RESUMEN
Five Lycopodium alkaloids featuring novel C17N2 (1 and 2), C29N3 (3 and 4), and C15N2 (5) skeletons were isolated from Lycopodium japonicum. Compound 1 is the first natural product containing a 3-aza[3.3.3]propellane motif. The structures of these compounds were elucidated by spectroscopic analysis, X-ray crystallography, and computational methods. Compounds 1 and 3-5 significantly inhibited TGF-ß1-induced fibronectin deposition in HK-2 cells at a nontoxic concentration of 20 µM.
Asunto(s)
Alcaloides , Lycopodium , Alcaloides/química , Alcaloides/farmacología , Cristalografía por Rayos X , Fibrosis , Lycopodium/química , Estructura MolecularRESUMEN
Diabetic nephropathy (DN) fibrosis is a major cause of end-stage renal disease with unsatisfactory therapy drugs and a low 5-year survival rate. There is a lack of specific and effective treatment drugs. In the present study, we report that asiatic acid (AA), a triterpenic acid found in Cyclocarya paliurus, has good anti-fibrosis activity both in vitro and in vivo. The STZ-induced diabetic model of rats was used to investigate the effects of AA on DN fibrosis. A 15-week AA treatment (10 mg kg-1 or 30 mg kg-1) markedly decreased urine albumin and blood urea nitrogen levels, and ameliorated increased mesangial matrix and glomerular fibrosis. HG + TGF-ß1-induced HK-2 cells were applied to evaluate the anti-fibrosis effect of AA. The results revealed AA selectively blocked the interaction of TGF-ß type I receptor (TGF-ßRI) with Smad3 by binding to TGF-ßRI, suppressed the subsequent phosphorylation and nuclear translocation of Smad3, and downregulated the major fibrotic protein expression of collagen I, fibronectin and a-smooth muscle actin (α-SMA), thereby switching the progress of epithelial-mesenchymal transition (EMT). Furthermore, the protein levels of LC3 and LAMP1 were significantly altered by AA administration, implying that the autophagy-lysosome system might be involved in DN fibrosis. However, the anti-fibrosis capacity of AA was partly counteracted by an autophagy-lysosome inhibitor (chloroquine). These findings indicate AA could decrease TGF-ß1 secretion and suppress tubulointerstitial fibrosis by directly inhibiting TGF-ßR1 and activating the autophagy-lysosome system. Altogether, AA may be a potential candidate drug for preventing DN fibrosis.
Asunto(s)
Diabetes Mellitus , Nefropatías Diabéticas , Juglandaceae , Animales , Autofagia , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Fibrosis , Lisosomas/metabolismo , Triterpenos Pentacíclicos , Ratas , Receptor Tipo I de Factor de Crecimiento Transformador beta , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
OBJECTIVES: Gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging is useful in assessing left ventricular (LV) myocardial perfusion and function. This study evaluated the LV functional changes after adenosine vasodilator stress, using gated SPECT. METHODS: The study population consisted of 70 patients who underwent adenosine-mediated stress and rest SPECT. All patients underwent coronary angiography. Semi-quantitative assessment of perfusion was analyzed and produced the summed rest score (SRS), the summed stress score (SSS) and the summed difference score (SDS). The global LV function parameters [ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV)] and regional LV function [the summed motion score (SMS) and the summed thickening score (STS)] were quantified by gated SPECT. RESULTS: Patients were divided into 2 groups: group 1 comprised 16 patients with worsening of LVEF (LVEFrest-LVEFado ≥5%), and group 2 comprised the other 54 patients. Compared with group 2, patients in group 1 had a significantly higher SSS and SDS (9.1 ± 6.8 vs. 5.6 ± 4.5 and 6.6 ± 3.8 vs. 3.6 ± 4.0, respectively; p < 0.05) and the severity of coronary artery stenosis was more serious (p < 0.05). CONCLUSION: Worsening of LVEF after adenosine-induced vasodilator stress, as shown by (99m)Tc-MIBI gated SPECT, is a valuable nonperfusion marker of significant CAD.