To explore the evolvement and new trends in the use of Shuanghuanglian injection (SHLI).

China National Knowledge Infrastructure (CNKI), PubMed, and Embase were extensively searched using the search terms “Shuanghuanglian injection” and “Shuanghuanglian fenzhen” to retrieve articles relevant to SHLI (1992–2020). Retrieved articles were further investigated by two authors to exclude those unrelated to SHLI. The bibliographical references of the included articles were exported as raw data and then treated using the CiteSpace tool to visualize the mapping of the SHLI research domain. Essential clusters and highly frequent keywords were quantified for further analysis. The clusters were automatically labeled by the algorithm of tf∗idf for objective analysis. Basic bibliometric features, including article types and yearly trend in article numbers were also determined and discussed.

The modules of the keywords of interest presented clear boundaries with a high modularity score (Q = 0.73). High-confidence clusters were identified, including bioactivity fingerprint (S = 0.99), equal pupils (S = 0.91), drug preparation department (S = 0.87), difficulty in respiration (S = 0.85), peristalsis (0.88), and Danshen powder injection (S = 0.94). The characteristic keywords in terms of frequency and burstiness were Shuanghuanglian powder for injection (F = 235, B = 5.22), SHLI (F = 112, B = 11.39), and adverse drug reactions (ADRs; F = 104, B = 7.35).

In the field of SHLI study, there are five major topic categories: bioactivity fingerprint; ADR mechanism and cause detection; proper preparation; clinical evidence accumulation; and efficacy in diseases with no effective treatment and combination usage. The trend for using modern methodologies from a science-based perspective to study SHLI will continue to exist. The causes of multi-factorial ADRs may be an important topic for future studies.

To explore the glucuronic acid metabolism of acacetin in human liver and intestinal microsomes to better characterize human uridine 5′-diphospho (UDP)-glucuronosyltransferase (UGT) isoforms. In addition, interspecies comparisons were performed to identify the most appropriate experimental animal model for an in vivo study.

Liquid chromatography tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) were used to confirm the successful biosynthesis of acacetin-7-O-glucuronide. Human isoforms of UGT and isozyme-specific chemical inhibitors were used for recombinant assays. Acacetin glucuronidation kinetics were assessed by combining acacetin with recombinant human UGT isoforms or with microsomes from humans or experimental animals. Kinetic differences between species were assessed in vitro using the same approach.

We identified multiple UGT isoforms that facilitated acacetin glucuronidation, and found that UGT1A1 was the major isoform that catalyzed this process. Acacetin-7-O-glucuronide formation exhibited clear substrate inhibition kinetics when combined with recombinant UGTs or with liver/intestinal microsomes derived from humans, monkeys, rats, mice, dogs, or pigs. Intrinsic metabolic clearance values of human intestinal microsomes were two-fold greater than those of human liver microsomes. Among the evaluated species, the K_m value of dog microsomes (0.86 μM) was greatest in acacetin glucuronidation, while mice exhibited the highest CL_int value, 5.05 mL/min/mg. The CL_int values of microsomes derived from monkeys and minipigs were 1.99 mL/min/mg and 2.12 mL/min/mg, respectively, exhibiting similar intrinsic metabolic clearance activity to that observed in humans.

Monkey may represent a suitable model for experimental studies of acacetin pharmacokinetics owing to a high sequence homology of UGT1A1 and similar UGT1A1 glucuronidation activity to humans.

To investigate the action mechanism of Rhizoma Atractylodis (Atractylodes lancea (Thunb.) Dc.) and Rhizoma Atractylodis Macrocephalae (Atractylodes macrocephala Koidz.), a two-herb ancient traditional Chinese medicine used to treat type 2 diabetes mellitus, using molecular docking.

The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform was searched for compounds in the two herbs and oral bioavailability and drug-likeness values were used to select compounds. The target proteins were selected based on a survey of the literature and related databases, and three receptors closely related to type 2 diabetes were chosen: insulin receptor, peroxisome proliferator activated receptor and dipeptidyl peptidase-IV. Molecular docking was performed using the CDocker module in Discovery Studio software. The interactions between targets and ligands were observed and analyzed, including the mode of action.

Nineteen compounds from the herbal pair interacted with the insulin receptor, the peroxisome proliferator activated receptor and dipeptidyl peptidase-IV. Among them, 10 compounds bound successfully with all three targets, one compound bound with two targets, and eight compounds bound with one target. According to CDocker Interaction Energy, most compounds from the herbal pair had good binding activities with receptors and nine compounds had even higher scores than those of the original ligands. These data indicate that these compounds may be active in reducing blood glucose levels for the treatment of type 2 diabetes.

Multiple compounds in the Rhizoma Atractylodis-Rhizoma Atractylodis Macrocephalae herbal pair can affect multiple human targets related to type 2 diabetes.