The microglia, displaying diverse phenotypes, play a significant regulatory role in the development, progression, and prognosis of Parkinson’s disease. Research has established that glycolytic reprogramming serves as a critical regulator of inflammation initiation in pro-inflammatory macrophages. Furthermore, the modulation of glycolytic reprogramming has the potential to reverse the polarized state of these macrophages. Previous studies have shown that Levistilide A (LA), a phthalide component derived from Angelica sinensis, possesses a range of pharmacological effects, including anti-inflammatory, antioxidant, and neuroprotective properties. In our study, we have examined the impact of LA on inflammatory cytokines and glucose metabolism in microglia induced by lipopolysaccharide (LPS). Furthermore, we explored the effects of LA on the AMPK/mTOR pathway and assessed its neuroprotective potential both in vitro and in vivo. The findings revealed that LA notably diminished the expression of M1 pro-inflammatory factors induced by LPS in microglia, while leaving M2 anti-inflammatory factor expression unaltered. Additionally, it reduced ROS production and suppressed IκB-α phosphorylation levels as well as NF-κB p65 nuclear translocation. Notably, LA exhibited the ability to reverse microglial glucose metabolism reprogramming and modulate the phosphorylation levels of AMPK/mTOR. In vivo experiments further corroborated these findings, demonstrating that LA mitigated the death of TH-positive dopaminergic neurons and reduced microglia activation in the ventral SNpc brain region of the midbrain and the striatum. In summary, LA exhibited neuroprotective benefits by modulating the polarization state of microglia and altering glucose metabolism, highlighting its therapeutic potential.

Background: Peripheral artery disease (PAD) is a high-risk vascular condition, and vascular remodeling has become a promising therapeutic approach. Paeoniflorin (PF) is the main bioactive compound in the roots of Paeonia lactiflora Pall, which is commonly used to treat a range of cardiovascular disorders. However, the mechanisms underlying the ameliorating effects of PF on PAD remain unclear. Therefore, the purpose of this study was to explore the therapeutic efficiency of PF on PAD and determine its mechanisms. Methods: The blood flow of mice was detected with a laser Doppler dot scanning imaging system. HE staining was used to observe the morphological changes of ischemic muscle. The changes in the serologic indexes were detected with an automatic biochemical assay, and the capillary density of ischemic gastrocnemius was detected with a Lectin immunofluorescence assay. The expression of angiogenesis-related proteins in ischemic gastrocnemius was detected with Western blotting, and the proportion of macrophages and neutrophils in total cells was detected with flow cytometry. Results: PF significantly increased blood flow, capillary density and protein expressions of vascular endothelial growth factor A (VEGFA), matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 2 (MMP9), and estrogen receptor α (ERα) in mouse ischemic tissue in a PAD model. PF enhances the migration of endothelial cells and promotes the formation of tubular structures, involving the ERα/ROCK2 signaling pathway. Furthermore, PF was found to promote the phenotypic transformation of macrophages and alleviated grave inflammatory responses during vascular remodeling. Conclusions: We determined that PF as a potent compound in promoting angiogenesis and mitigating inflammatory responses during revascularization.

Background: Nardostachys jatamansi DC. (Gansong), a widely utilized herb in traditional Chinese medicine, has been historically employed in the management of various neuropsychiatric disorders. Nardosinone (Nar), a sesquiterpenoid compound, has been identified as one of the principal bioactive constituents of N. jatamansi. This study investigated the effects of ethyl acetate extract (NJ-1A) from N. jatamansi and its active constituent nardosinone on neuroinflammatory mediator release, glucose metabolic reprogramming, and T cell migration using both in vitro and in vivo experimental models. Methods: Lipopolysaccharide(LPS)-induced BV-2 microglial cells and a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced male C57BL/6N mouse chronic model of Parkinson’s disease were applied. Results: Both NJ-1A and Nar could significantly suppress LPS-induced production of M1 pro-inflammatory factors or markers in microglia and could inhibit the glycolytic process and promote oxidative phosphorylation via the AKT/mTOR signaling pathway. Furthermore, they exhibited the capacity to attenuate chemokine release from activated microglia, consequently reducing T cell migration. In vivo experiments revealed that NJ-1A and Nar effectively inhibited microglial activation, diminished T cell infiltration, and mitigated the loss of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra of MPTP-induced mice. Conclusions: NJ-1A and nardosinone exert neuroprotective effects through the modulation of microglial polarization states, regulation of metabolic reprogramming, and suppression of T cell infiltration.

Adverse ventricular remodeling following myocardial infarction (MI) is a critical factor in the progression of heart failure (HF). However, clinical interventions are limited by the lack of reliable biomarkers and targeted therapies. Soluble suppression of tumorigenicity 2 (sST2) is recognized as a prognostic biomarker in HF, with elevated levels associated with poorer outcomes, while its reduction is indicative of successful therapeutic intervention in mitigating remodeling. Tetramethylpyrazine (TMPZ), a bioactive alkaloid derived from Ligusticum chuanxiong Hort., has demonstrated potential in the treatment of MI, with our previous research linking it to the suppression of sST2. Nevertheless, the mechanisms by which TMPZ regulates sST2-mediated remodeling remain inadequately understood. This study aims to elucidate the molecular mechanisms through which TMPZ modulates sST2 to alleviate ventricular remodeling post-MI. MI was induced in mice, followed by TMPZ treatment for 1, 3, 7, and 14 days​​. Cardiac function was monitored via echocardiography pre-surgery and on days 3, 7, and 14 post-MI. Serum myocardial enzymes were quantified automatically. Cardiac tissue fibrosis and histopathology were evaluated using Masson's trichrome and HE staining, while immunohistochemistry detected ventricular remodeling-associated proteins. sST2 secretion was measured by ELISA. Bioinformatic analyses (KEGG and GO) were performed on the overlapping targets between the cardiac transcriptomic dataset at 3 days post-MI (GSE217268) and Ligusticum chuanxiong Hort.. Primary cardiomyocytes were subjected to oxygen-glucose deprivation (OGD) and treated with TMPZ. Measurement of cell viability using the CCK-8 assay. qRT-PCR and Western blotting evaluated mRNA and protein expression of Sirt1, p300, Yy1, and sST2. Molecular docking and SPR analysis characterized TMPZ-Sirt1 binding. Sirt1 activity in cardiac tissue was measured colorimetrically. Co-immunoprecipitation (Co-IP) assessed p300 acetylation and Yy1 interaction. The Sirt1 inhibitor EX527 confirmed TMPZ-mediated sST2 regulation via Sirt1 in the MI model. TMPZ administration markedly improved cardiac function, reduced circulating biomarkers of myocardial injury, attenuated histopathological damage, and inhibited ventricular remodeling in a murine model of MI. Treatment with TMPZ also significantly lowered serum levels of sST2. Integrative bioinformatic analysis of GEO datasets and network pharmacology suggested that Ligusticum chuanxiong Hort. influences biological processes related to protein deacetylation, specifically via the differentially expressed gene Sirt1. Subsequent in vivo and in vitro experiments established that TMPZ mediates the downregulation of sST2 through the Sirt1/p300/Yy1/sST2 signaling cascade. Molecular docking and SPR analysis suggested a potential interaction between TMPZ and Sirt1. Based on this interaction, we further verified that TMPZ enhances Sirt1's deacetylase activity. Co-IP experiments showed that TMPZ treatment reduces acetylation of the transcriptional coactivator p300, which is a downstream effector of Sirt1, resulting in inhibition of Yy1 activation and consequent suppression of sST2 synthesis and secretion. Finally, in vivo inhibition of Sirt1 with EX527 confirmed that the cardioprotective effects of TMPZ against post-MI ventricular remodeling are dependent on Sirt1-mediated reduction of sST2 secretion. We found that increased serum sST2 levels were significantly correlated with the progression of adverse ventricular remodeling following MI. Furthermore, our study provides the first preclinical evidence demonstrating that TMPZ attenuates this remodeling process by targeting the Sirt1/p300/Yy1/sST2 signaling axis. Collectively, these findings not only highlight sST2 as a promising therapeutic target but also establish a mechanistic rationale for developing novel interventions through pharmacological modulation of the Sirt1/sST2 pathway.

The microglia, displaying diverse phenotypes, play a significant regulatory role in the development, progression, and prognosis of Parkinson's disease. Research has established that glycolytic reprogramming serves as a critical regulator of inflammation initiation in pro-inflammatory macrophages. Furthermore, the modulation of glycolytic reprogramming has the potential to reverse the polarized state of these macrophages. Previous studies have shown that levetistilide A (LA), a phthalide component derived from Angelica sinensis, possesses a range of pharmacological effects, including anti-inflammatory, antioxidant, and neuroprotective properties. In our study, we have examined the impact of LA on inflammatory cytokines and glucose metabolism in microglia induced by lipopolysaccharide (LPS). Furthermore, we explored the effects of LA on the AMPK/mTOR pathway and assessed its neuroprotective potential both in vitro and in vivo. The findings revealed that LA notably diminished the expression of M1 pro-inflammatory factors induced by LPS in microglia, while leaving M2 anti-inflammatory factor expression unaltered. Additionally, it reduced ROS production and suppressed IκB-α phosphorylation levels as well as NF-κB p65 nuclear translocation. Notably, LA exhibited the ability to reverse microglial glucose metabolism reprogramming and modulate the phosphorylation levels of AMPK/mTOR. In vivo experiments further corroborated these findings, demonstrating that LA mitigated the death of TH-positive dopaminergic neurons and reduced microglia activation in the ventral SNpc brain region of the midbrain and the striatum. In summary, LA exhibited neuroprotective benefits by modulating the polarization state of microglia and altering glucose metabolism, highlighting its therapeutic potential.

Suxiao Jiuxin Pills (SJP), as a classic Chinese patent medicine formula, is clinically used to treat angina pectoris and myocardial ischemia (MI). However, its pharmacodynamic basis and potential molecular mechanisms remain incompletely elucidated. Bioinformatics analysis identified S100A9 as a key MI target, and ligustilide (Lig) (primary active component of SJP) as its specific ligand. This study aims to elucidate the molecular mechanism by which Lig targets S100A9 to inhibit neutrophil activation and alleviate MI. Bioinformatics analysis of human MI datasets and murine MI model validation identified S100A9 as SJP's potential target for alleviating early post-MI inflammatory injury. Molecular docking, SPR, MD simulations, and CETSA screened SJP's S100A9-targeting components. In MI models, S100A9 expression (infarcted myocardium/peripheral blood) was quantified by qRT-PCR, Western blot, and ELISA. Cardiac function was evaluated by echocardiography, TTC staining, enzymatic and histopathological assays. Flow cytometry assessed post-MI myocardial neutrophil/monocyte infiltration and neutrophil S100A9 expression. NET formation and NLRP3 inflammasome-associated molecules expression were assessed by Western blot and qRT-PCR, respectively. The mRNA expression of inflammatory cytokines was analyzed by qRT-PCR. Serum IL-1β levels were quantified by ELISA. Flow cytometry analyzed bone marrow (BM)/spleen neutrophil/monocyte infiltration and BM cell subset proportions. qRT-PCR determined mRNA levels of BM proliferation- and differentiation-related factors. An ischemia-reperfusion (I/R) model further confirmed the cardioprotective effect of Lig targeting S100A9 to inhibit neutrophil activation. S100A9 was the key target mediating SJP's cardioprotection, with its major bioactive component Lig as a specific S100A9 ligand. Post-MI, Lig downregulated S100A9, attenuated inflammation and apoptosis, reduced infarct size, and improved cardiac function. It suppressed myocardial neutrophil/monocyte infiltration, NET formation, and NLRP3 inflammasome activation, and decreased cardiac TNF-α/IL-1β and serum IL-1β levels. Furthermore, it reduced inflammatory cell proportions in BM and spleen, increased BM Lin^- and LSK cells, decreased megakaryocyte-erythroid progenitor ratios, and downregulated granulocyte proliferation/differentiation-related mRNA. In the I/R model, Lig exerted consistent cardioprotection via targeting S100A9. Lig, the principal bioactive component of SJP, confers cardioprotection by targeting S100A9 to inhibit neutrophil activation and attenuate acute myocardial inflammatory injury post-MI.