus. We report the case of a woman without evidence of a lupus flare-up who presented with the unusual clinical course of ipsilateral carotidynia and recurrent ischemic stroke due to carotid thrombosis. To our knowledge, this is the first case of such an unusual manifestation in lupus and highlights distinctive challenges in the diagnosis and management of carotid artery thrombosis following carotidynia.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo , Enfermedades de las Arterias Carótidas , Trombosis de las Arterias Carótidas , Accidente Cerebrovascular Isquémico , Lupus Eritematoso Sistémico , Accidente Cerebrovascular , Femenino , Humanos , Trombosis de las Arterias Carótidas/diagnóstico por imagen , Trombosis de las Arterias Carótidas/etiología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Brote de los Síntomas , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Dolor , Accidente Cerebrovascular/etiologíaRESUMEN
4-O-methylhonokiol, a neolignan compound from Magnolia Officinalis, has been reported to have various biological activities including hair growth promoting effect. However, although transforming growth factor-ß (TGF-ß) signal pathway has an essential role in the regression induction of hair growth, the effect of 4-O-methylhonokiol on the TGF-ß signal pathway has not yet been elucidated. We thus examined the effect of 4-O-methylhonokiol on TGF-ß-induced canonical and noncanonical pathways in HaCaT human keratinocytes. When HaCaT cells were pretreated with 4-O-methylhonokiol, TGF-ß1-induced G1/G0 phase arrest and TGF-ß1-induced p21 expression were decreased. Moreover, 4-O-methylhonokiol inhibited nuclear translocation of Smad2/3, Smad4 and Sp1 in TGF-ß1-induced canonical pathway. We observed that ERK phosphorylation by TGF-ß1 was significantly attenuated by treatment with 4-O-methylhonokiol. 4-O-methylhonokiol inhibited TGF-ß1-induced reactive oxygen species (ROS) production and reduced the increase of NADPH oxidase 4 (NOX4) mRNA level in TGF-ß1-induced noncanonical pathway. These results indicate that 4-O-methylhonokiol could inhibit TGF-ß1-induced cell cycle arrest through inhibition of canonical and noncanonical pathways in human keratinocyte HaCaT cell and that 4-O-methylhonokiol might have protective action on TGF-ß1-induced cell cycle arrest.