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Acta Pharmaceutica Sinica B ; (6): 1083-1093, 2020.
Article in English | WPRIM | ID: wpr-828822


Understanding of the nephrotoxicity induced by drug candidates is vital to drug discovery and development. Herein, an metabolomics method based on air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was established for direct analysis of metabolites in renal tissue sections. This method was subsequently applied to investigate spatially resolved metabolic profile changes in rat kidney after the administration of aristolochic acid I, a known nephrotoxic drug, aimed to discover metabolites associated with nephrotoxicity. As a result, 38 metabolites related to the arginine-creatinine metabolic pathway, the urea cycle, the serine synthesis pathway, metabolism of lipids, choline, histamine, lysine, and adenosine triphosphate were significantly changed in the group treated with aristolochic acid I. These metabolites exhibited a unique distribution in rat kidney and a good spatial match with histopathological renal lesions. This study provides new insights into the mechanisms underlying aristolochic acids nephrotoxicity and demonstrates that AFADESI-MSI-based metabolomics is a promising technique for investigation of the molecular mechanism of drug toxicity.

Acta Pharmaceutica Sinica B ; (6): 301-312, 2020.
Article in English | WPRIM | ID: wpr-787627


Glioblastoma is the most common and aggressive primary tumor in the central nervous system, accounting for 12%-15% of all brain tumors. 3--Acetyl-11-keto--boswellic acid (AKBA), one of the most active ingredients of gum resin from Birdw., was reported to inhibit the growth of glioblastoma cells and subcutaneous glioblastoma. However, whether AKBA has antitumor effects on orthotopic glioblastoma and the underlying mechanisms are still unclear. An orthotopic mouse model was used to evaluate the anti-glioblastoma effects of AKBA. The effects of AKBA on tumor growth were evaluated using MRI. The effects on the alteration of metabolic landscape were detected by MALDI-MSI. The underlying mechanisms of autophagy reducing by AKBA treatment were determined by immunoblotting and immunofluorescence, respectively. Transmission electron microscope was used to check morphology of cells treated by AKBA. Our results showed that AKBA (100 mg/kg) significantly inhibited the growth of orthotopic U87-MG gliomas. Results from MALDI-MSI showed that AKBA improved the metabolic profile of mice with glioblastoma, while immunoblot assays revealed that AKBA suppressed the expression of ATG5, p62, LC3B, p-ERK/ERK, and P53, and increased the ratio of p-mTOR/mTOR. Taken together, these results suggested that the antitumor effects of AKBA were related to the normalization of aberrant metabolism in the glioblastoma and the inhibition of autophagy. AKBA could be a promising chemotherapy drug for glioblastoma.

Article in Chinese | WPRIM | ID: wpr-692318


Nanopore / nanochannel sensing technique drawing more attention in analytical chemistry due to its unique advantages and the fabricated electrochemical sensors and electrochemical responsive gates have been widely used for more target detection, including single molecule protein and DNA sequencing. Nanopore /nanochannel that used for fabricating electrochemical detection system is mainly divided into biological nanopore and solid state nanopore, and among them, solid state nanopore / nanochannel has a wide range of application due to its inherent properties, such as easy for modification, good mechanical property and stability. Resistive pulse sensing and current-voltage curves (ion current rectification) are two main methods of nanopore / nanochannel sensing technique used for target analysis, so in this review, we introduced the fundamentals and applications of nanopore sensing technique based on the above two methods. In addition, we concluded the application and development of single state nanopore / nanochannel in recent years, and also gave a brief look at the future challenges and prospects in the development of this field.

Chinese Pharmacological Bulletin ; (12): 934-941, 2017.
Article in Chinese | WPRIM | ID: wpr-620131


Aim To observe the effect of antibody NCX-3F10 on the main ion current of rat ventricular myocytes and its effect on arrhythmias induced by ischemia/reperfusion(I/R).Methods ① The whole-cell patch clamp technique was employed to record the Na+/Ca2+ exchange current(INa/Ca) and other major ion currents in rat ventricular myocytes.② The rat models of arrhythmia induced by ischemia/reperfusion were established by ligating the left coronary artery to in vivo and in vitro.Then the effects of antibody on the arrhythmia were observed.③ The IonOptix ion imaging system was used to observe the effect of antibody on calcium transients in single ventricular myocytes.Results ① The antibody NCX-3F10 dose-dependently inhibited INa/Ca from 5 to 40 mg·L-1.The IC50 for outward and inward currents was 11.15 and 11.69 mg·L-1, and the maximum inhibitory rates were 61% and 62%, respectively.The antibody also had an inhibitory effect on calcium current(ICa-L), and had no significant effect on inward rectifier potassium current(IK1), transient outward potassium current(Ito) and sodium current(INa).② In the isolated rat heart group I/R, 100% rats showed ventricular tachycardia, and 88.89% rats had ventricular fibrillation.After administration of antibody NCX-3F10(10 mg·L-1) 5 min before reperfusion, the incidence of ventricular tachycardia decreased to 44.43%(P<0.05), and the duration of ventricular tachycardia and ventricular fibrillation was also shortened remarkably(P<0.05).③ In the anesthetized rats after administration of antibody NCX-3F10(50 μg·kg-1) 5 min before reperfusion, the incidence and duration of ventricular tachycardia,the incidence and duration of ventricular fibrillation, and total number of ventricular premature beats were significantly decreased(P<0.05).④ From 5 to 40 mg·L-1, NCX-3F10 antibody decreased calcium transient amplitude in rat single ventricular myocytes dose-dependently(P<0.05).Conclusions The NCX-3F10 antibody shows significant arrhythmic effects on ischemia-reperfusion induced arrhythmia in rats both in vitro and in vivo, the underlying mechanism of which is related to NCX and L-type calcium current inhibition and calcium overload reduction by the NCX antibody.

Chinese Pharmacological Bulletin ; (12): 305-309, 2010.
Article in Chinese | WPRIM | ID: wpr-403331


Aim To assess the effects of N -[2-p-bromo-cinnamylamino-ethyl]-5-isoquinoline-sulfonamide (H-89), a potentially selective inhibitor of Protein Kinase A (PKA), on cardiac membrane ion channels and transporters, which will further fulfill our understanding of pharmacology of PKA inhibitors.Methods Whole-cell patch clamp was used to investigate the effects of H-89 on cardiac L-type Ca~(2+) current (I_(Ca-L)), Na~+ current (I_(Na)), inward rectifier K~+ current (I_(K1)), transient outward K~+ current (I_(to)) and Na~+-Ca~2+ exchanger current (I_(Na/Ca)) in enzymatic dissociated SD rat ventricular myocytes.Results H-89 at 1~10 μmol·L~(-1) could inhibit I_(Ca-L) , I_(Na) , and Ito in a concentration-relative manner (P <0.05). At low concentra-tion (5 μmol·L~(-1)), H-89 completely inhibited I_(K1) (P <0.05) just as the action of 0.5 mmol·L~(-1) BaCl_2.Further, H-89 at 1~10 μmol·L~(-1) had no significant effect on I_(Na/Ca) (P >0.05).Conclusion The direct or PKA-mediated indirect action maybe involved in the effects of H-89 on ion currents and transporter.