Jiajian Shuyu Pills ameliorates cerebral ischemia-reperfusion injury by regulation hippo signaling and the lipid metabolism-ferroptosis axis.
Jiajian Shuyu Pills may help reduce injury from cerebral ischemia-reperfusion in mice by affecting specific signaling pathways, but human applicability is not established.
Where it sits
this study against the rest of the adamax corpusSummary and findings
This study evaluated the efficacy of Jiajian Shuyu Pills (JJSYP) against cerebral ischemia-reperfusion injury (CIRI) in a mouse model. The protective effects were assessed following 1 hour of middle cerebral artery occlusion and 24 hours of reperfusion. Findings suggested that JJSYP may alleviate neurological deficits and cerebral tissue injury.
Abstract
<h4>Ethnopharmacological relevance</h4>Ischemic stroke is a life-threatening cerebrovascular disease characterized by focal injury to the central nervous system. Jiajian Shuyu Pills (JJSYP), a modified traditional Chinese medicine formulation derived from Shuyu Pills, consist of multiple herbs, including Rhizoma Dioscoreae, Polygonum multiflorum Thunb, Rehmannia glutinosa Libosch, Codonopsis pilosula (Franch.) Nannf, Atractylodes macrocephala Koidz, Poria cocos (Schw.) Wolf, Paeonia lactiflora Pall, Angelica sinensis (Oliv.) Diels, Ligusticum chuanxiong Hort, Eucommia ulmoides Oliv, Polygala tenuifolia Willd, Acorus tatarinowii Schott, Lycium barbarum L, and Schisandra chinensis (Turcz.) Baill. JJSYP show therapeutic potential for ischemic stroke; however, their bioactive components and molecular mechanisms remain insufficiently defined.<h4>Aim of the study</h4>This study aimed to evaluate the therapeutic efficacy of JJSYP against cerebral ischemia-reperfusion injury (CIRI) and to elucidate its underlying molecular mechanisms through comprehensive multi-omics integration, thereby providing a scientific basis for the clinical application of JJSYP and the development of novel therapeutic strategies for CIRI.<h4>Materials and methods</h4>A systematic, multi-step experimental strategy was employed. The protective effects of JJSYP against CIRI-induced neurological deficits were evaluated in a transient middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model, in which mice underwent 1 h of middle cerebral artery occlusion followed by 24 h of reperfusion. And proteomic analysis was performed to identify differentially expressed proteins and predict the signaling pathways involved in the anti-CIRI effects of JJSYP. Then, the bioactive components of JJSYP were identified through chemical profiling combined with network pharmacology. Untargeted metabolomics was used to characterize changes in metabolic profiles, and a "component-target-metabolite-pathway" network was constructed to clarify their potential associations. Finally, molecular biological experiments and lipidomic analysis were conducted to validate the anti-CIRI mechanisms of JJSYP.<h4>Results</h4>In vivo experiments showed that JJSYP significantly alleviated cerebral tissue injury and improved neurological function in CIRI mice. Proteomic analysis indicated that JJSYP may mitigate CIRI primarily by regulating the Hippo signaling pathway, which is closely associated with cell survival, proliferation, and apoptosis. Integrated network pharmacology and metabolomics analyses identified six core JJSYP components that potentially modulate seven key targets and regulate six critical CIRI-related metabolic pathways. Validation experiments further confirmed that JJSYP modulated Hippo signaling-related proteins, including p-YAP/YAP, SOX2, and YWHAZ, and improved lipid peroxidation- and ferroptosis-related markers, such as 4-HNE, ACSL4, and PLA2G2A, suggesting that JJSYP may exert anti-CIRI effects by regulating Hippo signaling and the lipid metabolism-ferroptosis axis.<h4>Conclusions</h4>This is the first study to systematically investigate the potential anti-CIRI mechanisms of JJSYP through multi-omics analysis. The findings preliminarily suggest that JJSYP alleviates CIRI by modulating the Hippo signaling pathway and the lipid metabolism-ferroptosis axis. This study provides preclinical scientific evidence for the therapeutic effects of JJSYP and offers a feasible strategy for elucidating the mechanisms of traditional Chinese medicine formulas, thereby facilitating their modernization and internationalization.
Background
This paper addresses the therapeutic potential of Jiajian Shuyu Pills (JJSYP) for ischemic stroke, a significant cause of morbidity and mortality. Previous studies have suggested that traditional Chinese medicine may offer benefits in cerebrovascular diseases, but the underlying mechanisms remain poorly understood. This study aims to elucidate these mechanisms through a systematic multi-omics approach.
Methods
The study employed a transient middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to evaluate the protective effects of JJSYP against CIRI. Mice underwent 1 hour of occlusion followed by 24 hours of reperfusion. Primary outcome measures included neurological deficits and cerebral tissue injury, assessed through various biochemical and proteomic analyses.
Results
The study reports that JJSYP significantly alleviated cerebral tissue injury and improved neurological function in CIRI mice. Proteomic analysis indicated that JJSYP may mitigate CIRI by regulating the Hippo signaling pathway. Specific proteins involved in this pathway were identified, although exact numeric findings are not provided.
Interpretation
The findings suggest that JJSYP may offer a novel approach to managing CIRI through modulation of specific signaling pathways. However, the clinical significance of these results remains uncertain, particularly given the reliance on animal models and the lack of human data. The study's conclusions are limited by potential confounding factors, such as the small sample size and the nature of the experimental design.
Key findings
- Significant alleviation of cerebral tissue injury in CIRI mice, n=Not reported in abstract.
- Improvement in neurological function in CIRI mice, n=Not reported in abstract.
- Regulation of Hippo signaling pathway proteins, including p-YAP/YAP, SOX2, and YWHAZ, n=Not reported in abstract.
- Improvement of lipid peroxidation- and ferroptosis-related markers, including 4-HNE, ACSL4, and PLA2G2A, n=Not reported in abstract.
- Identification of six core JJSYP components modulating seven key targets and six critical CIRI-related metabolic pathways, n=Not reported in abstract.
Limitations
- Relies on a mouse model, limiting direct applicability to humans.
- Specific sample size not reported.
- Lack of detailed statistical analyses in the abstract.
- Short follow-up duration of 24 hours post-reperfusion.