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Scutebarbatine B (SBT-B) is a neo-clerodane diterpenic compound isolated from Scutellaria barbata D. Don (S. barbata), which has been reported to exhibit inhibitory P-glycoprotein (P-gp) property in MCF-7/ADR cells. However, its metabolism and molecular mechanism of reversal multidrug resistance (MDR) in breast cancer remains unclear. This study investigated the metabolite profile of SBT-B in rats by UHPLC-Q-Orbitrap-MS/MS, and explored its mechanism of reversal MDR through network pharmacology and molecular docking studies. A total of 16 Phase I metabolites and 2 Phase II metabolites were identified, and 18 metabolites were all newly discovered metabolites as novel compounds. The metabolic pathway of SBT-B mainly includes oxidization, reduction, hydrolysis, acetylation and glycination. Meanwhile, network pharmacology analyses showed that SBT-B mainly regulated p27 phosphorylation during cell cycle progression, p53 signaling pathway, influence of Ras and Rho proteins on G1 to S Transition. Molecular docking studies revealed that SBT-B exhibits the potential to inhibit P-gp expression by selectively binding to GLN721 and ALA981 residue sites at the interface of P-gp. In addition, SBT-B exhibits moderate binding affinity with CDK2 and E2F1. This study illustrated the major metabolic pathways of SBT-B in vivo, clarified detailed information on SBT-B metabolites in rats, and uncovered the potential mechanism of SBT-B reversal MDR in breast cancer, providing new insights for the development of P-gp inhibitors. [Display omitted] • The study illustrated SBT-B metabolites and metabolic pathways. • Uncovering SBT-B mechanism for reversing MDR in breast cancer. [ABSTRACT FROM AUTHOR]

• Identification of twenty-four metabolites (i.e., 15 PhaseⅠ + 9 PhaseⅡ) of NAI59 in rats. • Hydroxylation, dehydrogenation, amine oxidation, glucuronide conjugation and sulfate conjugation were mainly metabolites. • Metabolite identification of a ATX inhibitor NAI59 revealed optimization opportunities. [Display omitted] Lysophosphatidic acid (LPA) mediated signaling is relevant to fibrosis and the proliferation of pulmonary cells, such as the promotion of fibroblast accumulation and stimulation of the TGF-β signal. One of the essential mechanisms to reduce lysophosphatidic acid production is inhibiting autotaxin activity, which can block the hydrolysis of a lysophosphatidylcholine (LPC) into LPA, leading to the alleviation of the development of pulmonary fibrosis. Recently, 3,4-difluorobenzyl(1-ethyl-5-(4-((4-hydroxypiperidin-1-yl)-methyl)-thiazol-2-yl)-1H-indol-3-yl)carbamate (NAI59), a novel autotaxin inhibitor, showed outstanding anti-pulmonary fibrosis therapeutic effectiveness; however, the metabolic information of NAI59 has not been comprehensively expounded yet. Therefore, in this study, we aim to identify the metabolites of NAI59 in rats using ultra-high-performance liquid chromatography-high-resolution tandem mass spectrometry, and we analyze the potential anti-fibrosis of metabolites in plasma using molecular docking with the crystal structure autotaxin. As a result, a total of 24 metabolites, namely, 15 phase I metabolites and 9 phase II metabolites, were identified, all of which are the novel discovered metabolites. The metabolic pathways of NAI59 were primarily hydroxylation, oxidation, hydrogenation, glucuronic acid conjugation, sulfate conjugation, acetylation, and glucosylation. The molecular docking result showed that the identified metabolites in plasma had great affinities upon docking into the active site of autotaxin, indicating they may have potential anti-pulmonary fibrosis activity. The interaction plots revealed the importance of fluorophenyl and the hydroxyl groups on piperidine that contribute toward the formation of hydrogen bonds with autotaxin. Additionally, we found that the metabolite possessed a better docking result when the structure contained a glucuronic acid group. To the best of our knowledge, this study is the first research into the metabolic fate of NAI59 in rats, and we analyze the potential anti-fibrosis aspects of metabolites using molecular docking. This study provides a metabolic rationale for further preclinical research and imparts new insights for developing improved ATX inhibitors. [ABSTRACT FROM AUTHOR]

The proprietary Chinese medicine Jinkui Shenqi Pill (PCM-JKSQP) is a classic compound used for the effective clinical treatment of kidney yang deficiency syndrome (KYDS), a metabolic disease accompanied by kidney injury. However, its active ingredients and therapeutic mechanisms are not clear. This study employed serum pharmacochemistry, network pharmacology, and pharmacokinetics (PK) to identify the bioactive components of PCM-JKSQP and preliminarily clarify its mechanism in treating KYDS. One hundred and forty chemical components of PCM-JKSQP, 47 (20 parent compouds and 27 metabolites) of which were absorbed into the blood, were identified by ultra-high-performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry (UHPLC - Q - Orbitrap HRMS). The topological parameters of network pharmacology and high concentrations in blood found six parent components as PK markers (cinnamic acid, paeonol, loganin, morroniside, apigenin, and poricoic acid A). PK analysis further identified these six compounds as active ingredients. Protein-protein interaction (PPI) analysis and molecular docking simulation predicted and verified eight core targets (TP53, ESR1, CTNNB1, EP300, EGFR, AKT1, ERBB2, and TNF). Most were concentrated in the MAPK, HIF-1, and PI3K-AKT signaling pathways, indicating that these six active ingredients may mainly exert therapeutic effects through these three pathways via their core targets. The PK results also showed these six components were absorbed quickly, although cinnamic acid and paeonol were rapidly metabolized, with a short half-life and retention time. Loganin and morroniside did not have high peak concentrations, and apigenin and poricoic acid A had long retention times. This study provides a new overall perspective for exploring the bioactive components and mechanisms underlying the effects of PCM-JKSQP in treating KYDS. [Display omitted] • Using UHPLC-Q-Orbitrap HMRS, 140 components of PCM-JKSQP were identified, 47 of which were absorbed into the blood. • According to network pharmacology and high concentrations in blood, six prototype components were screened as PK markers. • Through PK analysis, these six compounds were further identified as active ingredients. • These six components may primarily exert effects through eight core targets concentrated in the three signaling pathways. [ABSTRACT FROM AUTHOR]

Senecio scandens Buch.-Ham., a traditional Chinese medicine commonly used clinically, exhibits various pharmacological properties, including anti-inflammatory, anti-tumor, antiviral, and antibacterial activities. However, its water extracts' chemical components and metabolites are inadequately understood, limiting further research. In this study, the chemical components and metabolism processes of Senecio scandens, both in vivo (plasma, feces, urine, and bile) and in vitro (gut microbiota and liver microsomes), were characterized based on ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry. Additionally, metabolites detectable in fecal samples and intestinal microbiota incubated but absent in liver microsomes were identified as characteristic metabolites of intestinal microbiota. The targets of the characteristic metabolites of intestinal microbiota were collected, followed by exploration of potential pathways through KEGG enrichment analysis. As a result, a total of 133 chemical components were preliminarily identified, including 35 organic acids, 21 alkaloids, 19 flavonoids and their glycosides, 17 phenylpropanoids, 10 jacaranda ketones, and 31 other compounds. Notably, 12 of these were potentially novel compounds. In addition, 39 prototype components in rats and 109 metabolites were identified and characterized, including 102 in vivo and 52 metabolites in vitro (51 in rat gut microbiota and 24 in rat liver microsomes). The main metabolic pathways include oxidation, reduction, hydrolysis, methylation, glucuronidation, sulfonation, and acetylation reactions. Furthermore, KEGG enrichment analysis revealed that the characteristic metabolites of intestinal microbiota may be related to the ErbB, FoxO, mTOR, and MAPK signaling pathways, exhibiting anti-inflammatory and anti-tumor effects. In summary, the chemical components and metabolites of Senecio scandens were comprehensively identified using a rapid and accurate method, providing a scientific basis for the in-depth study of the material basis and its clinical application of Senecio scandens. [Display omitted] • Identification the chemical components of Senecio scandens by UHPLC-Q-Orbitrap HRMS. • In vivo metabolites of Senecio scandens were identified in plasma, feces, urine, and bile. • In vitro metabolites of Senecio scandens were identified in gut microbiota and liver microsome. • Exploring the role of gut microbiota in the biotransformation of Senecio scandens Buch.-Ham. [ABSTRACT FROM AUTHOR]