Metformin attenuates PM2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway in proximal renal tubular epithelial cells.

The harmful effects of PM2.5 on human health, including an increased risk of chronic kidney disease (CKD), have raised a lot of attention, but the underlying mechanisms are unclear. We used the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) to simulate the inhalation of PM2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM2.5) for 8 weeks. PM2.5 impaired the renal function of the mice, and the renal tubules underwent destructive changes. Analysis of NHANES data showed a correlation between reduced kidney function and higher blood levels of PM2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM2.5 exposure induced higher levels of AhR and CYP1A1 and oxidative stress as evidenced by the higher levels of ROS, MDA, and GSSG in kidneys of mice. PM2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM2.5-increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM2.5-induced kidney injury and the protective effect of metformin on PM2.5-induced cellular damage, offering new insights for air pollution-related renal diseases.

Comparison of Murraya exotica and Murraya paniculata by fingerprint analysis coupled with chemometrics and network pharmacology methods.

There are two source plants for the traditional Chinese medicine Murrayae Folium et Cacumen (MFC) in Chinese Pharmacopoeia, i.e. Murraya exotica L. and M. paniculata (L.) Jack. Herein, a chemical comparison of M. exotica and M. paniculata by high performance liquid chromatography (HPLC) fingerprint analysis coupled with chemometrics and network pharmacology was performed. The main peaks in the fingerprints were identified by liquid chromatography coupled with ion trap/time-of-flight mass spectrometry (LC-IT-TOF-MS) and authenticated by references. The chemometrics results showed that the HPLC fingerprints of these two species were clearly divided into two categories using hierarchical cluster analysis (HCA) and principal component analysis (PCA), and a total of 13 significantly differentiated markers were screened out by orthogonal partial least squares-discriminant analysis (OPLS-DA). However, the following network pharmacology analysis showed that these discriminated markers were found to act via many common targets and metabolic pathways, indicating the possibly similar pharmacological effects and mechanisms for M. exotica and M. paniculata. The above results provide valuable evidence for the equivalent use of these two plants in clinical settings. Moreover, the chromatographic fingerprint analysis coupled with chemometrics and network pharmacology supplies an efficient approach for the comparative analysis of multi-source TCMs like MFC.

Comparison of the preventive effects of Murraya exotica and Murraya paniculata on alcohol-induced gastric lesions by pharmacodynamics and metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Multi-source phenomenon is very common for traditional Chinese medicine (TCM). Both Murraya exotica L. (ME) and Murraya paniculata (L.) Jack (MP) are used as the source plants of Murrayae Folium et Cacumen (MFC), a traditional Chinese medicine recorded in Chinese Pharmacopoeia for promoting qi and relieving pain, mainly for the treatment of stomach pain, rheumatism and arthralgia. However, up to now, there has been no comparative study of these two plants on their efficacies and mechanisms, thus, further research is needed to evaluate their similarity and difference in order to judge the reasonability for their common usage. AIM OF THE STUDY: This study aims to compare the effects and potential mechanisms of ME and MP, the two source plants of MFC on gastric lesions in rats by pharmacodynamics and metabolomics. MATERIALS AND METHODS: A rat model of gastric lesions induced by 70% aqueous ethanol and 150 mmol/L HCl was established and adopted to evaluate the gastric protective effects of ME and MP by analysis of the lesion index, histopathological changes (observed by H&E staining and TUNEL staining) and cytokine levels (IL-1ß, IL-6, TNF-α, MTL, and GAS). The potential mechanisms were investigated by LC-MS metabolomic analysis of the rat plasma. RESULTS: ME and MP showed the similar effects on improving the lesions of rat stomachs and reducing the cytokine levels related to inflammation and digestion of rats. The metabolomics results showed that the metabolism of rats with gastric lesions was abnormal mainly in lipid metabolism, energy metabolism, and amino acid metabolism. ME and MP demonstrated a similar metabolic modulation for gastric lesions by acting on the similar pathways and metabolites. Also, PLA2 pathway was proved as an important pathway for ME and MP modulation of glycerophospholipid metabolism in gastric lesions. CONCLUSIONS: Our results proved that it is feasible and reasonable to use both of ME and MP as the source plants of MFC, at least for the treatment of gastric lesions, due to their similar pharmacodynamics and metabolic modulation ability. Moreover, the combination of pharmacodynamics and metabolomics is an efficient means for multi-source TCM study.

Pharmacokinetics/pharmacometabolomics-pharmacodynamics reveals the synergistic mechanism of a multicomponent herbal formula, Baoyuan decoction against cardiac hypertrophy.

Multicomponent herbal formulas (MCHFs) have earned a wide reputation for their definite efficacy in preventing or treating chronic complex diseases. However, holistic elucidation of the causal relationship between the bioavailable ingredients of MCHFs and their multitarget interactions is very challenging. To solve this problem, pharmacokinetics/pharmacometabolomics-pharmacodynamics (PK/PM-PD) combined with a multivariate biological correlation-network strategy was developed and applied to a classic MCHF, Baoyuan decoction (BYD), to clarify its active components and synergistic mechanism against cardiac hypertrophy (CH). First, multiple plasma metabolic biomarkers for ß-adrenergic agonist-induced CH rats were identified by using untargeted metabolomic profiling, and then, these CH-associated endogenous metabolites and the absorbed BYD-compounds in plasma at different treatment stages after oral administration of BYD were analyzed by using targeted PK and PM. Second, the dynamic relationship of BYD-related compounds and CH-associated endogenous metabolites and signaling pathways was built by using multivariate and bioinformatic correlation analysis. Finally, metabolic-related PD indicators were predicted and further verified by biological tests. The results demonstrated that the bioavailable BYD-compounds, such as saponins and flavonoids, presented differentiated and distinctive metabolic features and showed positive or negative correlations with various CH-altered metabolites and PD-indicators related to gut microbiota metabolism, amino acid metabolism, lipid metabolism, energy homeostasis, and oxidative stress at different treatment stages. This study provides a novel strategy for investigating the dynamic interaction between BYD and the biosystem, providing unique insight for disclosing the active components and synergistic mechanisms of BYD against CH, which also supplies a reference for other MCHF related research.

Large Volume Direct Injection Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry-Based Comparative Pharmacokinetic Study between Single and Combinatory Uses of Carthamus tinctorius Extract and Notoginseng Total Saponins.

The combination of Carthamus tinctorius extract (CTE) and notoginseng total saponins (NGTS), namely, CNP, presents a synergistic effect on myocardial ischemia protection. Herein, comparative pharmacokinetic studies between CNP and CTE/NGTS were conducted to clarify their synergistic mechanisms. A large volume direct injection ultra-high performance liquid chromatography-tandem mass spectrometry (LVDI-UHPLC-MS/MS) platform was developed for sensitively assaying the multi-component pharmacokinetic and in vitro cocktail assay of cytochrome p450 (CYP450) before and after compatibility of CTE and NGTS. The pharmacokinetic profiles of six predominantly efficacious components of CNP, including hydroxysafflor yellow A (HSYA); ginsenosides Rg1 (GRg1), Re (GRe), Rb1 (GRb1), and Rd (GRd); and notoginsenoside R1 (NGR1), were obtained, and the results disclosed that CNP could increase the exposure levels of HSYA, GRg1, GRe, GRb1, and NGR1 at varying degrees. The in vitro cocktail assay demonstrated that CNP exhibited more potent inhibition on CYP1A2 than CTE and NGTS, and GRg1, GRb1, GRd, quercetin, kaempferol, and 6-hydroxykaempferol were found to be the major inhibitory compounds. The developed pharmacokinetic interaction-based strategy provides a viable orientation for the compatibility investigation of herb medicines.