iridoids and Renal-Insufficiency--Chronic

Hyperuricemia is a common metabolic disease and is one of the factors that could induce chronic kidney disease (CKD). Geniposide (GEN) is a typical natural iridoid glucoside compound with a series of biological activities, but the poor bioavailability of GEN limits its clinical application. In this context, the pharmacological activity of the geniposide-phospholipid complex (GEN-PLC) in ameliorating posthyperuricemia CKD was evaluated by in vitro and in vivo experiments in this study. In vitro cell experiments showed that GEN-PLC treatment markedly decreased inflammatory cytokine levels and reactive oxygen species levels compared with those of GEN in uric acid-treated HKC cells. In vivo research results confirmed that a high concentration of uric acid could cause CKD by increasing inflammatory cytokines and reactive oxygen species in hyperuricemic mice. At the same time, GEN-PLC could regulate the PI3K/AKT/NF-κB and Keap1/Nrf2/HO-1 signaling pathways to effectively inhibit the inflammatory response and oxidative stress, thereby ameliorating posthyperuricemia CKD, and the therapeutic effect was better than that of GEN. In addition, the preparation technology of GEN-PLC was optimized, and the physiochemical analysis explained the intermolecular interactions of the two components. Based on the research results, GEN-PLC could enhance the bioavailability of GEN and become a promising candidate for clinical drug development.

Topics: Animals; Inflammation; Iridoids; Kelch-Like ECH-Associated Protein 1; Mice; NF-E2-Related Factor 2; Oxidative Stress; Phosphatidylinositol 3-Kinases; Phospholipids; Reactive Oxygen Species; Renal Insufficiency, Chronic; Uric Acid

Herbal medicines are widely used as therapeutic products in many countries. Fructus Corni, a traditional herb medicine, has been clinically used to cure chronic nephropathy for thousands of years. It could be converted by gut microflora in vivo to shape its pharmacological profiles. Thus, metabolic profiles of major active constituents in Fructus Corni extracts by gut microflora from rats in healthy and nephropathy state were firstly investigated in vitro by ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) in this study. According to the features of protonated ions, five metabolites (M1, M2, M3, M5 and M6) were found and preliminarily authenticated. Intestinal bacteria were capable of converting N0 (loganin) to its aglycone M1 (loganetin). The latter was further hydrogenated to the corresponding M2 (hydrogenated loganetin) and subsequently to M3 (hydrogenated and demethylated loganetin) by demethylation; While M5 (demethylated morronisid aglycone) and M6 (dehydroxylated morronisid aglycone) were identified as the two metabolites of N4 (morronisid) through demethylation and dehydroxylation. Gut microflora from healthy and nephropathy rats could degrade loganin and morronisid to the above metabolites. However, healthy rat intestinal bacteria showed more powerful degradation and much more amounts of M1 and M6 were obtained in their samples. Additionally, this work demonstrated that UPLC-Q-TOF/MS approach connected with MetaboLynx™ analysis software was rapid and reliable for screening and authentication of natural product metabolites.

Topics: Animals; Chromatography, High Pressure Liquid; Cornus; Gastrointestinal Microbiome; Glycosides; Iridoids; Mass Spectrometry; Plant Extracts; Rats; Renal Insufficiency, Chronic

Cornus officinalis-Rehmannia glutinosa herb couple is widely used herb medicine in clinical practice to treat chronic kidney disease (CKD). However, the in vivo integrated metabolism of its main bioactive components in CKD rats remains unknown. In this study, UPLC-Q-TOF/MS technique combined with Metabolynx

Topics: Administration, Oral; Animals; Case-Control Studies; Chromatography, High Pressure Liquid; Cornus; Feces; Glucosides; Glycosides; Iridoid Glucosides; Iridoids; Male; Phenols; Plant Extracts; Rats; Rehmannia; Renal Insufficiency, Chronic; Tandem Mass Spectrometry

Fructus Corni has been used for nourishing liver and kidney in clinical practice for many years. However, the in vivo integrated metabolism profile of its bioactive components remains unknown. In the present study, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry coupled with the MetaboLynxTM software was established for screening and identification of the metabolites of the loganin and the morroniside in normal and chronic kidney disease (CKD) rat plasma, urine and feces after oral administration of Fructus Corni extract. The results showed that 11 metabolites including taurine and glucuronide conjugates, deglycosylated, dehydrated, (de)hydroxylated, (de)methylated, acetylated products were tentatively detected in normal rat samples while only eight metabolites were obtained in the model samples. Two parent compounds were both absorbed into the blood circulation of the normal and CKD rats. However, the compounds in the CKD rat showed lower metabolic capability. Few kinds and minor amounts of the metabolites were appeared in the CKD rat plasma, urine and feces. While considerable amounts of the parent compounds were detected in the CKD plasma. This helped maintain a high blood drug concentration which might be beneficial for the treatment of CKD. These results will be helpful for the further investigation of the pharmacokinetic study of Fructus Corni in vivo.

Topics: Administration, Oral; Animals; Biomarkers; Chromatography, High Pressure Liquid; Cornus; Glycosides; Iridoids; Male; Metabolome; Metabolomics; Plant Extracts; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

A sensitive and rapid method for determination of loganin, morroniside, catalpol and acteoside in rat plasma after oral administration of Rehmannia glutinosa Libosch and Cornus officinalis Sieb drug pair based on ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS). Chromatographic separation was achieved using an Acquity UPLC BEH C18 column (100mm×2.1mm, 1.7μm) at a flow rate of 0.4mL/min, using gradient mode containing 0.1% formic acid in water and acetonitrile were used as the mobile phase A and B. Loganin, morroniside, catalpol, acteoside and the internal standard (chloramphenicol) were detected by selected reaction monitoring in the negative ion mode with the mass transition of m/z 451.0→179.0 (morroniside), m/z 435.0→227.0 (loganin), m/z 407.1→199.1 (catalpol), m/z 623.2→161.0 (acteoside) and m/z 320.8→151.9 (chloramphenicol), respectively. All calibration curves showed good linearity (r>0.991). The precision was evaluated by intra-day and inter-day assays and the RSD% were all within 9.58%. The recovery ranged from 67.62 to 80.14%. The method was successfully applied to pharmacokinetic study of the analytes in normal and doxorubicin-induced chronic kidney disease rat plasma.

Topics: Administration, Oral; Animals; Chromatography, High Pressure Liquid; Cornus; Drugs, Chinese Herbal; Glucosides; Glycosides; Iridoid Glucosides; Iridoids; Limit of Detection; Male; Mass Spectrometry; Phenols; Rats; Rats, Sprague-Dawley; Rehmannia; Renal Insufficiency, Chronic

Pharmacokinetic studies on traditional Chinese medicine are useful to evaluate and predict the drug efficacy and safety. The renal impairment may affect drug clearance and other pharmacokinetic processes which can increase toxicity and drug to drug interactions or cause ineffective therapy. Pharmacokinetic studies in pathological status rats might be meaningful for revealing the action mechanism and improving clinical medication of the herb medicine.. A highly sensitive and rapid ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method with multiple-reaction monitoring (MRM) mode was developed and validated for simultaneous quantitation of morroniside and loganin in normal and doxorubicin-induced chronic kidney disease (CKD) rat plasma after oral administration of Shanzhuyu (fruit of Cornus officinalis) extract.. Both calibration curves gave satisfactory linearity (r>0.99) at linear range of 1.96-1962.5ngmL(-1) for morroniside, 1.53-1531.25ngmL(-1) for loganin. The precision and accuracy of the in vivo study were assessed by intra-day and inter-day assays. The percentages of relative standard deviation (RSD) were all within 9.58% and the accuracy (RE) was in the -6.02% to 8.11% range. The extraction recoveries of morroniside, loganin and internal standard (IS) were all >67.62% and the matrix effects ranged from 95.07% to 102.75%.. The pharmacokinetic behavior of morroniside and loganin in normal and CKD rat plasma was determined in this paper. The significant different pharmacokinetic parameters might partly result from the changes of P-glycoprotein and metabolic enzymes in the pathological state. The pharmacokinetic research in the pathological state might provide more useful information to guide the clinical usage of the herb medicine.

Topics: Administration, Oral; Animals; Chromatography, Liquid; Cornus; Fruit; Glycosides; Iridoids; Male; Plant Extracts; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Tandem Mass Spectrometry