Fifth Affiliated Hospital of Xinjiang Medical University

The protective mechanism of tetramethylpyrazine (TMP), an alkaloid derived from the Chinese herbal remedy Ligusticum chuanxiong, in relation to myocardial ischemia/reperfusion injury (MIRI) is not yet fully understood. To investigate the therapeutic effects of TMP, we established an in vivo rat model of MIRI and an in vitro hypoxia and reoxygenation (H/R) model using H9c2 cells. First, TMP significantly reduced the infiltration of inflammatory cells in the myocardium, decreased serum levels of myocardial injury markers (CK-MB, cTnT and LDH), and alleviated myocardial infarct size in I/R rats. Additionally, TMP attenuated cell apoptosis and enhanced cell viability in H9c2 cells subjected to H/R. Furthermore, we employed NOD-like receptor protein 3 (NLRP3)-specific inhibitors (MCC950) and agonists (nigericin) to explore the role of the NLRP3 inflammasome in TMP's protective effects against MIRI. TMP was found to inhibit NLRP3 inflammasome activation and reduce caspase-1-dependent pyroptosis. We investigated the potential mechanism underlying the protective effect of TMP on MIRI using drug affinity responsive target stability (DARTS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) techniques. It was found that myosin light chain-2 (Myl2) was the molecule directly responsible for TMP's protective effect on MIRI. Following TMP treatment, the protein levels of Myl2 increased in the heart tissues of the I/R rats and in H9c2 cells subjected to H/R in a dose-dependent manner. Finally, the cardioprotective effects of TMP, including the inhibition of the NLRP3 inflammasome, were partially negated by the genetic silencing of Myl2 using siRNA. This study indicated that TMP mitigated MIRI by regulating the inhibition of the Myl2-mediated NLRP3 signaling pathway.

Therapeutic angiogenesis has demonstrated efficacy in revascularizing ischemic heart tissue and reducing the progression of cardiac remodeling following myocardial infarction. Recent studies have highlighted the significance of the glycolytic process in maintaining endothelial cell function and cardiac homeostasis. However, the specific role of glycolysis in angiogenesis post-myocardial infarction remains poorly understood. This study aims to explore whether ghrelin/GHSR-1a promotes angiogenesis after myocardial infarction through glycolysis.

Myocardial infarction was induced in mice, and our experiments showed that GHSR-1a overexpression led to a significant increase in the density of α-SMA-positive vessels in the peri-infarct zones, compared to the MI group, at day 7 post-infarction. Furthermore, elevated FGF-21 levels were observed in the border zone of the infarcted area seven days post-acute myocardial infarction. We also identified a modified GHSR-1a/FGF-21 axis in cardiac endothelial cells, where GHSR-1a knockdown reduced the expression of both FGF-21 and AMPK. In vitro, ghrelin enhanced glycolytic activity by increasing the expression of glycolytic enzymes. Moreover, ghrelin significantly stimulated endothelial tube formation and enhanced cell viability; however, these effects were attenuated following FGF-21 knockdown.

Our findings demonstrate that ghrelin/GHSR-1a improves neovascularization and enhances glycolysis in cardiac endothelial cells by modulating FGF-21. These results lay the groundwork for further experimental and clinical investigations to explore pharmaceutical approaches for treating ischemic heart disease.

The compound Bai Mao Yin (BMY) has demonstrated therapeutic efficacy in reducing uric acid (UA) levels; however, its underlying mechanisms remain unclear.

The UA-lowering effects of BMY were evaluated in a cohort of 40 patients with hyperuricemia (HUA) who received BMY treatment for 90 days. Fecal samples were collected at baseline (day 0), mid-treatment (day 30), and post-treatment (day 90) for metagenomic sequencing to analyze changes in gut microbiota and identify potential BMY targets in HUA. These clinical findings were validated in a hyperuricemic mouse model induced by xanthine and potassium oxonate. Mouse fecal samples were analyzed via 16S rDNA (V3-V4 region) sequencing to assess microbiota shifts. Additionally, fecal microbiota transplantation (FMT) from BMY-treated mice to HUA mice and in vitro cell experiments using HK2 cells were conducted to investigate the roles of BMY and the reconstructed microbiota in UA metabolism, renal UA transport, and inflammation through upstream signaling pathways.

Clinical cohort studies demonstrated that the BMY effectively lowers UA levels in patients with HUA without inducing hepatorenal toxicity. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of metagenomic data revealed that BMY modulates the gut microbiota and influences ATP-binding cassette transporters and UA metabolism-related pathways. In animal models, BMY increased the relative abundance of beneficial gut bacteria, reduced intestinal permeability, and regulated UA transporters in both intestinal and renal systems, contributing to UA reduction. In vitro assays showed that BMY directly decreased UA levels in the cell supernatant and suppressed interleukin-1β (IL-1β) and interleukin-6 (IL-6) expression by downregulating the TLR4/MYD88/NFκB signaling pathway, thereby alleviating inflammation.

Compound BMY was found to improve the intestinal microenvironment and modulate UA transport via the enterorenal axis, effectively reducing HUA.