Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Retinopathy , Sodium-Glucose Transporter 2 Inhibitors , Humans , Diabetes Mellitus, Type 2/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Glucagon-Like Peptide-1 Receptor/agonists , Diabetic Retinopathy/drug therapy , Glucose , SodiumABSTRACT
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.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Humans , Antitubercular Agents/pharmacology , Antitubercular Agents/metabolism , Diphosphates/pharmacology , Tuberculosis/drug therapy , Tuberculosis/microbiology , Mycobacterium smegmatisABSTRACT
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.
Subject(s)
Autonomic Nervous System Diseases , Carotid Artery Diseases , Carotid Artery Thrombosis , Ischemic Stroke , Lupus Erythematosus, Systemic , Stroke , Female , Humans , Carotid Artery Thrombosis/diagnostic imaging , Carotid Artery Thrombosis/etiology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , Symptom Flare Up , Carotid Artery Diseases/complications , Carotid Artery Diseases/diagnostic imaging , Pain , Stroke/etiologyABSTRACT
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.
