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Mechanistic study on the holistic actions of Hong-Hua-Xiao-Yao Tablet in alleviating premenstrual syndrome in rats
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DOI：10.1016/j.phymed.2026.158161.png)
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Abstract
En 中文
Background: Premenstrual syndrome (PMS) is a cyclical neuroendocrine disorder that adversely affects the physical and mental health of women globally. Hong-Hua-Xiao-Yao Tablet (HHXYT) is a marketed Chinese patent medicine, with well-established therapeutic effect on PMS in clinic. However, its underlying mechanisms are poorly understood due to the extreme complexity of both PMS and HHXYT itself. Purpose: To elucidate the systemic mechanisms of action of HHXYT ameliorates PMS. Methods: An integrated strategy combining serum metabolomics and tissue-specific transcriptomics was applied to identify key metabolic pathways affected by HHXYT. Additionally, 16S rRNA gene sequencing was employed to evaluate gut microbiota composition. In vitro assays were performed to assess anti-neuroinflammatory effects in PMS-related cells. The bioactivity of blood-absorbed compounds was further verified. The role of gut microbiota was further investigated using ex vivo cultures and pseudo germ-free models. Results: HHXYT affected the serum metabolite profiles and target organ transcriptional profiles in the glucose 6phosphate metabolism, sphingolipid metabolism, glycerophospholipid metabolism, which in turn improved the systemic symptoms of PMS. Moreover, HHXYT-containing serum specifically inhibited neuroinflammation in microglia, without affecting other PMS-associated target cells. Subsequently, we identified 62 blood-absorbed components, primarily derived from Glycyrrhiza uralensis (GC, 36 compounds). Among these, four GC-derived compounds-glycyrrhizic acid, 18 beta-glycyrrhetinic acid, liquiritin, and liquiritigenin significantly suppressed neuroinflammation in microglia. Interestingly, the lack of detected blood-absorbed components from the sovereign herb Bupleurum marginatum implies that its therapeutic benefits may occur via an indirect mechanism involving gut microbiota metabolism. Using ex vivo cultures and pseudo germ-free models, we further revealed that the gut microbiota partially mediated the therapeutic benefits of HHXYT and HHXYT contributed to the maintenance of gut microbiota homeostasis. Furthermore, we observed that gut microbiota-metabolized HHXYT contributed to the alleviation of inflammation, oxidative stress, and hormonal imbalance. Conclusion: This study provided a holistic perspective on the dual mechanism-direct bioactivity and microbiotadependent effects-underlying the efficacy of HHXYT against PMS, highlighting the importance of host-microbiota interactions in the action of herbal medicines.
Keywords:
Hong-Hua-Xiao-Yao Tablet
Premenstrual syndrome
Metabolomics
Transcriptomic
Gut microbiota
Blood-absorbed components
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