Asperulosidic Acid Ameliorates Renal Interstitial Fibrosis via Removing Indoxyl Sulfate by Up-Regulating Organic Anion Transporters in a Unilateral Ureteral Obstruction Mice Model.

Asperulosidic acid is a bioactive iridoid isolated from Hedyotis diffusa Willd. with anti-inflammatory and renal protective effects. However, its mechanism on renal interstitial fibrosis has not been elucidated yet. The present study aims to explore whether asperulosidic acid could retard renal fibrosis by reducing the circulating indoxyl sulfate (IS), which is a uremic toxin and accelerates chronic kidney disease progression by inducing renal fibrosis. In this paper, a unilateral ureteral obstruction (UUO) model of Balb/C mice was established. After the mice were orally administered with asperulosidic acid (14 and 28 mg/kg) for two weeks, blood, liver and kidney were collected for biochemical, histological, qPCR and Western blot analyses. Asperulosidic acid administration markedly reduced the serum IS level and significantly alleviated the histological changes in glomerular sclerosis and renal interstitial fibrosis. It is noteworthy that the mRNA and protein levels of the organic anion transporter 1 (OAT1), OAT3 and hepatocyte nuclear factor 1α (HNF1α) in the kidney were significantly increased, while the mRNA expressions of cytochrome P450 2e1 (Cyp2e1) and sulfotransferase 1a1 (Sult1a1) in the liver were not altered after asperulosidic acid administration. These results reveal that asperulosidic acid could accelerate the renal excretion of IS by up-regulating OATs via HNF1α in UUO mice, thereby alleviating renal fibrosis, but did not significantly affect its production in the liver, which might provide important information for the development of asperulosidic acid.

Strain differences in the drug transport capacity of intestinal glucose transporters in Sprague-Dawley versus Wistar rats, C57BL/6J versus Kunming mice.

Designing oral drug delivery systems using intestinal glucose transporters (IGTs) may be one of the strategies for improving oral bioavailability of drugs. However, little is known about the biological factors affecting the drug transport capacity of IGTs. Gastrodin is a sedative drug with a structure very similar to glucose. It is a highly water-soluble phenolic glucoside. It can hardly enter the intestine through simple diffusion but exhibits good oral bioavailability of over 80%. We confirmed that gastrodin is absorbed via the intestinal glucose transport pathway. It has the highest oral bioavailability among the reported glycosides' active ingredients through this pathway. Thus, gastrodin is the most selective drug substrate of IGTs and can be used to evaluate the drug transport capacity of IGTs. Obviously, strain is one of the main biological factors affecting drug absorption. This study firstly compared the drug transport capacity of IGTs between SD rats and Wistar rats and between C57 mice and KM mice by pharmacokinetic experiments and single-pass intestinal perfusion experiments of gastrodin. Then, the sodium-dependent glucose transporter type 1 (SGLT1) and sodium-independent glucose transporters type 2 (GLUT2) in the duodenum, jejunum, ileum and colon of these animals were quantified using RT-qPCR and Western blot. The results showed that the oral bioavailability of gastrodin in Wistar rats was significantly higher than in SD rats and significantly higher in KM mice than in C57 mice. Gastrodin absorption significantly differed among different intestinal segments in SD rats, C57 mice and KM mice, except Wistar rats. RT-qPCR and Western blot demonstrated that the intestinal expression distribution of SGLT1 and GLUT2 in SD rats and C57 mice was duodenum ≈ jejunum > ileum > colon. SGLT1 expression did not differ among different intestinal segments in KM mice, whereas the intestinal expression distribution of GLUT2 was duodenum ≈ jejunum ≈ ileum > colon. However, the expression of SGLT1 and GLUT2 did not differ among different intestinal segments in Wistar rats. It was reported that the intestinal expression distribution of SGLT1 and GLUT2 in humans is duodenum > jejunum > ileum > colon. Hence, the intestinal expression distribution of SGLT1 and GLUT2 of SD rats and C57 mice was more similar to that in humans. In conclusion, the drug transport capacity of IGTs differs in different strains of rats and mice. SD rats and C57 mice are more suitable for evaluating the pharmacokinetics of glycosides' active ingredients absorbed via the intestinal glucose transport pathway.

Pharmacokinetics and pharmacodynamics of bioactive compounds in Penyanqing preparation in THP-1 inflammatory cells induced by Lipopolysaccharide.

BACKGROUND: Penyanqing (PYQ), a traditional Chinese medicine (TCM), has a good clinical efficacy for the treatment of pelvic inflammatory disease (PID). Previously, researches on its anti-inflammatory effect and mechanism in vitro, in silico, and in vivo have been reported by our team. However, the interrelationship between the anti-inflammatory activity and the active compounds in PYQ are not clear. Here, the pharmacokinetics-pharmacodynamics (PK-PD) study was carried out for more proper clinical use. METHODS: The plasma concentrations of salvianolic acid B (SAB), protocatechualdehyde (PRO), paeoniflorin (PE), astilbin (AST), ferulic acid (FE), and chlorogenic acid (CH) in SD rats after PYQ administration were determined by a selective and rapid HPLC-MS/MS method. In addition, the PK-PD on cell model was used to explore the relationship between the plasma concentration and inflammatory biomarkers (TNF-α, IL-1ß). RESULTS: The results of this study showed that the six components could reach the peak blood concentration within 0.29 h, indicating the rapid absorption of it. The eliminations of AST, CH, FE, PE, and PRO were relatively fast due to their mean residence times (MRTs) within 3 h, while the elimination of SAB was slower (MRT 5.67 ± 0.66 h). Combined with a THP-1 cell model, there was a significant correlation between inflammatory factors and component plasma concentrations with correlation coefficients in the range of -0.9--0.746. Correspondingly, the drug-containing plasma obtained at 0.25 h point exhibited the best inhibition effect on production of IL-1ß and TNF-α in LPS-induced THP-1 cells. CONCLUSION: The six main components in PYQ could be quickly absorbed, and there was a potential good correlation between their pharmacokinetics and the pharmacodynamics of PYQ.

Comparison of the chronic unpredictable mild stress and the maternal separation in mice postpartum depression modeling.

Postpartum depression (PPD) is a serious mental health concern of new mothers worldwide. In view of the particularity of puerpera, the research on pathogenesis and drug development of PPD are highly dependent on animal models. Although both maternal separation (MS) and chronic unpredictable mild stress (CUMS) modeling approaches have been used in PPD studies, the characteristics of the two rodent models have not been compared to explain which is more advantageous in PPD research. In this study, we applied 21-day MS and CUMS paradigms to induce mouse model of PPD and compared their differences in behavior, physiology and gut microbiota. As a result, the two models exhibited significant increases of immobility time in forced swim test (FST) and tail suspension test (TST), whereas sucrose preference index and pup weight were significantly decreased. Both displayed depression-like behaviors, and CUMS was more obvious, which demonstrated by the lower levels of 5-hydroxytryptamine (5-HT) and higher hypothalamic-pituitary-adrenal (HPA) axis related mRNA expression (corticotropin releasing hormone, corticotropin releasing hormone receptor 1) in CMUS group than that in MS group. The gut microbiota in MS and CUMS groups were significantly different in terms of the relative abundances of Bacteroidetes, Firmicutes, Proteobacteria. In conclusion, MS model and CUMS model have different performance in behavior and physiology. The CUMS model showed more obvious parameter changes, which may be more suitable for PPD induced by various social environmental factors.

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics.

With the widespread clinical use of drug combinations, the incidence of drug-drug interactions (DDI) has significantly increased, accompanied by a variety of adverse reactions. Drug transporters play an important role in the development of DDI by affecting the elimination process of drugs in vivo, especially in the pathological state. Tubulointerstitial fibrosis (TIF) is an inevitable pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease. Here, the dynamic expression changes of eleven drug transporters in TIF kidney have been systematically investigated. Among them, the mRNA expressions of Oat1, Oat2, Oct1, Oct2, Oatp4C1 and Mate1 were down-regulated, while Oat3, Mrp2, Mrp4, Mdr1-α, Bcrp were up-regulated. Pearson correlation analysis was used to analyze the correlation between transporters and Creatinine (Cr), OCT2 and MATE1 showed a strong negative correlation with Cr. In contrast, Mdr1-α exhibited a strong positive correlation with Cr. In addition, the pharmacokinetics of cimetidine, ganciclovir, and digoxin, which were the classical substrates for OCT2, MATE1 and P-glycoprotein (P-gp), respectively, have been studied. These results reveal that changes in serum creatinine can indicate changes in drug transporters in the kidney, and thus affect the pharmacokinetics of its substrates, providing useful information for clinical use.

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking.

The kidneys are a pair of important organs that excretes endogenous waste and exogenous biological agents from the body. Numerous transporters are involved in the excretion process. The levels of these transporters could affect the pharmacokinetics of many drugs, such as organic anion drugs, organic cationic drugs, and peptide drugs. Eleven drug transporters in the kidney (OAT1, OAT3, OATP4C1, OCT2, MDR1, BCRP, MATE1, MATE2-K, OAT4, MRP2, and MRP4) have become necessary research items in the development of innovative drugs. However, the levels of these transporters vary between different species, sex-genders, ages, and disease statuses, which may lead to different pharmacokinetics of drugs. Here, we review the differences of the important transports in the mentioned conditions, in order to help clinicians to improve clinical prescriptions for patients. To predict drug-drug interactions (DDIs) caused by renal drug transporters, the molecular docking method is used for rapid screening of substrates or inhibitors of the drug transporters. Here, we review a large number of natural products that represent potential substrates and/or inhibitors of transporters by the molecular docking method.

Imperatae rhizoma-Hedyotis diffusa Willd. herbal pair alleviates nephrotic syndrome by integrating anti-inflammatory and hypolipidaemic effects.

BACKGROUND: Nephrotic syndrome (NS) is a common nephropathy with a complex and diverse aetiology. Both Imperatae rhizoma and Hedyotis diffusa Willd. are herbs that are widely used as medicine and functional food. In traditional Chinese medicine theory, they are used as an herbal pair (HP) to treat inflammation-related diseases in the clinic, especially disorders of the kidney. PURPOSE: This study aimed to investigate the anti-inflammatory and hypolipidaemic effects of HP in an NS rat model and provide scientific data for its clinical application. METHODS: An NS model was established by two-dose injection of Sprague-Dawley rats with adriamycin. Seven groups, including the sham, model, HP treatment (0.25, 0.5 and 1.0 g/kg/d), prednisone (positive control, 5 mg/kg/d), and atorvastatin (positive control, 4 mg/kg/d) groups, were tested. The biochemical indexes of renal function and inflammatory cytokines were determined by ELISA kits and/or qPCR assays, and the crucial protein involved in the signalling pathway were subsequently tested by qPCR and/or Western blotting. Based on specific compounds identified by LC-Q-TOF-MS, network pharmacological study was carried out. RESULTS: The levels of BUN, Scr, Upro, UA, Alb, TC, TG, and LDL-C were significantly elevated in model rats. HP treatment for four weeks improved the renal function and the dyslipidaemia by decreasing the levels of all parameters, except BUN and Scr. HP treatment (0.5 and 1.0 g/kg/d) upregulated the expression of PPARγ, CYP7b1, and LDLR in the liver, while it down-regulated PCSK9, showing a regulatory effect on lipid metabolism disorder. The levels of TNF-α and IL-1ß in the plasma and the mRNA expression of TNF-α, IL-1ß, MCP-1, and TGF-ß1 in the kidney were decreased in HP groups, revealing its anti-inflammatory effect in NS rats. The HP exerted an alleviation effect on the inflammatory response through the NF-κB pathway by inhibiting the mRNA and protein expression of p50 and p65. There were 34 compounds identified or tentatively characterized in HP. In the network pharmacological study, PPARG(PPARγ), PCSK9, RELA(p65), and NF-κB1(p50) were the top 20 targets for HP, supporting the animal experimental results. CONCLUSION: HP exhibited protective effects on NS rats. These effects might be closely related to the inhibition of NF-κB and PCSK9-LDLR and activation of the PPARγ-CYP7B1 signalling pathways.

The Herba Patriniae (Caprifoliaceae): A review on traditional uses, phytochemistry, pharmacology and quality control.

ETHNOPHARMACOLOGICAL RELEVANCE: Herba Patriniae has been used for thousands of years in China as a traditional Chinese medicine with heat-clearing and detoxicating effects. It is applied widly for the treatment of rheumatoid arthritis, diarrhea, acute hepatitis, pelvic inflammatory disease and ulcerative colitis in clinic. Two species, namely Patrinia scabiosaefolia Fisch. (PS) and Patrinia villosa Juss. (PV) from the Caprifoliaceae family, are considered as Herba Patriniae in the pharmaceutical industry. AIM OF THE REVIEW: This paper aims to comprehensively outline the traditional uses, botanical description, phytochemistry, pharmacology, toxicology, quality control, pharmacokinetics and patents of Herba Patriniae, and elaborate the same/different characteristics between PS and PV. MATERIALS AND METHODS: Detailed information of Herba Patriniae was collected from various online databases (Pubmed, Web of Science, Google Schola, China National Knowledge Infrastructure Database, National Intellectual Property Administration, PRC National Medical Products Administration), and those published resources (M.Sc. Thesis and books). RESULTS: A total of 233 compounds have been identified in Herba Patriniae, including triterpenoid saponins, flavonoids, organic acids, iridoids, and volatiles. A very distinct difference was observed, that PS is rich in triterpenoid saponins and volatiles, while PV contains more flavonoids. Two source species of Herba Patriniae gave similar pharmacological effects on anti-cancer, anti-inflammatory, antioxidant, antimicrobial, sedative and hypnotic effects. But there were no reports were on antipruritic, proangiogenic and anti-diarrheal effects for PS, and no studies on anti-diabetic effects for PV. Generally, Herba Patriniae showed non-toxic in the clinical dose, but mild side effects, such as temporary leukopenia, dizziness and nausea, could be found when large and excessive dosage is used. A variety of compounds have been quantified for the quality control of PS and PV. The variety, growth environment, growth time, and harvest time not only affected the contents but also the pharmacological activities of the bioactive compounds. In the past year, patents for compositions containing PV and PS have been filed, mainly involving human health, hygiene, agriculture, and animal husbandry. Unfortunately, the research on pharmacokinetics is insufficient. Only the prototype components and metabolites were repored after intragastric administration of total flavonoids extract from PV in rats. CONCLUSION: Herba Patriniae has displayed a significant medicinal value in clinic, but the differences in phytochemistry, pharmacological effects and the content of compounds have been found between two official recorded species. About side effects and pharmacokinetic characteristics, the differences between two species have not been well studied. For a better clinical use of Herba Patriniae, it is urgent to establish systematic pharmacology, quality control, pharmacokinetics, and clinical researches on the same/different characteristics between PS and PV.