Bibliometric analysis of Kampo medicine hotspots and trends for the decade: 2013-2022.

BACKGROUND: Kampo medicine is a traditional medicine that originated in ancient China and has since developed as a uniquely Japanese medicine. Although Kampo medicine is one of Japan's most important therapeutic modalities and numerous papers have been published recently, information on current hotspots and trends in Kampo research is lacking. This bibliometric analysis of Kampo medicine surveyed the latest research hotspots and trends. METHODS: Articles on Kampo medicine were retrieved from the Web of Science Core Collection. We used medical subject headings related to Kampo medicine and searched for publications from 2013 to 2022. The retrieved articles were analyzed for countries, authors, journals, references, and keywords related to Kampo medicine using CiteSpace, VOSviewer, and SCImago Graphica. RESULTS: A total of 1170 articles were included. The number of Kampo medicine-related publications and citations has recently increased, mainly from Japan. Author Keiko Ogawa-Ochiai published the most papers (40 papers), while Yoshio Kase had the highest frequency at 663 citations. Among the co-cited authors, Toru Kono was the most cited and had the highest total link strength. The journal with the most submissions was Evidence-based Complementary and Alternative Medicine. A comprehensive keyword and literature analysis revealed the following research hotspots: "Yokukansan and behavioral and psychological symptoms of dementia," "Ninjinyoeito and geriatric care," "Daikenchuto and postoperative gastrointestinal cancer," and "Rikkunshito and functional dyspepsia." We also identified a new research frontier by identifying an association between hochuekkito and COVID-19. CONCLUSIONS: Our findings reveal trends in Kampo medicine research, with specific hotspots and the authors and publications with the largest research impact. Collecting a large volume of literature data, analyzing the impact of studies, and identifying research hotspots, as in this study, will provide researchers with future directions for Kampo research.

Comprehensive evaluation of antioxidant effects of Japanese Kampo medicines led to identification of Tsudosan formulation as a potent antioxidant agent.

Oxidative stress due to the overproduction of reactive oxygen species plays an important role in the pathogenesis of various diseases. In the present study, we comprehensively evaluated the antioxidant activities of 147 oral formulations of Japanese traditional herbal medicines (Kampo medicines), representing the entire panel of oral Kampo medicines listed in the Japanese National Health Insurance Drug List, using in vitro radical scavenging assays, including the 2,2-diphenyl-1-picrylhydrazyl free radical scavenging activity assay, the superoxide anion scavenging activity assay, and the oxygen radical absorption capacity assay. Three of the formulations tested, namely, Tsudosan, Daisaikoto, and Masiningan, showed the most potent in vitro antioxidant activities and were selected for further investigation of their intracellular and in vivo antioxidant effects. The results of the 2',7'-dichlorodihydrofluorescin diacetate assay demonstrated that all three Kampo medicines significantly inhibited hydrogen peroxide-induced oxidative stress in human hepatocellular liver carcinoma HepG2 cells. In addition, Tsudosan significantly increased the serum biological antioxidant potential values when orally administrated to mice, indicating that it also had in vivo antioxidant activity. The potent antioxidant activity of Tsudosan may be one of the mechanisms closely correlated to its clinical usage against blood stasis.

Identification and evaluation of magnolol and chrysophanol as the principle protein tyrosine phosphatase-1B inhibitory compounds in a Kampo medicine, Masiningan.

ETHNOPHARMACOLOGICAL RELEVANCE: Masiningan is a traditional medicine consisting of six crude drugs that have been used for treating constipation and diabetes mellitus in both Japan and China. Masiningan has been reported to have significant PTP1B inhibitory activity and to affect cells in the insulin-signaling pathway. The aim of the present study is to identify the PTP1B inhibitory compounds in Masiningan. MATERIALS AND METHODS: Bioactivity peaks were identified by analytical HPLC profiling and PTP1B inhibitory activity profiling of sub-fractions from Masiningan extract. The bioactive compounds were isolated by tracking two identified bioactive peaks, and the chemical structures were determined by spectroscopic analyses. The bioactive compounds were further investigated for their inhibitory effect against PTP1B by enzymatic kinetic analysis, molecular docking simulation, inhibitory selectivity against other PTPs, and cellular activity in the insulin signal transduction pathway. RESULTS: From Masiningan, magnolol (1) and chrysophanol (2) were isolated as compounds that exhibited significant dose-dependent inhibitory activities against PTP1B, with IC50 values of 24.6 and 12.3µM, respectively. Kinetic analysis revealed that 1 is a non-competitive and that 2 is a competitive PTP1B inhibitor. In the molecular docking simulation, compound 2 was stably positioned in the active pocket of PTP1B, and the CDOCKER energy was calculated to be 24.3411kcal/mol. Both compounds demonstrated remarkably high selectivity against four PTPs and revealed cellular activity against the insulin signal transduction pathway. CONCLUSIONS: Magnolol (1) and chrysophanol (2) were identified as the principle PTP1B inhibitory active compounds in Masiningan, and their actions were investigated in detail. These findings demonstrated the effectiveness of Masiningan on diabetes mellitus through the inhibition of PTP1B at a molecular level as well as the potential of magnolol (1) and chrysophanol (2) as lead compounds in future anti-diabetes drug development.

Inhibitory activities of selected Kampo formulations on human aldose reductase.

BACKGROUND: Diabetes complications include various symptoms such as diabetic neuropathy and cognitive disorders. Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway and is one of the causal factors of diabetes complications. In this study, the bioactivities of eight selected Kampo formulations that are currently in clinical use for diabetes complications were assessed using human AR (hAR) inhibitory activity as the primary parameter to explore the possibilities of novel clinical applications of these formulations in the treatment of diabetes complications. METHODS: The hAR inhibitory activities of four Kampo formulations that are clinically used for diabetic neuropathy, four Kampo formulations that are used for cognitive disorders, and a total of 21 component crude drugs were measured. Furthermore, the hAR inhibitory activity of Glycyrrhizae Radix preparata was measured to determine the effect of frying, which is one of the specific processing of Glycyrrhizae Radix. hAR inhibitory activity was determined by measuring the rate of decline in the absorbance of NAPH at 340 nm using 0.5 mM NADPH, 10 mM D,L-glyceraldehyde, and 3.6 mU/mL hAR in phosphate buffer solution (0.2 M, pH 6.2). RESULTS: All of the Kampo formulations exhibited significant hAR inhibitory activity; Chotosan exhibited particularly strong activity. Among the 21 crude drugs tested, adequate inhibitory activities were found for the following, in descending order of activity: Glycyrrhizae Radix > Paeoniae Radix > Chrysanthemi Flos > Cinnamomi Cortex > Phellodendri Cortex > Uncariae Uncis cum Ramulus > Bupleuri Radix. Glycyrrhizae Radix preparata exhibited an inhibitory activity that was nearly identical to that of Glycyrrhizae Radix. CONCLUSIONS: Despite their seemingly different treatment objectives, all of the Kampo formulations that are clinically used for diabetes complications demonstrated significant hAR inhibitory activity. This activity might underlie the characteristic multi-target effects of Kampo formulations. Although the overall effect of a Kampo formulation is certainly difficult to evaluate based on specific herbal medications or components, the approach as taken in this study might nonetheless contribute to further advancement in the development of new drugs via the review of proper usage and re-examination of the chemical compounds from a new perspective.

Evaluation of 147 Kampo prescriptions as novel protein tyrosine phosphatase 1B (PTP1B) inhibitory agents.

BACKGROUND: Protein tyrosine phosphatase (PTP) 1B, a negative regulator of the insulin and leptin signaling pathways, is currently considered a promising target for the development of novel therapeutic approaches used to treat insulin-resistant type 2 diabetes mellitus (IR-T2DM). In this study, we examined the PTP1B inhibitory activity of 147 Japanese prescription Kampo formulations to evaluate their potential for clinical application in IR-T2DM treatment. METHODS: We specifically defined the prescribed daily dose as 1 Unit (U), and 147 Japanese prescription Kampo formulations were screened for PTP1B inhibitory activity at a final concentration of 0.1 mU/mL. We investigated the dependence of the inhibitory activity on the concentration of the Kampo formulations that exhibited high PTP1B inhibitory activity. Their inhibition mode by kinetic analysis, inhibitory selectivities against four homologous PTPs (TCPTP, VHR, SHP-1 and SHP-2) and cellular activity in the insulin-signaling pathway by increasing the insulin-stimulated Akt phosphorylation level in human hepatocellular liver carcinoma HepG2 cells, were also investigated. The statistical partial least squares regression method was used to identify the crude drugs with the greatest contribution to the PTP1B inhibitory activity of the Kampo formulations. RESULTS: Daiokanzoto, Masiningan, Tokakujokito, Keimakakuhanto and Choijokito exhibited high PTP1B inhibitory activity, which was concentration-dependent. Daiokanzoto, Masiningan and Tokakujokito inhibited PTP1B by mixed inhibition modes and exhibited different inhibitory selectivities against four homologous PTPs. Masiningan also exhibited cellular activity. Statistical analyses indicated that the constituent crude drug Rhei Rhizoma provided the greatest contribution to the PTP1B inhibitory activity of these Kampo formulations. CONCLUSIONS: High PTP1B inhibitory activity was predominantly associated with formulations that were classified as Jyokito in Kampo medicine and with a modern clinical indication of constipation. Currently, there is no clinical treatment for IR-T2DM that uses a mechanism of action based on PTP1B inhibition. Thus, we propose the Kampo formulations identified in this study as strong PTP1B inhibitors, which could be developed as clinical therapeutic agents to treat IR-T2DM.