Evaluation of Antimycobacterial Activity of Higenamine Using Galleria mellonella as an In Vivo Infection Model

The Phytochemical investigation on MeOH extract on the bark of Aristolochia brasiliensis Mart.&Zucc(Aristolochi-aceae)led to the isolation of major compound(1)as light brown grainy crystals.The compound was identified as 1-(4-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol(higenamine)on the basis of spectroscopic analysis,including 1D and 2D NMR spectroscopy.The compound was evaluated for its antimycobacterial activity against Mycobacterium indicus pranii(MIP),using Galleria mellonella larva as an in vivo infection model.The survival of MIP infected larvae after a single dose treatment of 100 mg/kg body weight of higenamine was 80%after 24 h.Quantitatively the compound exhibited a dose dependent activity,as evidenced by the reduction of colony density from 10^(5) to 10^(3) CFU for test concentrations of 50,100,150 and 200 mg/kg body weight respectively.The IC50 value for higenamine was 161.6 mg/kg body weight as calculated from a calibration curve.Further analysis showed that,a complete inhibition of MIP in the G.mellonella could be achieved at 334 mg/kg body weight.Despite the fact that MIP has been found to be highly resistant against isoniazid(INH)in an in vitro assay model,in this study the microbe was highly susceptible to this standard anti-TB drug.The isolation of higenamine from the genus Aristolochia and the method used to evaluate its in vivo antimycobacterial activity in G.mellonella are herein reported for the first time.

附子强心成分Higenamine及其结构

最近,作者分离得混杂在 yokonoside 中的微量强心成分,将之稀释至10-9浓度时,仍显示强心活性。此成分为无色板状结晶,熔点260°,为水溶性异喹啉类生物碱,定名为 higenamine 盐酸盐,结构式为:

A novel β_(2)-AR agonist,Higenamine,induces β-arrestin-biased signaling

The biased ligands in G protein-coupled receptors(GPCRs)have opened new avenues for developing safer and more effective drugs.However,the identification of such biased ligands as drug candidates is highly desirable.Here,we report that Higenamine,a compound isolated from a Chinese herb,functions as a novel β-arrestin-biased ligand of the β_(2)-adrenergic receptor(β_(2)-AR).The radioligand binding assays demonstrated that Higenamine was the ligand of β_(2)-AR.Higenamine induced phosphorylation of extracellular signal-regulated kinase 1/2(ERK1/2),which can be blocked by propranolol,an inhibitor of β_(2)-AR.The Gi protein inhibitor,pertussis toxin,had no effect on the phosphorylation of ERK1/2 induced by Higenamine.Furthermore,Higenamine induced ERK1/2 phosphorylation through transactivation of Epithelial growth factor receptor(EGFR).We also found that Higenamine-induced-ERK1/2 phosphorylation is dependent on β-arrestin1/2,and HG inhibits Doxorubicin-induced cardiomyocyte apoptosis.Our results identify Higenamine as a novel biased ligand via the β-arrestin-dependent pathway.These findings give us a better understanding of Higenamine’s potential role in designing diagnostic and therapeutic strategies.

Hige namine as a Potential Pharmacologic Stress Age nt in the Detection of Coro nary Artery Disease

Myocardial perfusion imaging(MPI) is valuable for the diagnosis,prognosis,and management of coronary artery disease(CAD).The most commonly used pharmacologic stress agents at present are vasodilators and adrenergic agents.However,these agents have contraindications and may cause adverse effects in some patients.Thus,other stress agents feasible for more patients are required.Higenamine(HG) is a β-adrenergic receptor agonist currently approved for clinical trials as a stress agent for myocardial infarction.It also has a promising value in MPI for the detection of CAD in preclinical and clinical studies.This review summarizes the application of HG on MPI,including its mechanism of action,stress protocol,efficacy,and safety.