Tokishakuyakusan, a traditional Japanese medicine (Kampo) mitigates <scp>iNKT</scp> cell‐mediated pregnancy loss in mice

Nagamatsu, Takeshi; Schust, Danny J.; Tsuchiya, Naho; Tokita, Yohei; Hoya, Mari; Akiba, Naoya; Iriyama, Takayuki; Kawana, Kei; Osuga, Yutaka; Fujii, Tomoyuki

doi:10.1111/aji.13021

Cited by 14 publications

(12 citation statements)

References 29 publications

(61 reference statements)

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“…Some researchers have demonstrated the ameliorative effects of TS on preeclampsia, fetal growth restriction, and recurrent pregnancy loss [29,30]. It has been reported that TS regulates the immunity of invariant natural killer T cells during early pregnancy (in mice), and thus reduces the rate of pregnancy loss [31]. The antihypertensive effects of TS have also been reported [29].…”

Section: Plos Onementioning

confidence: 99%

Potency of Tokishakuyakusan in treating preeclampsia: Drug repositioning method by in vitro screening of the Kampo library

et al. 2020

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Introduction Preeclampsia therapy has not been established, except for the termination of pregnancy. The aim of this study was to identify a potential therapeutic agent from traditional Japanese medicine (Kampo) using the drug repositioning method. Materials and methods We screened a library of 74 Kampo to identify potential drugs for the treatment of preeclampsia. We investigated the angiogenic effects of these drugs using human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assays were performed to measure the levels of placental growth factor (PlGF) in conditioned media treated with 100 μg/mL of each drug. We assessed whether the screened drugs affected cell viability. We performed tube formation assays to evaluate the angiogenic effects of PlGF-inducing drugs. PlGF was measured after administering 10, 50, 100, and 200 μg/mL of the candidate drug in the dose correlation experiment, and at 1, 2, 3, 6, 12, and 24 h in the time course experiment. We also performed tube formation assays with the candidate drug and 100 ng/mL of soluble fms-like tyrosine kinase 1 (sFlt1). PlGF production by the candidate drug was measured in trophoblastic cells (BeWo and HTR-8/SVneo). The Mann-Whitney U test or one-way analyses of variance followed by the Newman-Keuls post-hoc test were performed. P–values < 0.05 were considered significant. Results Of the 7 drugs that induced PlGF, Tokishakuyakusan (TS), Shoseiryuto, and Shofusan did not reduce cell viability. TS significantly facilitated tube formation (P = 0.017). TS administration increased PlGF expression in a dose- and time-dependent manner. TS significantly improved tube formation, which was inhibited by sFlt1 (P = 0.033). TS also increased PlGF production in BeWo (P = 0.001) but not HTR-8/SVneo cells (P = 0.33). Conclusions By using the drug repositioning method in the in vitro screening of the Kampo library, we identified that TS may have a therapeutic potential for preeclampsia. Its newly found mechanisms involve the increase in PlGF production, and improvement of the antiangiogenic state.

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Section: Plos Onementioning

confidence: 99%

Potency of Tokishakuyakusan in treating preeclampsia: Drug repositioning method by in vitro screening of the Kampo library

et al. 2020

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“…[5][6][7] Currently, the mechanisms of TSS have been reported to involve immunological effects on murine endometriosis and pregnancy loss model. 8,9 These reports promisingly suggest that TSS may potentially contribute to management of endometriosis symptoms.…”

Section: Introductionmentioning

confidence: 95%

Efficacy of Tokishakuyakusan add‐on therapy with low‐dose oral contraceptive pills on endometriosis patients with dysmenorrhea

Taniguchi

Tokita

Ota

et al. 2020

J of Obstet and Gynaecol

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Aim: Tokishakuyakusan (TSS) is representative of popular Kampo medicines for Japanese women to treat dysmenorrhea, irregular menstruation and menopause. Current hormonal treatments and low-dose oral contraceptives (OCs) used as a first-choice drug for primary symptoms, however, have a high incidence of adverse events without improving patients' satisfaction. We evaluated the efficacy of TSS as additional treatment on the quality of life (QOL) of patients taking OCs with reduced therapeutic satisfaction. Methods: Twelve patients treated with OCs for endometriosis were enrolled. TSS (7.5 g/day) in combination with OCs were given for three menstrual cycles. The main outcome was the degree of QOL assessed using the Endometriosis Health Profile-30 (EHP-30). Secondary outcomes were the Menstrual Distress Questionnaire (MDQ), patient's satisfaction using a Likert scale and cold feeling-visual analogue scale (VAS). Results: In EHP-30, significant changes by TSS with OCs in each menstrual cycle were not found, although the scores for pain and emotional well-being tended to decrease. In MDQ, water retention in the premenstrual phase was improved. With regard to cold feeling-VAS, 61.6 mm at pretreatment decreased to 31.3 mm at the endpoint. Average Likert scale values after TSS treatment declined from 4.3 to 2.6. Cold feeling and patient's satisfaction have improved. Conclusion: Although the influence of TSS add-on therapy on QOL was moderate, possible improvement of cold feeling and menstruation-related symptoms was suggested.

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“…These results indicate the activated innate immune cells DCs and iNKT cells directly lead to miscarriage without microbial-associated inflammation. Interestingly, miscarriage and preterm birth induced by a-GalCer were ameliorated by treatment with rosiglitazone [58] and Tokishakuyakusan, a traditional Japanese medicine [109]. Innate immune cells, DCs, and iNKT cells are therefore associated with not only preterm both but also miscarriage in the absence of infection.…”

Section: Miscarriage and Infertilitymentioning

confidence: 99%

Harmful and beneficial effects of inflammatory response on reproduction: sterile and pathogen-associated inflammation

Negishi

Shima

Takeshita

et al. 2020

Immunological Medicine

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In reproduction, inflammatory processes play important roles in the development of many pregnancy complications such as preterm labor/birth, recurrent pregnancy loss, recurrent implantation failure, and preeclampsia. Inflammation can be initiated by both microbial and non-microbial causes. Bacterial infection in the feto-maternal interface and uterus can provoke preterm labor/birth, miscarriage, and chronic endometritis. By contrast, inflammation without infection, or 'sterile inflammation,' can also lead to many kinds of complications, such as preterm labor/birth, miscarriage, or preeclampsia. Aberrant inflammation is facilitated by immune cells such as macrophages, dendritic cells, natural killer cells, and invariant natural killer T cells. In addition, cytokines, chemokines, and several kinds of inflammatory mediators are involved. On the other hand, appropriate inflammation is required for a successful offspring during the progression of the entire pregnancy. Herein, we discuss the relation between pregnancy and inflammation with immunological alterations. Understanding the role of inflammation in complications during pregnancy may establish new perspectives of the progress of normal pregnancy as well as treatments during pregnancy complications.

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Tokishakuyakusan, a traditional Japanese medicine (Kampo) mitigates iNKT cell‐mediated pregnancy loss in mice

Abstract: The findings in this study suggest that the inhibitory effects of TSS on pregnancy loss may involve immune modulation of iNKT cells during early pregnancy.

Cited by 14 publications

References 29 publications

Potency of Tokishakuyakusan in treating preeclampsia: Drug repositioning method by in vitro screening of the Kampo library

Potency of Tokishakuyakusan in treating preeclampsia: Drug repositioning method by in vitro screening of the Kampo library

Efficacy of Tokishakuyakusan add‐on therapy with low‐dose oral contraceptive pills on endometriosis patients with dysmenorrhea

Harmful and beneficial effects of inflammatory response on reproduction: sterile and pathogen-associated inflammation

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